Refractory Diffuse Large B Cell Lymphoma (DLBCL), Relapsed Diffuse Large B-Cell Lymphoma, Transformed Follicular Lymphoma (TFL), Primary Mediastinal B-cell Lymphoma (PMBCL), High Grade B-cell Lymphoma (HGBCL)
Conditions
Brief summary
This study will be separated into 3 distinct phases designated as the Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2 safety management study (Cohort 3 and Cohort 4, Cohort 5 and Cohort 6). The primary objectives of this study are: * Phase 1 Study: Evaluate the safety of axicabtagene ciloleucel regimens * Phase 2 Pivotal Study; Evaluate the efficacy of axicabtagene ciloleucel * Phase 2 Safety Management Study: Assess the impact of prophylactic regimens or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.
Interventions
DRUGCisplatin
Administered according to package insert
BIOLOGICALAxicabtagene Ciloleucel
A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg.
DRUGFludarabine
Administered according to package insert
DRUGCyclophosphamide
Administered according to package insert
DRUGLevetiracetam
Administered according to package insert
DRUGTocilizumab
Administered according to package insert
DRUGDexamethasone
Administered according to package insert
Administered according to package insert
DRUGBendamustine
Administered according to package insert
DRUGRituximab
Administered according to package insert
DRUGDoxorubicin
Administered according to package insert
DRUGPrednisone
Administered according to package insert
DRUGVincristine
Administered according to package insert
DRUGIfosfamide
Administered according to package insert
DRUGCarboplatin
Administered according to package insert
DRUGEtoposide
Administered according to package insert
DRUGGemcitabine
Administered according to package insert
DRUGOxaliplatin
Administered according to package insert
DRUGMethylprednisolone
Administered according to package insert
Sponsors
Kite, A Gilead Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria 1. Histologically confirmed: * Diffuse Large B Cell Lymphoma (DLBCL) * Primary Mediastinal Large B Cell Lymphoma (PMBCL) * Transformation Follicular Lymphoma (TFL) * High grade B-cell lymphoma (HGBCL) 2. Chemotherapy-refractory disease, defined as one of more of the following: * No response to last line of therapy i. Progressive disease (PD) as best response to most recent therapy regimen ii. Stable disease (SD) as best response to most recent therapy with duration no longer than 6 month from last dose of therapy OR * Refractory post-autologous stem cell transplant (ASCT) i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy 3. Individuals must have received adequate prior therapy including at a minimum: * Anti-cluster of differentiate 20 (CD20) monoclonal antibody unless investigator determines that tumor is CD20-negative and * an anthracycline containing chemotherapy regimen * for individual with transformed FL must have chemorefractory disease after transformation to DLBCL. 4. At least one measurable lesion per revised international working group (IWG Response Criteria 5. Eastern cooperative oncology group (ECOG) performance status of 0 or 1 6. Absolute neutrophil count (ANC) ≥ 1000/microliters (uL) 7. Absolute lymphocyte count ≥ 100/uL 8. Platelet count ≥ 75,000/uL 9. Adequate renal, hepatic, pulmonary and cardiac function defined as: * Creatinine clearance (as estimated by Cockcroft Gault) \> 60 mL/min * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) \< 2.5 upper limit of normal (ULN) * Total bilirubin \< 1.5 mg/dL, except in individuals with Gilbert's syndrome * Cardiac ejection fraction \>50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant pleural effusion * Baseline oxygen saturation \>92% on room air 10. All individuals or legally appointed representatives/caregivers, must personally sign and date the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved consent form before initiating any study specific procedures or activities. 11. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy Key
Exclusion criteria
1. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years 2. History of allogeneic stem cell transplantation 3. Prior chimeric antigen receptor (CAR) therapy or other genetically modified T cell therapy 4. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment 5. History of human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection. Individuals with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines 6. Individuals with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases 7. History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) | First infusion date of axicabtagene ciloleucel up to 30 days | DLT was defined as axicabtagene ciloleucel-related events with onset within first 30 days following infusion: * Grade (GR) 4 neutropenia lasting \> 21 days and GR 4 thrombocytopenia lasting \> 35 days from day of cell transfer; * Any axicabtagene ciloleucel-related AE requiring intubation; * All other GR 3 toxicities lasting \> 3 days and all GR 4 toxicities, with exception of following conditions which were not considered DLTs: aphasia/dysphasia or confusion/cognitive disturbance which resolved to GR ≤ 1 within 2 weeks and to baseline within 4 weeks; fever GR 3; myelosuppression defined as lymphopenia, decreased hemoglobin, neutropenia and thrombocytopenia unless neutropenia and thrombocytopenia met DLT definition described above; immediate hypersensitivity reactions occurring within 2 hours of cell infusion that were reversible to a ≤ GR 2 within 24 hours of cell administration with standard therapy; hypogammaglobulinemia GR 3 or 4. |
| Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator Per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma | First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7 years) | ORR was defined as the percentage of participants achieving either a complete response (CR) or a partial response (PR), as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules. 95% confidence interval (CI) was calculated by Clopper-Pearson method. |
| Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 6.8 years) | TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or continuous venovenous hemodialysis (CVVHD), and Grade 5: Death. Neurologic toxicities were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE. |
| Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 5.4 years) | TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE. |
| Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.4 years) | TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE. |
| Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.1 years) | TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007 | First objective response up to the data cutoff date of 11 August 2018 (maximum: 2.7 years) | Among participants who experience an objective response, DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to PD, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death regardless of cause. CR and PR as defined in outcome measure 2. PD was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. Kaplan-Meier (KM) estimates was used for analyses. |
| Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years) | The best overall response for each participant was based on the assessments of response (CR, PR, stable disease \[SD\], PD, and not done \[ND\]) made by the the IRRC using IWG 2007 criteria (Cheson et al, 2007). CR and PR as defined in outcome measure 2. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentage of participants with best overall response of CR, PR, SD, PD, and ND was reported. |
| Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007 | First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years) | PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. KM estimates was used for analyses. |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years) | An adverse event was defined as any untoward medical occurrence in a clinical trial participants. The event did not necessarily have a relationship with study treatment. Adverse events included worsening of a pre-existing medical condition. Worsening indicated that the pre-existing medical condition had increased in severity, frequency, and/or duration or had an association with a worse outcome. A pre-existing condition that had not worsened during the study or involved an intervention such as elective cosmetic surgery or a medical procedure while on study, was not considered an adverse event. TEAE was defined as any AE with onset on or after the start of treatment. |
| Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs | First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years) | Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening. |
| Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies | First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively) | — |
| Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | Baseline up to Month 60 (for Phase 1 and Phase 2 Cohorts 1, 2, and 3); Baseline up to Month 24 (for Phase 2 Cohorts 4, 5, and 6) | Peak was defined as the maximum number of CAR T cells measured post-infusion. |
| Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Baseline up to Month 3 | Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: interferon-gamma induced protein 10 (IP-10), ferritin, granzyme B, intercellular adhesion molecule (ICAM-1), interferon-gamma (IFN-gamma), interleukin-1 receptor antagonist (IL-1RA), IL-2, interleukin-2 receptor alpha (IL-2 R alpha), IL-6, IL-7, IL-8, IL-10, IL-15, perforin, tumor necrosis factor alpha (TNF alpha), and vascular cell adhesion molecule- 1 (VCAM-1). |
| Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | First OR to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively) | Among participants who experience an objective response (OR), DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to disease progression per the revised IWG Response Criteria for Malignant Lymphoma or death regardless of cause. CR and PR as defined in outcome measure 2. Disease progression (PD) was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. Kaplan-Meier (KM) estimates was used for analyses. |
| Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | Baseline up to Month 3 | Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1. |
| Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum | Baseline up to Month 3 | Peak was defined as the maximum post-baseline level of the cytokine. |
| Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2) | Baseline up to Month 3 | Peak was defined as the maximum post-baseline level of the cytokine. |
| Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3) | Baseline up to Month 3 | Peak was defined as the maximum post-baseline level of the cytokine. |
| Percentage of Participants With Positive Replication Competent Retrovirus (RCR) | Day 0 (pre-infusion) up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively) | RCR was analyzed in blood samples by central laboratory. Because axicabtagene ciloleucel comprised retroviral vector transduced T cells, the presence of RCR in the blood of treated participants was reported. |
| Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline, Week 4, Month 3, and Month 6 | EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant scoring 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was divided into 5 levels of severity: No problem, Slight problems, Moderate problems, Severe problems, and Extreme problems (unable to perform). EQ-5D health states, defined by the EQ-5D descriptive system, are converted into a single summary index by applying a formula that attaches values (also called QOL weights or QOL utilities) to each of the levels in each dimension. EQ-5D Summary Index values range from -0.11 (worst health state) to 1.00 (perfect health state). |
| Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Baseline, Week 4, Month 3, and Month 6 | EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant. The EQ-5D-VAS records the participant's self-rated health on a vertical visual analogue scale and is asked to make a global assessment of their current state of health with 0 indicating the worst health they can imagine and 100 indicating the best health they can imagine. |
| Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | Baseline up to Month 3 | Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: IP-10, granzyme B, IFN-gamma, IL-1 RA, IL-2, IL-6, IL-7, IL-8, IL-10, IL-15, TNF alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF). |
| Phase 1 Study: ORR as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months) | ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules. |
| Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC) | First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years) | ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma. CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method. |
| Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma | First infusion date of axicabtagene ciloleucel to last follow-up visit (maximum duration: 6.8, 5.4, 4.4, 4.1 years for Cohorts 3, 4, 5, and 6 respectively) | ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method. |
| Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | First infusion date of axicabtagene ciloleucel to disease progression or death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively) | PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Disease progression was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. KM estimates was used for analyses. |
| Phase 2: Overall Survival (OS) | First infusion date of axicabtagene ciloleucel to the date of death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively) | OS was defined as the time from axicabtagene ciloleucel infusion to the date of death. Participants who did not die by the analysis data cutoff date were censored at their last contact date. KM estimates was used for analyses. |
Countries
Canada, France, Germany, Israel, Netherlands, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Canada, France, Germany, Israel, Netherlands, and the United States.
Pre-assignment details
390 participants were screened. Participants who initially responded and subsequently relapsed, became eligible for second course of conditioning chemotherapy and axicabtagene ciloleucel. Participants received the same axicabtagene ciloleucel regimen as the original target dose.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy Participants with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL) received conditioning chemotherapy (fludarabine 30 mg/m\^2 intravenously \[IV\] over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel chimeric antigen receptor (CAR) transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of body weight (BW) on Day 0. | 7 |
| Phase 2 (Pivotal Study): Cohort 1 Participants with refractory DLBCL received conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. | 77 |
| Phase 2 (Pivotal Study): Cohort 2 Participants with refractory PMBCL or TFL received conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. | 24 |
| Phase 2 (Safety Management Study): Cohort 3 Participants with relapsed or refractory transplant ineligible DLBCL, PMBCL, or TFL received conditioning chemotherapy (fludarabine 30 mg/m\^2 IV over 30 minutes and cyclophosphamide 500 mg/m\^2 IV over 60 minutes) on Days -5, -4, and -3; followed by a single infusion of axicabtagene ciloleucel CAR transduced autologous T cells administered IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants also received a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and tocilizumab (8 mg/kg IV over 1 hour (not to exceed 800 mg)) on Day 2). | 38 |
