Acute Lymphoblastic Leukemia (ALL)
Conditions
Brief summary
The purpose of Phase 1b of this study is to: * Asses the safety, tolerability and activity of carfilzomib, alone and in combination with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic leukemia (ALL). * Determine the maximum tolerated dose (MTD) and to recommend a phase 2 dose of carfilzomib in combination with induction chemotherapy. The purpose of Phase 2 of this study is to compare the rate of complete remission (CR) of carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin (VXLD) at the end of induction therapy to an appropriate external control.
Interventions
DRUGDaunorubicin
DRUGCarfilzomib
DRUGDexamethasone
DRUGMitoxantrone
DRUGPEG-asparaginase
DRUGVincristine
DRUGIntrathecal (IT) Methotrexate
DRUGIntrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
DRUG6-Mercaptopurine
DRUGCyclophosphamide
DRUGCytarabine
Sponsors
Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) - Study Design & Execution Collaborator
Innovative Therapies For Children with Cancer Consortium
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to 21 Years
Healthy volunteers
No
Inclusion criteria
Phase 1b Key Inclusion Criteria: 1. Age 21 years or younger at the time of initial ALL diagnosis and age \> 1 year at the time of study treatment initiation. 2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease. -To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as: * Early first relapse (\< 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following the original diagnosis after achieving a CR (T-ALL) * First refractory bone marrow relapse occurring any time after original diagnosis after achieving a CR (ie, ≥1 failed attempt to induce a second remission) OR * Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses) OR * Failing to achieve a CR from original diagnosis after at least 1 induction attempt 3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment. 4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit of normal (ULN) according to age. If serum creatinine level is \> 1.5 × ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2. 5. Adequate liver function, defined as both of the following: * Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert Syndrome * Alanine aminotransferase (ALT) ≤ 5 × institutional ULN 6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects \> 16 years old or ≤ 16 years old, respectively. Phase 2 Inclusion Criteria: 1. Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated, except for standard of care local testing as permitted per protocol. 2. Age greater than or equal to 1 month to less than 21 years. Subjects greater than or equal to 18 years must have had their original diagnosis at less than 18 years of age. 3. Subjects must be diagnosed with relapsed or refractory relapsed ALL. 4. Subjects must have a documented first remission, less than 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease. 5. T-cell ALL with bone marrow relapse (defined as greater than or equal to 5% leukemia blasts in bone marrow) or refractory relapse with or without extramedullary disease. OR B-cell ALL bone marrow relapse or refractory relapse (defined as greater than or equal to 5% leukemia blasts in bone marrow) after having received a targeted B-cell immune therapy (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without extramedullary disease.. 6. Adequate liver function: bilirubin less than or equal to 1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) less than or equal to 5 x ULN. 7. Adequate renal function: serum creatinine less than or equal to 1.5 x ULN or glomerular filtration rate (GFR) greater than or equal to 70 mL/min/1.73 m\^2; or for children less than 2 years of age, greater than or equal to 50 mL/min/1.73 m\^2. 8. Adequate cardiac function: shortening fraction greater than or equal to 30% or ejection fraction greater than or equal to 50%. 9. Karnofsky (subjects greater than or equal to 16 years of age) or Lansky (subjects 12 months to less than 16 years of age) performance status greater than or equal to 50%. 10. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment (for example: recovery from gastrointestinal toxicity may occur more rapidly than less reversible organ toxicities such as sinusoidal obstruction syndrome or non-infectious pneumonitis, for serious prior toxicities recommended discussion with Amgen medical monitor). 11. Life expectancy of greater than 6 weeks per investigator's judgement at time of screening. Phase 1b Key
Exclusion criteria
