Relapsed/Refractory Burkitt Lymphoma, Relapsed/Refractory Hairy Cell Leukemia, Relapsed/Refractory Richter Transformation, Relapsed/Refractory Waldenstrom Macroglobulinemia
Conditions
Brief summary
Master protocol: The goal of this master clinical study is to test how well the study drug, brexucabtagene autoleucel, works in participants with rare B-cell malignancies: relapsed/refractory Waldenstrom macroglobulinemia (r/r WM) (Substudy A), r/r Richter transformation (RT) (Substudy B), r/r Burkitt lymphoma (BL) (Substudy C) and r/r hairy cell leukemia (HCL) (Substudy D).
Detailed description
This study will use a basket study design with separate, indication-specific substudies, to investigate r/r RT and r/r BL. After completing the treatment period, all participants will be followed in the post-treatment follow-up period. Thereafter, participants will transition to a separate long-term follow-up study (KT-US-982-5968) to continue follow-up out to 15 years. All substudies have been early terminated by the sponsor. Below is summary of enrollment in each Substudy: * Substudy-A This substudy was withdrawn. Therefore no participants were enrolled. * Substudy-B enrollment closed, actual enrollment is 6. * Substudy-C enrollment closed, actual enrollment is 12. * Substudy-D enrollment closed, actual enrollment is 1.
Interventions
BIOLOGICALBrexucabtagene Autoleucel
Administered intravenously
DRUGCyclophosphamide
Administered intravenously
DRUGFludarabine
Administered intravenously
Sponsors
Kite, A Gilead Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: All Substudies: * Presence of toxicities due to prior therapy must be stable and recovered to Grade 1 or lower. * Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 * Adequate hematologic and end-organ function. * Individuals of childbearing potential who engage in heterosexual intercourse must agree to use specified method(s) of contraception. Substudy B: * Confirmed diagnosis of chronic lymphocytic leukemia (CLL) based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria with histologically confirmed Richter transformation (RT) to a diffuse large B-cell lymphoma (DLBCL) subtype. * Relapsed or refractory disease after 1 line of therapy, defined as at least 1 of the following: * Refractory disease, defined as progressive disease or stable disease as best response to first-line therapy. * Relapsed disease, defined as complete remission to first-line therapy followed by biopsy-proven disease relapse. * At least 1 measurable lesion based on the Lugano Classification. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. Substudy C: * Histologically confirmed mature B-cell non-Hodgkin lymphoma (NHL) Burkitt lymphoma/leukemia. * Relapsed or refractory disease after first-line chemoimmunotherapy, defined as 1 of the following: * Refractory disease, defined as progressive disease or stable disease as best response to first-line therapy; individuals who are intolerant to first-line therapy are excluded. * Relapsed disease, defined as complete remission to first-line therapy followed by biopsy-proven disease relapse. * At least 1 measurable lesion based on the Lugano Classification. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy. Key
Exclusion criteria
All Substudies: * Prior chimeric antigen receptor (CAR) therapy or treatment with any anti-Cluster of Differentiation 19 (CD19) therapy. * human immunodeficiency virus (HIV)-positive patients, unless taking appropriate anti-HIV medications, having an undetectable viral load by quantitative polymerase chain reaction (qPCR) and a CD4 count \> 200 cells/μL. * Presence of detectable cerebrospinal fluid malignant cells or brain metastases. * History of autoimmune disease (eg, Crohn's disease, rheumatoid arthritis, systemic lupus). Substudy B: * Diagnosis of RT not of DLBCL subtype (including, but not limited to, Hodgkin lymphoma (HL) and prolymphocytic leukemia). * Prior allogeneic or autologous stem cell transplant \< 3 months prior to screening and/or \< 4 months prior to planned infusion of brexucabtagene autoleucel. * Presence of active graft-versus-host disease following prior stem cell transplant. Substudy C: * Burkitt-like lymphoma with 11q aberration, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, or high-grade B-cell lymphoma not otherwise specified. * Prior allogeneic stem cell transplant \< 3 months prior to screening and/or \< 4 months prior to planned infusion of brexucabtagene autoleucel. * Presence of active graft-versus-host disease following prior allogeneic stem cell transplant. * Presence of central nervous system (CNS) involvement. Individuals with a prior history of CNS involvement are eligible if they show a negative cerebrospinal fluid (CSF) and no involvement by imaging. Substudies A and D have been early terminated by the sponsor. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Substudy D: ORR Determined by Central Assessment Per the Response Criteria Described by Grever and Colleagues | Up to 2 years | ORR was defined as the percentage of participants who achieved a best response of either CR or PR per Grever and colleagues. CR: Near normalization of peripheral blood counts: hemoglobin \>11 g/dL (without transfusion); platelets \>100 000/μL; absolute neutrophil count \>1500/μL. Regression of splenomegaly on physical examination. Absence of morphologic evidence of HCL on both the peripheral blood smear and the bone marrow examination. PR: PR required near normalization of the peripheral blood count (as in CR) with a minimum of 50% improvement in organomegaly and bone marrow biopsy infiltration with HCL. |
| Substudy A: Combined Rate of Complete Response (CR) and Very Good Partial Response (VGPR) Determined by Central Assessment Per the Sixth International Workshop in Waldenstrom Macroglobulinemia (WM) | Up to 2 years | The combined rate of CR and VGPR was defined as the percentage of participants who achieved a best response of either CR or VGPR per the Sixth International Workshop in WM. |
| Substudy B: Objective Response Rate (ORR) Determined by Central Assessment Per the Lugano Classification | Up to 2 years | ORR was defined as the percentage of participants who achieved a best response of either CR or PR per the Lugano Classification. |
| Substudy C: ORR Determined by Central Assessment Per the Lugano Classification | Up to 2 years | ORR was defined as the percentage of participants who achieved a best response of either CR or PR per the Lugano Classification. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Substudies (Substudies A, B, C and D): Overall Survival (OS) | Up to 2 years | OS was defined as the time from the date of brexucabtagene autoleucel infusion to the date of death from any cause. |
| All Substudies (Substudies A, B, C and D): Progression Free Survival (PFS) | Up to 2 years | PFS was defined as the time from the date of brexucabtagene autoleucel infusion to the date of PD or death from any cause. PD is defined in outcome measure #6. |
| All Substudies (Substudies A, B, C and D): Time to Next Treatment (TTNT) | Up to 2 years | TTNT defined as the time from the date of brexucabtagene autoleucel infusion to the start of new anti-cancer (including stem cell transplant) therapy prior to documented progression, or death from any cause. KM estimates were used in the outcome measure analysis. |
| All Substudies (Substudies A, B, C and D): Time to First Objective Response | Up to 2 years | Time to first objective response was defined as time from the date of brexucabtagene autoleucel infusion to the date of first response per the Sixth International Workshop in WM for r/rWM, per the Lugano Classification for r/rRT and r/r BL, and per Grever and colleagues for r/rHCL. Objective response (OR) is defined in OM#25 (Substudy B), 28 (Substudy C), and 29 (Substudy D). |
| All Substudies (Substudies A, B, C and D): Time to Best Objective Response | Up to 2 years | Time to best objective response was defined as time from the date of brexucabtagene autoleucel infusion to the date of best response per the Sixth International Workshop in WM for r/rWM, per the Lugano Classification for r/rRT and r/r BL, and per Grever and colleagues for r/rHCL. Objective response (OR) is defined in OM#25 (Substudy B), 28 (Substudy C), and 29 (Substudy D). |
| All Substudies (Substudies A, B, C and D): Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | First infusion date of brexucabtagene autoleucel up to 2 years | TEAE was defined as any adverse event with onset on or after the brexucabtagene autoleucel infusion. |
| All Substudies (Substudies A, B, C and D): Number of Participants With Increase in Laboratory Values Reported as Grade 3 or Higher | First infusion date of brexucabtagene autoleucel up to 2 years | Laboratory results were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CTCAE grading is a standardized system from the NCI that classifies the severity of side effects (adverse events) from cancer treatments, using a 1-5 scale: Grade 1 (Mild), Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life-threatening), and Grade 5 (Death) The incidence of post-infusion worst-grade lab toxicities for all analytes were summarized. |
| All Substudies (Substudies A, B, C and D): Number of Participants With Decrease in Laboratory Values Reported as Grade 3 or Higher | First dose date up to 2 years | Laboratory results were graded according to NCI CTCAE version 5.0. The incidence of post-infusion worst-grade lab toxicities for all analytes were summarized. |