| Phase 2 (Safety Management Study): Cohort 4 Participants with r/r DLBCL, PMBCL ,TFL, or high-grade B-cell lymphoma (HGBCL) after 2 systemic lines of therapy received optional bridging therapy (dexamethasone 20mg to 40mg,either orally or IV daily for 1 to 4 days or 1g/m\^2 of high-dose methylprednisolone(HDMP) for 3 days with rituximab at 375mg/m\^2 weekly for 3 weeks or bendamustine 90 mg/m\^2 on Days 1 and 2 and rituximab 375mg/m\^2 on Day 1), conditioning chemotherapy (fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW. Participants also received a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0). Participants received tocilizumab (initiated on persistent Grade 1 CRS for over 24 hours) and dexamethasone (persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity). | 41 |
| Phase 2 (Safety Management Study): Cohort 5 Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy received debulking therapy (R-CHOP:rituximab 375mg/m\^2 D1,doxorubicin 50mg/m\^2 D1,prednisone 100mg D1 to D5,cyclophosphamide 750mg/m\^2 D1,vincristine 1.4 mg/m\^2 D1 or R-ICE:rituximab 375mg/ m\^2 D1,ifosfamide 5g/m\^2 24h-CI D2,carboplatin AUC5 D2 maximum dose 800mg,etoposide 100 mg/m\^2/day D1 to D3 or R-GEMOX:rituximab 375mg/m\^2 D1,gemcitabine 1000mg/m\^2 D2,oxaliplatin 100mg/m\^2 D2 or R-GDP:rituximab 375mg/m\^2 D1 or D8,gemcitabine 1g/m\^2 D1 & D8,dexamethasone 40mg D1 to D4,cisplatin 75mg/m\^2 D1(or carboplatin AUC5 D1) or radiotherapy:20 to 30 Gy), conditioning chemotherapy (fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants also received a prophylactic regimen of levetiracetam (750 mg orally or IV BID starting on D0).D=Day. | 50 |
| Phase 2 (Safety Management Study): Cohort 6 Participants with r/r DLBCL, PMBCL ,TFL, or HGBCL after 2 systemic lines of therapy may have received bridging therapy (dexamethasone 20mg to 40mg, either orally or IV daily for 1 to 4 days or 1g/m\^2 of high-dose methylprednisolone(HDMP) for 3 days with rituximab at 375mg/m\^2 weekly for 3 weeks or bendamustine 90 mg/m\^2 on Days 1 and 2 and rituximab 375mg/m\^2 on Day 1), conditioning chemotherapy (fludarabine 30mg/m\^2 IV and cyclophosphamide 500mg/m\^2 IV)on Days -5,-4, and -3; followed by single infusion of axicabtagene ciloleucel CAR transduced autologous T cells IV at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg of BW on Day 0. Participants also received a prophylactic regimen of levetiracetam (750 mg orally or IV twice daily (BID) starting on Day 0) and corticosteroids (dexamethasone, 10 mg once daily on Days 0, 1, and 2). Participants received tocilizumab (initiated on persistent Grade 1 CRS for over 24 hours) and dexamethasone (persistent Grade 1 CRS for over 72 hours and at onset of Grade 1 neurologic toxicity). | 40 |
| Total | 277 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 5 | 53 | 11 | 20 | 16 | 32 | 17 |
| Overall Study | Enrolled but did not initiate axicabtagene ciloleucel | 1 | 4 | 6 | 4 | 5 | 8 | 2 |
| Overall Study | Full consent withdrawal | 0 | 0 | 0 | 1 | 3 | 0 | 3 |
| Overall Study | Lost to Follow-up | 0 | 5 | 2 | 0 | 1 | 1 | 1 |
| Overall Study | Reason not specified | 2 | 19 | 11 | 17 | 21 | 17 | 19 |
Baseline characteristics
| Characteristic | Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 (Pivotal Study): Cohort 1 | Phase 2 (Pivotal Study): Cohort 2 | Phase 2 (Safety Management Study): Cohort 3 | Phase 2 (Safety Management Study): Cohort 4 | Phase 2 (Safety Management Study): Cohort 5 | Phase 2 (Safety Management Study): Cohort 6 | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 17 Participants | 7 Participants | 8 Participants | 13 Participants | 15 Participants | 20 Participants | 83 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 60 Participants | 17 Participants | 30 Participants | 28 Participants | 35 Participants | 20 Participants | 194 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 17.5 | 57 years STANDARD_DEVIATION 10.6 | 53 years STANDARD_DEVIATION 15.5 | 51 years STANDARD_DEVIATION 13 | 57 years STANDARD_DEVIATION 12.9 | 58 years STANDARD_DEVIATION 9.9 | 64 years STANDARD_DEVIATION 9.4 | 57 years STANDARD_DEVIATION 12.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 16 Participants | 2 Participants | 5 Participants | 0 Participants | 1 Participants | 2 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 61 Participants | 22 Participants | 33 Participants | 40 Participants | 49 Participants | 38 Participants | 249 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 5 Participants | 0 Participants | 9 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 11 Participants |
| Race/Ethnicity, Customized Race Other or More Than One Race | 1 Participants | 5 Participants | 2 Participants | 3 Participants | 8 Participants | 10 Participants | 5 Participants | 34 Participants |
| Race/Ethnicity, Customized Race White | 5 Participants | 69 Participants | 18 Participants | 31 Participants | 33 Participants | 33 Participants | 34 Participants | 223 Participants |
| Region of Enrollment Canada | 0 participants | 0 participants | 0 participants | 1 participants | 7 participants | 15 participants | 0 participants | 23 participants |
| Region of Enrollment France | 0 participants | 0 participants | 0 participants | 0 participants | 9 participants | 13 participants | 8 participants | 30 participants |
| Region of Enrollment Germany | 0 participants | 0 participants | 0 participants | 0 participants | 12 participants | 9 participants | 0 participants | 21 participants |
| Region of Enrollment Israel | 0 participants | 0 participants | 1 participants | 2 participants | 2 participants | 0 participants | 1 participants | 6 participants |
| Region of Enrollment Netherlands | 0 participants | 0 participants | 0 participants | 5 participants | 11 participants | 13 participants | 6 participants | 35 participants |
| Region of Enrollment United States | 7 participants | 77 participants | 23 participants | 30 participants | 0 participants | 0 participants | 25 participants | 162 participants |
| Sex: Female, Male Female | 2 Participants | 27 Participants | 6 Participants | 17 Participants | 13 Participants | 14 Participants | 17 Participants | 96 Participants |
| Sex: Female, Male Male | 5 Participants | 50 Participants | 18 Participants | 21 Participants | 28 Participants | 36 Participants | 23 Participants | 181 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 8 | 49 / 81 | 13 / 30 | 23 / 42 | 20 / 46 | 37 / 58 | 20 / 42 | 1 / 1 | 8 / 9 | 2 / 2 | 1 / 2 | 2 / 2 | 2 / 2 | 0 / 0 |
| other Total, other adverse events | 7 / 7 | 77 / 77 | 23 / 24 | 38 / 38 | 41 / 41 | 50 / 50 | 40 / 40 | 1 / 1 | 9 / 9 | 2 / 2 | 2 / 2 | 2 / 2 | 2 / 2 | 0 / 0 |
| serious Total, serious adverse events | 5 / 7 | 40 / 77 | 14 / 24 | 26 / 38 | 24 / 41 | 27 / 50 | 25 / 40 | 1 / 1 | 5 / 9 | 1 / 2 | 2 / 2 | 0 / 2 | 0 / 2 | 0 / 0 |
Outcome results
Primary
Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)
DLT was defined as axicabtagene ciloleucel-related events with onset within first 30 days following infusion: * Grade (GR) 4 neutropenia lasting \> 21 days and GR 4 thrombocytopenia lasting \> 35 days from day of cell transfer; * Any axicabtagene ciloleucel-related AE requiring intubation; * All other GR 3 toxicities lasting \> 3 days and all GR 4 toxicities, with exception of following conditions which were not considered DLTs: aphasia/dysphasia or confusion/cognitive disturbance which resolved to GR ≤ 1 within 2 weeks and to baseline within 4 weeks; fever GR 3; myelosuppression defined as lymphopenia, decreased hemoglobin, neutropenia and thrombocytopenia unless neutropenia and thrombocytopenia met DLT definition described above; immediate hypersensitivity reactions occurring within 2 hours of cell infusion that were reversible to a ≤ GR 2 within 24 hours of cell administration with standard therapy; hypogammaglobulinemia GR 3 or 4.