1. Known allergy to any of the drugs used in the study (Subjects who have had a previous allergy to PEG-asparaginase and if able, may receive Erwinia asparaginase at the investigator's discretion) 2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib) 3. Left ventricular fractional shortening \< 30% 4. History of ≥ Grade 2 pancreatitis 5. Active graft-versus-host disease requiring systemic treatment 6. Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment 7. Down Syndrome 8. Prior therapy restrictions: * Subjects must have completed therapy with granulocyte-colony stimulating factor (G-CSF) or other myeloid growth factors at least 7 days before study treatment initiation, or at least 14 days before study treatment initiation, if pegylated myeloid growth factors were administered. * Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation. * Subjects must have received the last dose of a non-monoclonal antibody biologic agent at least 7 days before study treatment initiation. * At least 3 antibody half-lives must have elapsed since the last dose of monoclonal antibody (e.g., 66 days for rituximab and 69 days for epratuzumab) before subjects may initiate study treatment. * Subjects must not have received other antineoplastic agents with therapeutic intent, excluding hydroxyurea and antimetabolites administered as part of maintenance chemotherapy, within 7 days prior to study treatment initiation. 9. Hepatitis B infection with positive hepatitis B DNA Phase 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | From first dose up to 30 days after the last dose of study treatment; maximum duration of treatment was 8 weeks | An adverse event (AE) is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. Treatment-related AEs (TRAEs) were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. A serious AE (SAE) was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event. |
| Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Up to approximately 35 days | A DLT was defined as any of the following toxicities assessed by the investigator as possibly, probably, or definitely attributable to carfilzomib, with protocol defined exclusions: Any Grade 4 nonhematologic toxicity, ≥ Grade 4 neutropenia or ≥ Grade 3 thrombocytopenia. |
| Phase 2: Percentage of Participants With Complete Remission (CR) After Induction Therapy | Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [Day 36 to Day 50 for infants]) | CR was defined as: 1. Attainment of M1 bone marrow status (less than 5% blasts in a bone marrow aspirate and at least 200 cells counted) with no evidence of circulating blasts or extramedullary disease. 2. Recovery of peripheral counts: * Absolute neutrophil count (ANC) greater than or equal to 1000/µL * Platelet count greater than or equal to 100000/µL. * Assessed between days 29 and 45 Data was adjusted as inverse probability of treatment weight (IPTW) for the average treatment effect of the treated (IPTW-ATTW). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle | Up to approximately Day 29 of Induction Cycle (28-days cycle, assessment on Day 29) | CR was defined as the attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC \> 750 mcl and platelet count \> 75,000 mcl). CRp was defined as the attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease and with recovery of ANCs (ANC \> 750 mcl), but with insufficient recovery of platelets (\< 75,000 mcl). |
| Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Up to approximately Day 29 of Induction Cycle (28-days cycle, assessment on Day29) | MRD was defined as the quantification of residual lymphoblast in the blood. Assessed by next generation sequencing (NGS). |
| Phase 2: Number of Participants Who Experienced TEAEs | From first dose up to 30 days after the last dose of study treatment; maximum duration of treatment was 8 weeks | An AE is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. TRAEs were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. An SAE was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event. |
| Phase 2: Percentage of Participants With CR With Incomplete Hematologic Recovery (CRi) After Induction Therapy or Better Remission Status | Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants]) | CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. ANC and platelet counts not fulfilling criteria for CR with partial hematologic recovery (CRh), CR without platelet recovery (CRp), or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 1000/µL ii. Platelet count \< 100 000/µL. CRh was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. Recovery of peripheral counts: i. ANC ≥ 500/µL but \< 1000/µL ii. Platelet count ≥ 50 000/µL but \< 100 000/µL. Data was IPTW adjusted. |
| Phase 2: Event Free Survival (EFS) | Up to approximately 2 years | EFS was defined as time from initiation of therapy until treatment failure (defined as failure to reach at least a CRi after consolidation or after induction in participants that did not receive consolidation), relapse, or death from any cause. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp, or CR. Data was IPTW adjusted. Medians were estimated using the Kaplan-Meier (KM) method. |
| Phase 2: Overall Survival (OS) | Up to approximately 2 years | OS was defined as time from initiation of therapy until death from any cause. Data was IPTW adjusted. Medians were estimated using the KM method. |