| All Substudies (Substudies A, B, C and D): Number of Participants With Replication-competent Retrovirus (RCR) in Peripheral Blood Mononuclear Cells (PBMCs) | Up to 2 years | — |
| All Substudies (Substudies A, B, C and D): Number of Participants With Deterioration Scores From Screening in the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire-30 (EORTC QLQ-C30) | Day -5, Day 0, Day 28, Month 3, Month 6, Month 9 and Month 12 | EORTC QLQ-C30 is a quality of life (QOL) questionnaire for cancer participants, that has 30 items. 5 functional scales (physical, role, emotional, cognitive, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulties). Scoring of the QLQ-C30 was performed according to QLQ-C30 Scoring manual. Participants with deterioration scores from screening for various questions of EORTC QLQ C-30 are reported. Deterioration was defined as scores at specific time point lesser than scores at baseline. |
| All Substudies (Substudies A, B, C and D): Number of Participants With Deterioration Scores From Screening in the European Quality of Life Five Dimensions Five Levels Questionnaire (EQ-5D-5L) | Day -5, Day 0, Day 28, Month 3, Month 6, Month 9 and Month 12 | EQ-5D-5L was an instrument for use as a measure of health outcome. The EQ-5D-5L consisted of 2 sections: EuroQoL (5 dimensions) (EQ-5D) descriptive system and the EuroQoL visual analogue scale (EQ-VAS). EQ-5D comprised the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension had 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Number of participants with deterioration scores from screening for each category are reported. Deterioration was defined as scores at specific time point lesser than scores at baseline. |
| All Substudies (Substudies A, B, C and D): Change From Screening in the EQ-ED-5L Visual Analogue Scale (EQ-VAS) Score | Screening, Day -5, Day 0, Day 28, Month 3, Month 6, Month 9 and Month 12 | The EQ-VAS recorded the participant's self-rated health on a vertical VAS, where the end points were labeled "the best health you can imagine" and "the worst health you can imagine." The EQ-VAS could be used as a quantitative measure of a health outcome that reflected the participant's own judgment. The EQ-VAS recorded the participant's self-rated health on a vertical VAS, with a score numbered from 0 to 100, where '100 meant the best health you can imagine' and '0 meant the worst health you can imagine". |
| Substudy A: ORR (CR, VGPR, or PR) Determined by Central Assessment Per the Sixth International Workshop in WM | Up to 2 years | ORR was defined as the percentage of participants who achieved a best response of CR, VGPR, or PR per the Sixth International Workshop in WM. |
| Substudy A: Percentage of Participants With Combined CR and VGPR Determined by Investigator Assessment Per the Sixth International Workshop in WM | Up to 2 years | The combined rate of CR and VGPR was defined as the percentage of participants who achieved a best response of either CR or VGPR. |
| Substudy A: PR Rate Determined by Central Assessment Per the Sixth International Workshop in WM | Up to 2 years | PR rate was defined as percentage of participants who achieve PR. |
| Substudy A: VGPR Rate Determined by Central Assessment Per the Sixth International Workshop in WM | Up to 2 years | VGPR rate was defined as percentage of participants who achieve VGPR. |
| Substudy B: Number of Participants With OR Determined by Investigator Assessment Per the Lugano Classification | Up to 2 years | OR: CR (complete metabolic response (CMR)+complete radiological response (CRR))+PR (partial MR response (PMR)+partial RR(PRR)). CMR: score 1(no uptake above background)/2(uptake≤mediastinum)/3(uptake \>mediastinum but ≤liver)with/without a residual mass on positron emission tomography 5-point scale;no new lesions,CRR:target nodes/nodal masses regressed to ≤1.5 cm in longest transverse diameter of lesion (LDi);no extralymphatic sites of disease;absent non-measured lesion(NMLs);organ enlargement regress to normal; no new sites;bone marrow normal by morphology. PMR:score 4(uptake moderately\>liver)/5(uptake markedly\>liver, new lesions) with reduced uptake compared with baseline and residual mass;no new lesions;responding disease at interim/residual disease at end of treatment. PRR:≥50% decrease in sum of product of diameters up to 6 target nodes and extra-nodal sites;absent/ normal,regressed,but no increase of NMLs;spleen regressed by\>50% in length beyond normal. |
| Substudy B: Number of Participants With OR Based on Clonal Relationship to the Underlying CLL by Central Assessment Per the Lugano Classification | Up to 2 years | OR is defined as participants with CR or PR. |