Time frame: First infusion date of axicabtagene ciloleucel up to 30 days
Population: DLT-Evaluable Analysis Set included participants treated in Phase 1 dosing cohort who received the target dose and were followed for at least 30 days after the axicabtagene ciloleucel infusion; or dose of anti-CD19 CAR T cells (axicabtagene ciloleucel) lower than the target for that cohort and experienced a DLT during the 30 day post-infusion period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 1 Study: Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) | 1 Participants |
Primary
Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator Per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma
ORR was defined as the percentage of participants achieving either a complete response (CR) or a partial response (PR), as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules. 95% confidence interval (CI) was calculated by Clopper-Pearson method.
Time frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7 years)
Population: The Modified Intent-to-Treat (mITT) analysis set included all participants treated with at least 1.0 x 10\^6 anti-CD19 CAR T cells/kg.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator Per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma | 83 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): Overall Response Rate (ORR) as Assessed by Investigator Per Revised International Working Group (IWG) Response Criteria for Malignant Lymphoma | 83 percentage of participants |
Primary
Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades
TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or continuous venovenous hemodialysis (CVVHD), and Grade 5: Death. Neurologic toxicities were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.
Time frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 6.8 years)
Population: The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 3 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 1 CRS | 34 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 2 CRS | 55 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 4 CRS | 3 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 5 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade ≥ 3 CRS | 3 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 1 Neurologic Toxicities | 24 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 2 Neurologic Toxicities | 21 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 3 Neurologic Toxicities | 37 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 4 Neurologic Toxicities | 3 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade 5 Neurologic Toxicities | 3 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 3): Percentage of Participants With Treatment-Emergent Cytokine Release Syndrome (CRS) and Neurologic Toxicities by Severity Grades | Worst Grade ≥ 3 Neurologic Toxicities | 42 percentage of participants |
Primary
Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.
Time frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 5.4 years)
Population: The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 1 CRS | 32 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 2 CRS | 59 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 3 CRS | 2 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 4 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 5 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade ≥ 3 CRS | 2 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 1 Neurologic Toxicities | 34 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 2 Neurologic Toxicities | 10 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 3 Neurologic Toxicities | 17 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 4 Neurologic Toxicities | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 5 Neurologic Toxicities | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 4): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade ≥ 3 Neurologic Toxicities | 17 percentage of participants |
Primary
Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.
Time frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.4 years)
Population: The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 1 CRS | 38 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 2 CRS | 46 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 3 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 4 CRS | 2 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 5 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade ≥ 3 CRS | 2 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 1 Neurologic Toxicities | 26 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 2 Neurologic Toxicities | 18 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 3 Neurologic Toxicities | 10 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 4 Neurologic Toxicities | 2 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 5 Neurologic Toxicities | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 5): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade ≥ 3 Neurologic Toxicities | 12 percentage of participants |
Primary
Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades
TEAE was defined as any AE with onset on or after the start of treatment. CRS events were graded by Lee et al 2014. Grade 1 : No life threatening symptoms and require symptomatic treatment only; Grade 2: Symptoms require and respond to moderate intervention; Grade 3: Symptoms require and respond to aggressive intervention; Grade 4: Life-threatening symptoms and requirements for ventilator support or CVVHD, and Grade 5: Death. Neurologic toxicities were graded by CTCAE version 4.03. Grade 1: Mild, asymptomatic or mild symptoms and intervention not indicated; Grade 2: Moderate and minimal, local or noninvasive intervention indicated; Grade 3: Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4: Life-threatening and urgent intervention indicated; Grade 5: Death related to AE.
Time frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 4.1 years)
Population: The Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 1 CRS | 35 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 2 CRS | 45 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 3 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 4 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 5 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade ≥ 3 CRS | 0 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 1 Neurologic Toxicities | 23 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 2 Neurologic Toxicities | 18 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 3 Neurologic Toxicities | 8 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 4 Neurologic Toxicities | 5 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade 5 Neurologic Toxicities | 5 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohort 6): Percentage of Participants With Treatment-Emergent CRS and Neurologic Toxicities by Severity Grades | Worst Grade ≥ 3 Neurologic Toxicities | 18 percentage of participants |
Secondary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
An adverse event was defined as any untoward medical occurrence in a clinical trial participants. The event did not necessarily have a relationship with study treatment. Adverse events included worsening of a pre-existing medical condition. Worsening indicated that the pre-existing medical condition had increased in severity, frequency, and/or duration or had an association with a worse outcome. A pre-existing condition that had not worsened during the study or involved an intervention such as elective cosmetic surgery or a medical procedure while on study, was not considered an adverse event. TEAE was defined as any AE with onset on or after the start of treatment.