| Phase 2: Duration of Remission (DOR) | Up to approximately 2 years | DOR was defined as time from earliest of CR, CRp, CRh, or CRi to relapse or death from any cause. CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp) or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 1000/µL ii. Platelet count \< 100 000/µL. CRh was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 500/µL but \< 1000/µL ii. Platelet count ≥ 50 000/µL but \< 100 000/µL. |
| Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CR After Induction Therapy | Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants]) | MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with next generation sequencing (NGS). |
| Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15 minutes (m) after the start of infusion, immediately (within 2m) before the end of infusion (EOI), EOI, 10m, 30m, 1 hour (h), 2 h, and 4h post-dose | The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval. |
| Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy | Up to Day 100 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants] + 28-day cycle of consolidation therapy + + recovery window from Day 29 to Day 45 [up to Day 50 for infants]) | MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with NGS. |
| Phase 2: Percentage of Participants Who Underwent Stem Cell Transplant or Chimeric Antigen Receptor T-cell (CAR-T) Without Intervening Relapse Following Protocol-Specified Therapy | Up to approximately 2 years | Percentage of participants who successfully underwent stem cell transplant or CAR-T therapy without experiencing a relapse after receiving the protocol-specified treatment. |
| Phase 2: Percentage of Participants With CRi or Better Remission Status After Consolidation Therapy | Up to Day 100 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants] + 28-day cycle of consolidation therapy + + recovery window from Day 29 to Day 45 [up to Day 50 for infants]) | CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. ANC and platelet counts not fulfilling criteria for CRh, CRp, or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ to 1000/µL ii. Platelet count \< 100 000/µL. CRh was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. Recovery of peripheral counts: i. ANC ≥ 500/µL but \< 1000/µL ii. Platelet count ≥ 50 000/µL but \< 100 000/µL. Data was IPTW adjusted. |
| Phase 2: AUClast of Carfilzomib | Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle) | AUClast refers to the total exposure of a drug in the body over time, calculated from the time of administration until the last measurable concentration in the blood. |
| Phase 2: AUCinf of Carfilzomib | Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle) | AUCinf represents the total drug exposure over time, extrapolated from the time of administration until the drug is completely eliminated from the body. |
| Phase 2: Cmax of Carfilzomib | Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle) | Cmax is the maximum concentration of a drug in the bloodstream after administration. |
| Phase 2: Terminal Half-life (t1/2,z) of Carfilzomib | Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle) | T1/2,z refers to the time required for the plasma concentration of a drug to decrease by half during the final phase of elimination from the body. |
| Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Induction Therapy | Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants]) | MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with NGS. |
| Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose | The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval. |
| Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose | The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval. |
Countries
Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Chile, Colombia, Czechia, Denmark, France, Greece, Hong Kong, Israel, Italy, Mexico, Netherlands, Norway, Poland, Portugal, Romania, Russia, Saudi Arabia, Singapore, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were recruited in Australia, Argentina, Austria, Brazil, Bulgaria, Canada, Chile, Colombia, Czech Republic, Denmark, France, Greece, Hong Kong, Italy, Israel, Mexico, Netherlands, Norway, Poland, Portugal, Romania, Russia, Saudi Arabia, Singapore, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey, the UK and the US between February 2015 and June 2024.
Pre-assignment details
Phase 1b: Participants underwent a 4-week induction and 4-week consolidation cycle, receiving two treatments. Phase 2: After a 7-day screening, participants received VXLD (vincristine, PEG-asparaginase, daunorubicin, dexamethasone) with carfilzomib during a 28-day induction. One B-cell group participant did not receive carfilzomib and was excluded from the primary analysis. Participants were followed for up to 2 years post-treatment.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Dose Escalation 1 (20 mg/m^2) Participants with relapsed or refractory ALL received carfilzomib 20 mg/m\^2 in combination with R3 IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle). | 5 |