| Substudy B: Number of Participants With OR (CR, CRi, or PR) Determined by Investigator Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 Criteria | Up to 2 years | OR was defined as the number of participants who achieved a best response of either CR, CRi, or PR by investigator assessment per IWCLL 2018 criteria. CR: Lymph nodes- none ≥1.5 cm; Liver or spleen size- Spleen size \<13 cm; liver size normal; Constitutional symptoms, Circulating lymphocyte count- none; Platelet count- ≥100 × 109/L; Hemoglobin- ≥11.0 g/dL (untransfused and without erythropoietin); Marrow- Normocellular, no CLL cells, no B-lymphoid nodules. CRi: ; PR: Lymph nodes- Decrease ≥50% (from baseline); Liver or spleen size- Decrease ≥50% (from baseline); Constitutional symptoms- any, Circulating lymphocyte count- Decrease ≥50% from baseline; Platelet count- ≥100 × 109/L or increase ≥50% over baseline; Hemoglobin-≥11 g/dL or increase ≥50% over baseline; Marrow- Presence of CLL cells, or of B-lymphoid nodules, or not done. |
| Substudy C: Number of Participants With OR Determined by Investigator Assessment Per the Lugano Classification | Up to 2 years | OR was defined as the number of participants who achieved a best response of either CR or PR per the Lugano Classification. CR and PR per Lugano classification is defined in outcome measure #25. |
| All Substudies (Substudies A, B, C and D): Number of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) | First infusion date of brexucabtagene autoleucel up to 28 days | Dose-limiting toxicity is defined as protocol-defined brexucabtagene autoleucel-related events with onset within the first 28 days following brexucabtagene autoleucel infusion. |
| Substudy D: Number of Participants With OR Determined by Investigator Assessment Per Grever and Colleagues | Up to 2 years | OR was defined as the number of participants who achieved a best response of either CR or PR per Grever and colleagues. CR: Near normalization of peripheral blood counts: hemoglobin \>11 g/dL (without transfusion); platelets\>100 000/μL; absolute neutrophil count \>1500/μL. Regression of splenomegaly on physical examination. Absence of morphologic evidence of HCL on both the peripheral blood smear and the bone marrow examination. PR: PR required near normalization of the peripheral blood count (as in CR) with a minimum of 50% improvement in organomegaly and bone marrow biopsy infiltration with HCL. |
| All Substudies (Substudies A, B, C and D): Number of Participants With Positive Anti-brexucabtagene Autoleucel Antibodies | Up to 2 years | — |
| All Substudies (Substudies A, B, C and D): Complete Response (CR) Rate Determined by Central Assessment | Up to 2 years | CR Rate is defined as the percentage of participants with CR. |
| All Substudies (Substudies A, B, C and D): Duration of Response (DOR) | Up to 2 years | DOR was defined as time from first objective response (OR) to disease progression (PD) or death. OR is defined in OM#25 (Substudy B), 28 (Substudy C), and 29 (Substudy D). PD: score 4 (uptake moderately \>liver) or 5 (uptake markedly\>liver and/or new lesions) with an increase in intensity of uptake from baseline; new FDG-avid foci consistent with lymphoma at interim or end of treatment assessment; new FDG-avid foci consistent with lymphoma rather than another etiology (eg, infection, inflammation); new or recurrent FDG-avid foci in bone marrow. |
Countries
Austria, France, Germany, Italy, Netherlands, Spain, Switzerland, United States
Contacts
STUDY_DIRECTORKite Study Director
Kite, A Gilead Company
Participant flow
Recruitment details
Participants were enrolled at study sites in Netherlands, Italy, Germany, Switzerland, Spain, and the United States.
Pre-assignment details
29 participants were screened (Substudy A:1; Substudy B: 10; Substudy C: 16; Substudy D: 2). Substudy A was withdrawn, prior to enrollment of any participants. Therefore, the results below are reported only for Substudies B, C, and D.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Age, Continuous | 56 years STANDARD_DEVIATION 11.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment Germany | 0 Participants |
| Region of Enrollment Italy | 1 Participants |
| Region of Enrollment Netherlands | 4 Participants |
| Region of Enrollment Spain | 0 Participants |
| Region of Enrollment Switzerland | 1 Participants |
| Region of Enrollment United States | 4 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 6 | 5 / 12 | 0 / 1 |
| other Total, other adverse events | 4 / 4 | 10 / 10 | 1 / 1 |
| serious Total, serious adverse events | 3 / 4 | 6 / 10 | 0 / 1 |
Outcome results
None listed