Time frame: First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 3 | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 4 | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 5 | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 6 | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 6 | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 100 percentage of participants |
Secondary
Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies
Time frame: First infusion date of axicabtagene ciloleucel up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies | 29 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies | 5 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 3 | Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies | 8 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 4 | Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies | 11 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 5 | Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies | 0 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 6 | Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies | 8 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 6 | Percentage of Participants With Anti-Axicabtagene Ciloleucel Antibodies | 8 percentage of participants |
Secondary
Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs
Grading categories were determined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening.
Time frame: First infusion date of axicabtagene ciloleucel up to last follow up visit (maximum duration: 7.7 years)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs | 100 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs | 96 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 3 | Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs | 96 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 4 | Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs | 97 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 5 | Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs | 98 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 6 | Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs | 100 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 6 | Percentage of Participants With Clinically Significant Changes in Laboratory Values Reported as Grade 3 or Higher TEAEs | 100 percentage of participants |
Secondary
Percentage of Participants With Positive Replication Competent Retrovirus (RCR)
RCR was analyzed in blood samples by central laboratory. Because axicabtagene ciloleucel comprised retroviral vector transduced T cells, the presence of RCR in the blood of treated participants was reported.
Time frame: Day 0 (pre-infusion) up to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Phase 1 and Phase 2 Cohorts 1, 2, 3, 4, 5, and 6 respectively)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Percentage of Participants With Positive Replication Competent Retrovirus (RCR) | 0 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Percentage of Participants With Positive Replication Competent Retrovirus (RCR) | 0 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 3 | Percentage of Participants With Positive Replication Competent Retrovirus (RCR) | 0 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 4 | Percentage of Participants With Positive Replication Competent Retrovirus (RCR) | 0 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 5 | Percentage of Participants With Positive Replication Competent Retrovirus (RCR) | 0 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 6 | Percentage of Participants With Positive Replication Competent Retrovirus (RCR) | 0 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 6 | Percentage of Participants With Positive Replication Competent Retrovirus (RCR) | 0 percentage of participants |
Secondary
Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum
Peak was defined as the maximum post-baseline level of the cytokine.
Time frame: Baseline up to Month 3
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum | 112.6 mg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum | 215.7 mg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum | 186.6 mg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum | 137.8 mg/mL |
| Phase 2 (Safety Management Study): Cohort 5 | Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum | 126.53 mg/mL |
| Phase 2 (Safety Management Study): Cohort 6 | Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum | 74.84 mg/mL |
| Phase 2 (Safety Management Study): Cohort 6 | Pharmacodynamics: Peak Level of Cytokine (CRP) in Serum | 76.11 mg/mL |
Secondary
Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2)
Peak was defined as the maximum post-baseline level of the cytokine.
Time frame: Baseline up to Month 3
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2) | 1973400.0 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2) | 3681400.0 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 1 and Phase 2 Cohorts 1 and 2) | 1979360.0 pg/mL |
Secondary
Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3)
Peak was defined as the maximum post-baseline level of the cytokine.
Time frame: Baseline up to Month 3
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokine (Ferritin) in Serum (Phase 2 Cohort 3) | 2440.2 ng/mL |
Secondary
Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6)
Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1.
Time frame: Baseline up to Month 3
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | Perforin | 17.22 ng/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | VCAM-1 | 1255.32 ng/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | ICAM-1 | 907.97 ng/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | Ferritin | 1086.36 ng/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-2 R | 10.78 ng/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | Ferritin | 1516.11 ng/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | Perforin | 10.85 ng/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-2 R | 7.82 ng/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | ICAM-1 | 636.74 ng/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | VCAM-1 | 854.63 ng/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | VCAM-1 | 836.04 ng/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | Ferritin | 903.50 ng/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | ICAM-1 | 654.81 ng/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-2 R | 6.43 ng/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (Ferritin, ICAM-1, IL-2 R, Perforin, and VCAM-1) in Serum (Phase 2 Cohorts 4, 5, and 6) | Perforin | 10.12 ng/mL |
Secondary
Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3)
Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: interferon-gamma induced protein 10 (IP-10), ferritin, granzyme B, intercellular adhesion molecule (ICAM-1), interferon-gamma (IFN-gamma), interleukin-1 receptor antagonist (IL-1RA), IL-2, interleukin-2 receptor alpha (IL-2 R alpha), IL-6, IL-7, IL-8, IL-10, IL-15, perforin, tumor necrosis factor alpha (TNF alpha), and vascular cell adhesion molecule- 1 (VCAM-1).
Time frame: Baseline up to Month 3
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IP-10 | 2000.0 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-15 | 57.1 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-7 | 51.5 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | ICAM-1 | 792754.3 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-8 | 86.4 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-10 | 52.5 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IFN-gamma | 792.0 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Granzyme B | 33.1 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | TNF alpha | 10.5 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-1 RA | 2173.3 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-2 | 18.4 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Perforin | 5389.0 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-2 R alpha | 16872.7 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | VCAM-1 | 1387033.6 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-6 | 305.3 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-6 | 89.4 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-15 | 56.5 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-1 RA | 2371.2 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-7 | 38.9 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Granzyme B | 31.1 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-10 | 43.9 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Perforin | 11309.5 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-8 | 118.4 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | ICAM-1 | 1322829.3 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-2 R alpha | 14383.7 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | VCAM-1 | 1478356.8 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | TNF alpha | 8.6 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-2 | 25.0 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IFN-gamma | 493.8 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IP-10 | 2000.0 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-6 | 44.6 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IP-10 | 2000.0 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Granzyme B | 17.3 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | ICAM-1 | 989188.4 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IFN-gamma | 364.9 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-1 RA | 1999.9 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-2 | 13.4 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-2 R alpha | 7817.3 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-7 | 44.1 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-8 | 77.2 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-10 | 18.8 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-15 | 47.6 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Perforin | 8278.7 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | TNF alpha | 6.8 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | VCAM-1 | 1058453.9 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-2 R alpha | 12386.4 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Granzyme B | 44.1 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-15 | 50.3 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-2 | 20.0 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-1 RA | 2160.5 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IP-10 | 2000.0 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | Perforin | 15411.9 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IFN-gamma | 1857.2 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | ICAM-1 | 1009966.4 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | VCAM-1 | 1367940.7 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-8 | 120.9 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-7 | 38.8 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | TNF alpha | 10.9 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-10 | 48.2 pg/mL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacodynamics: Peak Level of Cytokines in Serum (Phase 1 and Phase 2 Cohorts 1, 2, and 3) | IL-6 | 921.8 pg/mL |
Secondary
Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6)
Peak was defined as the maximum post-baseline level of the cytokine. Following key cytokines were measured: IP-10, granzyme B, IFN-gamma, IL-1 RA, IL-2, IL-6, IL-7, IL-8, IL-10, IL-15, TNF alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF).