| Phase 1b: Dose Escalation 1 (20/27 mg/m^2) Participants with relapsed or refractory ALL received carfilzomib 20 mg/m\^2 for the first dose, followed by the target 27 mg/m\^2 dose in combination with R3 IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle). | 6 |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) Participants with relapsed or refractory ALL received carfilzomib 20 mg/m\^2 for the first dose, followed by the target 27 mg/m\^2 dose in combination with VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle). | 3 |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) Participants with relapsed or refractory ALL received carfilzomib 20 mg/m\^2 for the first dose, followed by the target 36 mg/m\^2 dose in combination with VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle). | 7 |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2) Participants with relapsed or refractory ALL received carfilzomib 20 mg/m\^2 for the first dose, followed by the target 45 mg/m\^2 dose in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle). | 4 |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) Participants with relapsed or refractory ALL received carfilzomib 20 mg/m\^2 for the first dose, followed by the target 56 mg/m\^2 dose in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle). | 10 |
| Phase 2: B-cell (20/56 mg/m^2) Eligible participants with relapsed or refractory ALL (B-cell, after having received a targeted B-cell therapy) were treated with VXLD plus carfilzomib 20/56 mg/m\^2 for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator's discretion, be treated with 1 28-day consolidation cycle of BFM therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and IT therapy plus carfilzomib. | 61 |
| Phase 2: T-cell (20/56 mg/m^2) Eligible participants with relapsed or refractory ALL (T-cell) were treated with VXLD plus carfilzomib 20/56 mg/m\^2 for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator's discretion, be treated with 1 28-day consolidation cycle of BFM therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and IT therapy plus carfilzomib. | 44 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 2 | 0 | 0 | 0 | 3 | 41 | 29 |
| Overall Study | Decision by sponsor | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol-specified criteria | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Withdrawal prior to Carfilzomib dosing | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase 1b: Dose Escalation 1 (20 mg/m^2) | Phase 1b: Dose Escalation 1 (20/27 mg/m^2) | Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Dose Escalation 2 (20/45 mg/m^2) | Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 2: B-cell (20/56 mg/m^2) | Phase 2: T-cell (20/56 mg/m^2) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized > 17 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 3 Participants | 9 Participants |
| Age, Customized < 1 month | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 1 month - <= 17 years | 5 Participants | 6 Participants | 3 Participants | 7 Participants | 3 Participants | 9 Participants | 57 Participants | 41 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 28 Participants | 11 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants | 5 Participants | 4 Participants | 10 Participants | 33 Participants | 33 Participants | 97 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 9 Participants | 6 Participants | 16 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other (Indian, Brown, Brazilian indigenous, Hispanic Mestizo, Mestizo breed, Hispanic, and Mixed) | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 9 Participants | 1 Participants | 13 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 5 Participants | 2 Participants | 7 Participants | 3 Participants | 6 Participants | 38 Participants | 33 Participants | 99 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 19 Participants | 5 Participants | 35 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 3 Participants | 6 Participants | 3 Participants | 7 Participants | 42 Participants | 39 Participants | 105 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 2 / 6 | 0 / 3 | 0 / 7 | 0 / 4 | 3 / 10 | 41 / 62 | 29 / 44 |
| other Total, other adverse events | 5 / 5 | 6 / 6 | 3 / 3 | 7 / 7 | 4 / 4 | 9 / 10 | 61 / 61 | 43 / 44 |
| serious Total, serious adverse events | 4 / 5 | 4 / 6 | 3 / 3 | 6 / 7 | 4 / 4 | 7 / 10 | 44 / 61 | 31 / 44 |
Outcome results
Primary
Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
A DLT was defined as any of the following toxicities assessed by the investigator as possibly, probably, or definitely attributable to carfilzomib, with protocol defined exclusions: Any Grade 4 nonhematologic toxicity, ≥ Grade 4 neutropenia or ≥ Grade 3 thrombocytopenia.