Time frame: Baseline up to Month 3
Population: Participants in the Safety Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IP-10 | 1549.70 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | Granzyme B | 23.10 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IFN-gamma | 334.50 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-1 RA | 1093.70 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-2 | 11.20 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-6 | 136.70 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-7 | 33.10 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-8 | 67.40 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-10 | 19.60 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-15 | 45.80 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | TNF alpha | 5.70 pg/mL |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | GM-CSF | 4.40 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | GM-CSF | 2.90 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IP-10 | 1746.15 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-7 | 29.80 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-10 | 14.45 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | Granzyme B | 27.90 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-6 | 97.95 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | TNF alpha | 5.25 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IFN-gamma | 314.90 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-8 | 75.10 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-2 | 11.85 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-1 RA | 908.00 pg/mL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-15 | 34.15 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-1 RA | 1279.50 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-2 | 8.40 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-15 | 37.20 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-6 | 47.25 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-7 | 28.25 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-8 | 52.55 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | TNF alpha | 4.80 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IP-10 | 1560.03 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | Granzyme B | 18.40 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IL-10 | 13.30 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | IFN-gamma | 207.95 pg/mL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacodynamics: Peak Level of Cytokines (IP-10, Granzyme B, IFN-gamma, IL-1 RA, IL-10, IL-15, IL-2, IL-6, IL-7, IL-8, TNF Alpha, and GM-CSF) in Serum (Phase 2 Cohorts 4, 5, and 6) | GM-CSF | 1.90 pg/mL |
Secondary
Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood
Peak was defined as the maximum number of CAR T cells measured post-infusion.
Time frame: Baseline up to Month 60 (for Phase 1 and Phase 2 Cohorts 1, 2, and 3); Baseline up to Month 24 (for Phase 2 Cohorts 4, 5, and 6)
Population: Participants in the Safety Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | 58.512 cells/µL |
| Phase 2 (Pivotal Study): Cohort 2 | Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | 31.512 cells/µL |
| Phase 2 (Safety Management Study): Cohort 3 | Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | 58.633 cells/µL |
| Phase 2 (Safety Management Study): Cohort 4 | Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | 53.670 cells/µL |
| Phase 2 (Safety Management Study): Cohort 5 | Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | 52.91 cells/µL |
| Phase 2 (Safety Management Study): Cohort 6 | Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | 26.63 cells/µL |
| Phase 2 (Safety Management Study): Cohort 6 | Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood | 64.38 cells/µL |
Secondary
Phase 1 Study: ORR as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules.
Time frame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 27 January 2017 (maximum: 20 months)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 1 Study: ORR as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | 71 percentage of participants |
Secondary
Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
Among participants who experience an objective response (OR), DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to disease progression per the revised IWG Response Criteria for Malignant Lymphoma or death regardless of cause. CR and PR as defined in outcome measure 2. Disease progression (PD) was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. Kaplan-Meier (KM) estimates was used for analyses.
Time frame: First OR to last follow-up visit (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)
Population: Participants in the mITT Analysis Set with objective response were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | 5.0 months |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | 75.4 months |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | NA months |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | NA months |
| Phase 2 (Safety Management Study): Cohort 5 | Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | 27.5 months |
| Phase 2 (Safety Management Study): Cohort 6 | Phase 2: Duration of Response (DOR) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | NA months |
Secondary
Phase 2: Overall Survival (OS)
OS was defined as the time from axicabtagene ciloleucel infusion to the date of death. Participants who did not die by the analysis data cutoff date were censored at their last contact date. KM estimates was used for analyses.
Time frame: First infusion date of axicabtagene ciloleucel to the date of death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)
Population: Participants in the mITT Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2: Overall Survival (OS) | 15.4 months |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2: Overall Survival (OS) | NA months |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2: Overall Survival (OS) | 34.8 months |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2: Overall Survival (OS) | NA months |
| Phase 2 (Safety Management Study): Cohort 5 | Phase 2: Overall Survival (OS) | 20.6 months |
| Phase 2 (Safety Management Study): Cohort 6 | Phase 2: Overall Survival (OS) | NA months |
Secondary
Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007
The best overall response for each participant was based on the assessments of response (CR, PR, stable disease \[SD\], PD, and not done \[ND\]) made by the the IRRC using IWG 2007 criteria (Cheson et al, 2007). CR and PR as defined in outcome measure 2. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentage of participants with best overall response of CR, PR, SD, PD, and ND was reported.
Time frame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)
Population: Participants in the mITT Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | PR | 19 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | PD | 8 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | SD | 21 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | ND | 1 percentage of participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | CR | 51 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | ND | 4 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | CR | 67 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | PR | 21 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | SD | 4 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): Best Overall Response Using IRRC Per Cheson 2007 | PD | 4 percentage of participants |
Secondary
Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007
Among participants who experience an objective response, DOR was defined as the date of their first objective response (CR or PR which was subsequently confirmed) to PD, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death regardless of cause. CR and PR as defined in outcome measure 2. PD was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. Kaplan-Meier (KM) estimates was used for analyses.