Time frame: Up to approximately 35 days
Population: Phase 1b DLT Evaluable Analysis Set: All participants who received all planned dose of carfilzomib and the chemotherapy backbone per protocol during the lead-in window and induction cycle, or received at least one dose of carfilzomib and the chemotherapy backbone per protocol and experienced a DLT prior to completion of the lead-in window or induction cycle, or as clinically indicated.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Pulmonary haemorrhage | 0 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Platelet count decreased | 0 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Haemolytic uraemic syndrome | 0 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Platelet count decreased | 0 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Haemolytic uraemic syndrome | 1 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Pulmonary haemorrhage | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Haemolytic uraemic syndrome | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Pulmonary haemorrhage | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Platelet count decreased | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Pulmonary haemorrhage | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Haemolytic uraemic syndrome | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Platelet count decreased | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Platelet count decreased | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Pulmonary haemorrhage | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Haemolytic uraemic syndrome | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Pulmonary haemorrhage | 1 Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Platelet count decreased | 1 Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Haemolytic uraemic syndrome | 0 Participants |
Primary
Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. Treatment-related AEs (TRAEs) were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. A serious AE (SAE) was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
Time frame: From first dose up to 30 days after the last dose of study treatment; maximum duration of treatment was 8 weeks
Population: Phase 1b Safety Analysis Set: All participants who received any amount of the study treatment regimen.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TRAEs | 5 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 4 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 5 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TEAEs | 0 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TRAEs | 0 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TRAEs | 4 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TRAEs | 0 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 6 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 4 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TEAEs | 2 Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TEAEs | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 3 Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 3 Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TRAEs | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TRAEs | 3 Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TRAEs | 7 Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TEAEs | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 7 Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TRAEs | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 6 Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TEAEs | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 4 Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TRAEs | 0 Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 4 Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TRAEs | 4 Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 7 Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TRAEs | 1 Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 9 Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All fatal TEAEs | 3 Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TRAEs | 8 Participants |
Primary
Phase 2: Percentage of Participants With Complete Remission (CR) After Induction Therapy
CR was defined as: 1. Attainment of M1 bone marrow status (less than 5% blasts in a bone marrow aspirate and at least 200 cells counted) with no evidence of circulating blasts or extramedullary disease. 2. Recovery of peripheral counts: * Absolute neutrophil count (ANC) greater than or equal to 1000/µL * Platelet count greater than or equal to 100000/µL. * Assessed between days 29 and 45 Data was adjusted as inverse probability of treatment weight (IPTW) for the average treatment effect of the treated (IPTW-ATTW).
Time frame: Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [Day 36 to Day 50 for infants])
Population: Phase 2: Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants With Complete Remission (CR) After Induction Therapy | 14.8 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants With Complete Remission (CR) After Induction Therapy | 13.6 Percentage of Participants |
Secondary
Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib
The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval.
Time frame: Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose
Population: Phase 1b PK Analysis Set: All participants who received the study treatment regimen during the lead-in cycle and induction cycles, and had available data. Phase 1b Dose Escalation 2 arms did not have a 1-week lead-in cycle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Dose Escalation 1 - Lead in Cycle Day 1 | 387 hr*ng/mL | Standard Deviation 125 |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Induction Cycle Day 8 | 361 hr*ng/mL | Standard Deviation 160 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Dose Escalation 1 - Lead in Cycle Day 1 | 240 hr*ng/mL | Standard Deviation 113 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Induction Cycle Day 8 | 374 hr*ng/mL | Standard Deviation 273 |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Induction Cycle Day 8 | 214 hr*ng/mL | Standard Deviation 155 |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Induction Cycle Day 8 | 529 hr*ng/mL | Standard Deviation 210 |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Induction Cycle Day 8 | 829 hr*ng/mL | Standard Deviation 479 |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib | Induction Cycle Day 8 | 4000 hr*ng/mL | Standard Deviation 6370 |
Secondary
Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib
The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval.
Time frame: Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose
Population: Phase 1b PK Analysis Set: All participants who received the study treatment regimen during the lead-in cycle and induction cycles, and had available data. Phase 1b Dose Escalation 2 arms did not have a 1-week lead-in cycle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Dose Escalation 1 - Lead in Cycle Day 1 | 387 hr*ng/ mL | Standard Deviation 124 |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Induction Cycle Day 8 | 368 hr*ng/ mL | Standard Deviation 184 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Induction Cycle Day 8 | 374 hr*ng/ mL | Standard Deviation 273 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Dose Escalation 1 - Lead in Cycle Day 1 | 268 hr*ng/ mL | Standard Deviation 101 |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Induction Cycle Day 8 | 406 hr*ng/ mL | Standard Deviation 0 |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Induction Cycle Day 8 | 565 hr*ng/ mL | Standard Deviation 243 |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Induction Cycle Day 8 | 848 hr*ng/ mL | Standard Deviation 510 |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib | Induction Cycle Day 8 | 1300 hr*ng/ mL | Standard Deviation 1440 |
Secondary
Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination
The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval.