Time frame: First objective response up to the data cutoff date of 11 August 2018 (maximum: 2.7 years)
Population: Participants in the mITT Analysis Set with objective response were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007 | NA months |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): Duration of Response (DOR) Using IRRC Per Cheson 2007 | NA months |
Secondary
Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC)
ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma. CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method.
Time frame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)
Population: Participants in the mITT Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC) | 70 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): ORR Per Independent Radiological Review Committee (IRRC) | 88 percentage of participants |
Secondary
Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007
PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression as assessed by the IRRC using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. PD defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. KM estimates was used for analyses.
Time frame: First infusion date of axicabtagene ciloleucel to the data cutoff date of 11 August 2018 (maximum: 2.7 years)
Population: Participants in the mITT Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007 | 6.9 months |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Pivotal Study (Cohorts 1 and 2): PFS Using IRRC Per Cheson 2007 | NA months |
Secondary
Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma
PFS was defined as the time from the axicabtagene ciloleucel infusion date to the date of disease progression per the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death from any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. Disease progression was defined by at least one of the following: ≥ 50% increase from nadir in the sum of the products of at least 2 lymph nodes, or at least a 50% increase in the product of the diameters of a single lymph node; appearance of a new lesion \> 1.5 cm in any axis; ≥ 50% increase in size of splenic or hepatic nodules; ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. KM estimates was used for analyses.
Time frame: First infusion date of axicabtagene ciloleucel to disease progression or death regardless of cause (maximum duration: 7.7, 6.8, 5.4, 4.4, 4.1 years for Cohorts 1, 2, 3, 4, 5, and 6 respectively)
Population: Participants in the mITT Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | 5.1 months |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | 49.1 months |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | 6.2 months |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | NA months |
| Phase 2 (Safety Management Study): Cohort 5 | Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | 3.1 months |
| Phase 2 (Safety Management Study): Cohort 6 | Phase 2: Progression-Free Survival (PFS) as Assessed by Investigator Per Revised IWG Response Criteria for Malignant Lymphoma | NA months |
Secondary
Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma
ORR was defined as the percentage of participants achieving either a CR or a PR, as assessed by the study investigators using revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; all lymph nodes and nodal masses must have regressed to normal size; spleen and/or liver must be normal size, not be palpable, and no nodules; bone marrow aspirate and biopsy must show no evidence of disease. PR: a ≥ 50% decrease in SPD of up to 6 of the largest dominant nodes or nodal masses; no increase in size of nodes, liver or spleen and no new sites of disease; multiple splenic and hepatic nodules (if present) must regress by ≥ 50% in the SPD; \> 50% decrease in the greatest transverse diameter for single nodules. 95% CI was calculated by Clopper-Pearson method.
Time frame: First infusion date of axicabtagene ciloleucel to last follow-up visit (maximum duration: 6.8, 5.4, 4.4, 4.1 years for Cohorts 3, 4, 5, and 6 respectively)
Population: Participants in the mITT Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma | 63 percentage of participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma | 76 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma | 72 percentage of participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study (Cohorts 3, 4, 5, and 6): ORR as Assessed by Investigator Per the Revised IWG Response Criteria for Malignant Lymphoma | 95 percentage of participants |
Secondary
Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score
EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant. The EQ-5D-VAS records the participant's self-rated health on a vertical visual analogue scale and is asked to make a global assessment of their current state of health with 0 indicating the worst health they can imagine and 100 indicating the best health they can imagine.
Time frame: Baseline, Week 4, Month 3, and Month 6
Population: Participants in Safety Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Baseline | 71.2 units on a scale | Standard Deviation 21.3 |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Week 4 | 67.8 units on a scale | Standard Deviation 15.6 |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Month 3 | 74.9 units on a scale | Standard Deviation 16.6 |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Month 6 | 77.1 units on a scale | Standard Deviation 21.4 |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Week 4 | 67.2 units on a scale | Standard Deviation 20.9 |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Month 6 | 85.1 units on a scale | Standard Deviation 12.1 |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Baseline | 69.5 units on a scale | Standard Deviation 18.8 |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Month 3 | 78.8 units on a scale | Standard Deviation 14.7 |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Baseline | 66.7 units on a scale | Standard Deviation 20.7 |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Month 6 | 77.1 units on a scale | Standard Deviation 14.7 |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Month 3 | 73.3 units on a scale | Standard Deviation 19.9 |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Week 4 | 70.8 units on a scale | Standard Deviation 14.8 |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Month 6 | 79.8 units on a scale | Standard Deviation 14 |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Baseline | 70.9 units on a scale | Standard Deviation 17 |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Week 4 | 76.1 units on a scale | Standard Deviation 13.2 |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: EQ-5D Visual Analogue Scale (VAS) Score | Month 3 | 76.5 units on a scale | Standard Deviation 15 |
Secondary
Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score
EQ-5D is a self-reported questionnaire used for assessing the overall health status of a participant scoring 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension was divided into 5 levels of severity: No problem, Slight problems, Moderate problems, Severe problems, and Extreme problems (unable to perform). EQ-5D health states, defined by the EQ-5D descriptive system, are converted into a single summary index by applying a formula that attaches values (also called QOL weights or QOL utilities) to each of the levels in each dimension. EQ-5D Summary Index values range from -0.11 (worst health state) to 1.00 (perfect health state).