Time frame: Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15 minutes (m) after the start of infusion, immediately (within 2m) before the end of infusion (EOI), EOI, 10m, 30m, 1 hour (h), 2 h, and 4h post-dose
Population: Phase 1b PK Analysis Set: All participants who received the study treatment regimen during the lead-in cycle and induction cycles, and had available data. Phase 1b Dose Escalation 2 arms did not have a 1-week lead-in cycle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Dose Escalation 1 - Lead in Cycle Day 1 | 927 ng/mL | Standard Deviation 259 |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Induction cycle Day 8 | 771 ng/mL | Standard Deviation 151 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Dose Escalation 1 - Lead in Cycle Day 1 | 637 ng/mL | Standard Deviation 241 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Induction cycle Day 8 | 792 ng/mL | Standard Deviation 580 |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Induction cycle Day 8 | 445 ng/mL | Standard Deviation 260 |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Induction cycle Day 8 | 1070 ng/mL | Standard Deviation 359 |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Induction cycle Day 8 | 1630 ng/mL | Standard Deviation 875 |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination | Induction cycle Day 8 | 11200 ng/mL | Standard Deviation 16400 |
Secondary
Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle
MRD was defined as the quantification of residual lymphoblast in the blood. Assessed by next generation sequencing (NGS).
Time frame: Up to approximately Day 29 of Induction Cycle (28-days cycle, assessment on Day29)
Population: Phase 1b Induction SAS: All participants who received any amount of the study treatment regimen during the induction period and had available data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^4 lymphoblasts | 0 Percentage of Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^3 lymphoblasts | 0 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^3 lymphoblasts | 0 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^4 lymphoblasts | 0 Percentage of Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^3 lymphoblasts | 0 Percentage of Participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^4 lymphoblasts | 0 Percentage of Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^3 lymphoblasts | 14.3 Percentage of Participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^4 lymphoblasts | 14.3 Percentage of Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^3 lymphoblasts | 25.0 Percentage of Participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^4 lymphoblasts | 25.0 Percentage of Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^4 lymphoblasts | 0 Percentage of Participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle | Achieved MRD status < 10^3 lymphoblasts | 0 Percentage of Participants |
Secondary
Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle
CR was defined as the attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC \> 750 mcl and platelet count \> 75,000 mcl). CRp was defined as the attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease and with recovery of ANCs (ANC \> 750 mcl), but with insufficient recovery of platelets (\< 75,000 mcl).
Time frame: Up to approximately Day 29 of Induction Cycle (28-days cycle, assessment on Day 29)
Population: Phase 1b Induction SAS: All participants who received any amount of the study treatment regimen during the induction period and had available data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle | 40.0 Percentage of participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle | 20.0 Percentage of participants |
| Phase 1b: Dose Escalation 2 (20/27 mg/m^2) | Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle | 33.3 Percentage of participants |
| Phase 1b: Dose Escalation 2 (20/36 mg/m^2) | Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle | 28.6 Percentage of participants |
| Phase 1b: Dose Escalation 2 (20/45 mg/m^2 | Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle | 25.0 Percentage of participants |
| Phase 1b: Dose Escalation 2 (20/56 mg/m^2) | Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle | 20.0 Percentage of participants |
Secondary
Phase 2: AUCinf of Carfilzomib
AUCinf represents the total drug exposure over time, extrapolated from the time of administration until the drug is completely eliminated from the body.
Time frame: Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle)
Population: Phase 2 PK analysis set: All participants who received at least 1 dose of carfilzomib, had 1 PK sample collected and a quantifiable number of observations. Per SAP, analysis was not planned to compare T-cell and B-cell.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: AUCinf of Carfilzomib | 4070 hr*ng/mL | Standard Deviation 11000 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: AUCinf of Carfilzomib | 1200 hr*ng/mL | Standard Deviation 2480 |
Secondary
Phase 2: AUClast of Carfilzomib
AUClast refers to the total exposure of a drug in the body over time, calculated from the time of administration until the last measurable concentration in the blood.
Time frame: Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle)
Population: Phase 2 PK analysis set: All participants who received at least 1 dose of carfilzomib, had 1 PK sample collected and a quantifiable number of observations. Per SAP, analysis was not planned to compare T-cell and B-cell.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: AUClast of Carfilzomib | 4330 hr*ng/mL | Standard Deviation 10300 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: AUClast of Carfilzomib | 9410 hr*ng/mL | Standard Deviation 36200 |
Secondary
Phase 2: Cmax of Carfilzomib
Cmax is the maximum concentration of a drug in the bloodstream after administration.