Time frame: Baseline, Week 4, Month 3, and Month 6
Population: Participants in Safety Analysis Set with available data were analyzed.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Moderate problem | 9 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Slight problem | 5 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Moderate problem | 11 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | No problem | 9 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Moderate problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Severe problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Moderate problem | 7 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Unable to perform | 2 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Slight problem | 12 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | No problem | 12 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | No problem | 8 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Moderate problem | 4 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Unable to perform | 2 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Severe problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Slight problem | 9 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Unable to perform | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Moderate problem | 8 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Slight problem | 9 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Moderate problem | 5 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | No problem | 18 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Severe problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Slight problem | 11 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Severe problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Moderate problem | 3 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | No problem | 16 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Slight problem | 5 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | No problem | 9 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | No problem | 19 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Moderate problem | 2 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Slight problem | 4 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Moderate problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Slight problem | 7 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Moderate problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Slight problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | No problem | 30 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Unable to perform | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Slight problem | 6 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Moderate problem | 3 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | No problem | 10 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Slight problem | 5 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | No problem | 9 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | No problem | 17 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | No problem | 25 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Slight problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | No problem | 37 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Moderate problem | 6 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Slight problem | 5 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Moderate problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | No problem | 11 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Severe problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Moderate problem | 7 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Slight problem | 5 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Slight problem | 15 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | No problem | 9 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | No problem | 22 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Unable to perform | 2 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Slight problem | 10 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Moderate problem | 2 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Moderate problem | 3 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Slight problem | 16 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Moderate problem | 4 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Slight problem | 6 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | No problem | 16 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Severe problem | 2 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Moderate problem | 1 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Moderate problem | 5 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Slight problem | 4 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | No problem | 8 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | No problem | 6 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | No problem | 14 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Severe problem | 0 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Slight problem | 13 Participants |
| Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Unable to perform | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Slight problem | 10 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | No problem | 33 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Slight problem | 3 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Severe problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | No problem | 29 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Slight problem | 2 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | No problem | 25 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Slight problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | No problem | 22 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Slight problem | 6 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Moderate problem | 8 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Severe problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Unable to perform | 2 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | No problem | 12 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Slight problem | 11 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Moderate problem | 8 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Severe problem | 3 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Unable to perform | 3 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | No problem | 16 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Slight problem | 9 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Moderate problem | 5 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Severe problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | No problem | 15 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Slight problem | 7 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Moderate problem | 3 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | No problem | 17 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Slight problem | 17 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Moderate problem | 5 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | No problem | 19 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Slight problem | 13 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Moderate problem | 2 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Severe problem | 3 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | No problem | 10 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Slight problem | 14 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Moderate problem | 6 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Severe problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | No problem | 9 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Slight problem | 14 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Moderate problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Severe problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | No problem | 23 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Slight problem | 13 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Moderate problem | 3 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | No problem | 25 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Slight problem | 8 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Moderate problem | 3 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | No problem | 19 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Slight problem | 8 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Moderate problem | 4 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | No problem | 14 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Moderate problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | No problem | 25 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Slight problem | 9 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Moderate problem | 5 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | No problem | 21 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Slight problem | 7 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Moderate problem | 5 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Severe problem | 3 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Unable to perform | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | No problem | 20 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Slight problem | 8 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Moderate problem | 2 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Severe problem | 1 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | No problem | 19 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Slight problem | 4 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Moderate problem | 2 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Severe problem | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | No problem | 38 Participants |
| Phase 2 (Pivotal Study): Cohort 2 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Slight problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Slight problem | 8 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | No problem | 24 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Slight problem | 13 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Unable to perform | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Moderate problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | No problem | 11 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Moderate problem | 6 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | No problem | 21 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | No problem | 33 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | No problem | 44 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Slight problem | 5 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Slight problem | 12 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Slight problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Slight problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Moderate problem | 7 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Unable to perform | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Moderate problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Moderate problem | 5 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | No problem | 32 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | No problem | 6 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Unable to perform | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Moderate problem | 8 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | No problem | 10 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Unable to perform | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | No problem | 18 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Slight problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | No problem | 23 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Moderate problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Unable to perform | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | No problem | 16 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Slight problem | 6 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Moderate problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Moderate problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | No problem | 16 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Slight problem | 17 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | No problem | 31 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Slight problem | 9 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Slight problem | 18 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Slight problem | 12 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Slight problem | 10 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Slight problem | 8 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Moderate problem | 7 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Slight problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Moderate problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Severe problem | 5 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Slight problem | 13 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | No problem | 19 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Moderate problem | 6 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Unable to perform | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Moderate problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | No problem | 20 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Moderate problem | 10 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Unable to perform | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | No problem | 16 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Slight problem | 10 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | No problem | 12 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Moderate problem | 5 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | No problem | 21 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Severe problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Severe problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Slight problem | 6 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | No problem | 7 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Moderate problem | 8 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | No problem | 18 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Slight problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 3 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Slight problem | 9 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Moderate problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Slight problem | 5 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Moderate problem | 5 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | No problem | 12 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Severe problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | No problem | 12 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Slight problem | 8 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Severe problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Moderate problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | No problem | 22 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Severe problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Moderate problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Slight problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | No problem | 21 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | Slight problem | 14 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Slight problem | 9 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Slight problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Usual activities | No problem | 16 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Moderate problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | No problem | 23 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Slight problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | No problem | 24 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | No problem | 32 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | No problem | 19 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | Slight problem | 7 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Slight problem | 7 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Moderate problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Self-care | No problem | 20 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | No problem | 18 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Slight problem | 5 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Moderate problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | No problem | 15 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Anxiety/Depression | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | No problem | 26 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | Slight problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Slight problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Self-care | No problem | 25 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Slight problem | 8 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Mobility | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | No problem | 11 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Self-care | Slight problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Slight problem | 12 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | No problem | 20 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Moderate problem | 2 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Usual activities | Unable to perform | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | No problem | 15 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | Slight problem | 14 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Slight problem | 14 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Slight problem | 5 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Moderate problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Usual activities | No problem | 12 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Self-care | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 6: Mobility | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Baseline: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Unable to perform | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | No problem | 17 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Moderate problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Slight problem | 9 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Severe problem | 1 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Moderate problem | 3 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Moderate problem | 4 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Pain/Discomfort | Unable to perform | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Mobility | Severe problem | 0 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Month 3: Pain/Discomfort | No problem | 16 Participants |
| Phase 2 (Safety Management Study): Cohort 4 | Phase 2 Safety Management Study: Number of Participants With the European Quality of Life Five Dimension Five Level Scale (EQ-5D) Score | Week 4: Usual activities | Slight problem | 11 Participants |