Time frame: Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle)
Population: Phase 2 PK analysis set: All participants who received at least 1 dose of carfilzomib, had 1 PK sample collected and a quantifiable number of observations. Per SAP, analysis was not planned to compare T-cell and B-cell.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Cmax of Carfilzomib | 9590 ng/mL | Standard Deviation 27800 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Cmax of Carfilzomib | 13800 ng/mL | Standard Deviation 44200 |
Secondary
Phase 2: Duration of Remission (DOR)
DOR was defined as time from earliest of CR, CRp, CRh, or CRi to relapse or death from any cause. CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp) or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 1000/µL ii. Platelet count \< 100 000/µL. CRh was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 500/µL but \< 1000/µL ii. Platelet count ≥ 50 000/µL but \< 100 000/µL.
Time frame: Up to approximately 2 years
Population: Phase 2: Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib. Only participants who achieved CRi or a better remission status were included in the analysis. Data was IPTW adjusted. Medians were estimated using the KM method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Duration of Remission (DOR) | 7.55 Months |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Duration of Remission (DOR) | 9.01 Months |
Secondary
Phase 2: Event Free Survival (EFS)
EFS was defined as time from initiation of therapy until treatment failure (defined as failure to reach at least a CRi after consolidation or after induction in participants that did not receive consolidation), relapse, or death from any cause. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp, or CR. Data was IPTW adjusted. Medians were estimated using the Kaplan-Meier (KM) method.
Time frame: Up to approximately 2 years
Population: Phase 2: Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Event Free Survival (EFS) | 1.18 Months |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Event Free Survival (EFS) | 1.20 Months |
Secondary
Phase 2: Number of Participants Who Experienced TEAEs
An AE is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. TRAEs were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. An SAE was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
Time frame: From first dose up to 30 days after the last dose of study treatment; maximum duration of treatment was 8 weeks
Population: Phase 2 Safety Analysis Set: All participants enrolled to study 20140106 who received at least 1 dose of carfilzomib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | TRAEs | 50 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | SAEs | 44 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | Serious TRAEs | 25 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | TEAEs | 61 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | Fatal TRAEs | 5 Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | Fatal TEAEs | 15 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | Fatal TRAEs | 1 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | TEAEs | 44 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | SAEs | 31 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | TRAEs | 39 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | Serious TRAEs | 24 Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Number of Participants Who Experienced TEAEs | Fatal TEAEs | 3 Participants |
Secondary
Phase 2: Overall Survival (OS)
OS was defined as time from initiation of therapy until death from any cause. Data was IPTW adjusted. Medians were estimated using the KM method.
Time frame: Up to approximately 2 years
Population: Phase 2: Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Overall Survival (OS) | 5.23 Months |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Overall Survival (OS) | 4.51 Months |
Secondary
Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CR After Induction Therapy
MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with next generation sequencing (NGS).
Time frame: Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
Population: Phase 2 Induction Safety Analysis Set: All participants who started the induction cycle and received at least 1 dose of carfilzomib during the induction period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CR After Induction Therapy | Percentage of Participants Achieving MRD <10-³ Cells | 8.2 Percentage of Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CR After Induction Therapy | Percentage of Participants Achieving MRD <10-⁴ Cells | 3.3 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CR After Induction Therapy | Percentage of Participants Achieving MRD <10-³ Cells | 4.5 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CR After Induction Therapy | Percentage of Participants Achieving MRD <10-⁴ Cells | 4.5 Percentage of Participants |
Secondary
Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy
MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with NGS.
Time frame: Up to Day 100 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants] + 28-day cycle of consolidation therapy + + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
Population: Phase 2 Consolidation Safety Analysis Set: All participants who started the consolidation cycle and received at least 1 dose of study treatment during the consolidation period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy | Percentage of Participants Achieving MRD <10-³ Cells | 16.0 Percentage of Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy | Percentage of Participants Achieving MRD <10-⁴ Cells | 16.0 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy | Percentage of Participants Achieving MRD <10-³ Cells | 20.0 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy | Percentage of Participants Achieving MRD <10-⁴ Cells | 20.0 Percentage of Participants |
Secondary
Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Induction Therapy
MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with NGS.
Time frame: Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
Population: Phase 2 Induction Safety Analysis Set: All participants who started the induction cycle and received at least 1 dose of carfilzomib during the induction period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Induction Therapy | Percentage of Participants Achieving MRD <10-³ Cells | 18.0 Percentage of Participants |
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Induction Therapy | Percentage of Participants Achieving MRD <10-⁴ Cells | 9.8 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Induction Therapy | Percentage of Participants Achieving MRD <10-³ Cells | 9.1 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Induction Therapy | Percentage of Participants Achieving MRD <10-⁴ Cells | 6.8 Percentage of Participants |
Secondary
Phase 2: Percentage of Participants Who Underwent Stem Cell Transplant or Chimeric Antigen Receptor T-cell (CAR-T) Without Intervening Relapse Following Protocol-Specified Therapy
Percentage of participants who successfully underwent stem cell transplant or CAR-T therapy without experiencing a relapse after receiving the protocol-specified treatment.
Time frame: Up to approximately 2 years
Population: Phase 2: Safety analysis set: All participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Who Underwent Stem Cell Transplant or Chimeric Antigen Receptor T-cell (CAR-T) Without Intervening Relapse Following Protocol-Specified Therapy | 19.7 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants Who Underwent Stem Cell Transplant or Chimeric Antigen Receptor T-cell (CAR-T) Without Intervening Relapse Following Protocol-Specified Therapy | 27.3 Percentage of Participants |
Secondary
Phase 2: Percentage of Participants With CRi or Better Remission Status After Consolidation Therapy
CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. ANC and platelet counts not fulfilling criteria for CRh, CRp, or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ to 1000/µL ii. Platelet count \< 100 000/µL. CRh was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. Recovery of peripheral counts: i. ANC ≥ 500/µL but \< 1000/µL ii. Platelet count ≥ 50 000/µL but \< 100 000/µL. Data was IPTW adjusted.
Time frame: Up to Day 100 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants] + 28-day cycle of consolidation therapy + + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
Population: Phase 2 Consolidation Safety Analysis Set: All participants who started the consolidation cycle and received at least 1 dose of study treatment during the consolidation period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants With CRi or Better Remission Status After Consolidation Therapy | 36.0 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants With CRi or Better Remission Status After Consolidation Therapy | 50.0 Percentage of Participants |
Secondary
Phase 2: Percentage of Participants With CR With Incomplete Hematologic Recovery (CRi) After Induction Therapy or Better Remission Status
CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. ANC and platelet counts not fulfilling criteria for CR with partial hematologic recovery (CRh), CR without platelet recovery (CRp), or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 1000/µL ii. Platelet count \< 100 000/µL. CRh was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. Recovery of peripheral counts: i. ANC ≥ 500/µL but \< 1000/µL ii. Platelet count ≥ 50 000/µL but \< 100 000/µL. Data was IPTW adjusted.
Time frame: Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
Population: Phase 2: Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants With CR With Incomplete Hematologic Recovery (CRi) After Induction Therapy or Better Remission Status | 42.6 Percentage of Participants |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Percentage of Participants With CR With Incomplete Hematologic Recovery (CRi) After Induction Therapy or Better Remission Status | 27.3 Percentage of Participants |
Secondary
Phase 2: Terminal Half-life (t1/2,z) of Carfilzomib
T1/2,z refers to the time required for the plasma concentration of a drug to decrease by half during the final phase of elimination from the body.
Time frame: Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle)
Population: Phase 2 PK analysis set: All participants who received at least 1 dose of carfilzomib, had 1 PK sample collected and a quantifiable number of observations. Per SAP, analysis was not planned to compare T-cell and B-cell.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: B-cell (20/56 mg/m^2) | Phase 2: Terminal Half-life (t1/2,z) of Carfilzomib | 0.371 hour | Standard Deviation 0.162 |
| Phase 2: T-cell (20/56 mg/m^2) | Phase 2: Terminal Half-life (t1/2,z) of Carfilzomib | 0.332 hour | Standard Deviation 0.0894 |