Study of Brexucabtagene Autoleucel in Adults With Rare B-cell Malignancies

Study Overview
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Brief Summary
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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 - no longer recruiting), relapsed/refractory Richter transformation (r/r RT) (Substudy B), relapsed/refractory Burkitt lymphoma (r/r BL) (Substudy C and relapsed/refractory hairy cell leukemia (r/r HCL) (Substudy D - no longer recruiting).

Detailed Description
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Master protocol: The primary objective of this study is to evaluate the efficacy of brexucabtagene autoleucel in two rare B-cell malignancies. 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. Substudies A and D have been early terminated by the sponsor.

Official Title
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A Phase 2, Open-Label, Multicenter, Basket Study Evaluating the Efficacy of Brexucabtagene Autoleucel in Adults With Rare B-cell Malignancies (ZUMA-25)

Conditions
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Relapsed/Refractory Waldenstrom Macroglobulinemia, Relapsed/Refractory Richter Transformation, Relapsed/Refractory Burkitt Lymphoma, Relapsed/Refractory Hairy Cell Leukemia

Intervention / Treatment
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* Biological: Brexucabtagene Autoleucel
* Drug: Cyclophosphamide
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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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 CAR therapy or treatment with any anti-CD19 therapy. 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/uL. 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 CNS involvement. Individuals with a prior history of CNS involvement are eligible if they show a negative CSF and no involvement by imaging. Substudies A and D have been early terminated by the sponsor. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy A (Relapsed/Refractory Waldenstrom Macroglobulinemia): Brexucabtagene Autoleucel<br>Participants will receive fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day lymphodepletion chemotherapy for 3 days followed by a single infusion of brexucabtagene autoleucel at target dose of 2 × 10^6 anti-CD19 chimeric antigen receptor (CAR) T cells/kg. This arm is no longer recruiting. | Biological: Brexucabtagene Autoleucel<br>* Administered intravenously<br>* Other names: KTE-X19;Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|
| Experimental: Substudy B (Relapsed/Refractory Richter Transformation): Brexucabtagene Autoleucel<br>Participants will receive fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day lymphodepletion chemotherapy for 3 days followed by a single infusion of brexucabtagene autoleucel at target dose of 2×10^6 anti-CD19 CAR T cells/kg. | Biological: Brexucabtagene Autoleucel<br>* Administered intravenously<br>* Other names: KTE-X19;Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|
| Experimental: Substudy C (Relapsed/Refractory Burkitt Lymphoma): Brexucabtagene Autoleucel<br>Participants will receive fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day lymphodepletion chemotherapy for 3 days followed by a single infusion of brexucabtagene autoleucel at a target dose of 2x10^6 anti-CD19 CAR T cells/kg. | Biological: Brexucabtagene Autoleucel<br>* Administered intravenously<br>* Other names: KTE-X19;Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|
| Experimental: Substudy D (Relapsed/Refractory hairy cell leukemia): Brexucabtagene Autoleucel<br>Participants will receive fludarabine 30 mg/m^2/day and cyclophosphamide 500 mg/m^2/day lymphodepletion chemotherapy for 3 days followed by a single infusion of brexucabtagene autoleucel at a target dose of 2 × 10^6 anti-CD19 CAR T cells/kg. This arm is no longer recruiting. | Biological: Brexucabtagene Autoleucel<br>* Administered intravenously<br>* Other names: KTE-X19;Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Combined rate is defined as the proportion of participants who achieve either CR or VGPR. | Up to 5 years | 
| Substudy B: Objective Response Rate (ORR) Determined by Central Assessment per the Lugano Classification | ORR is defined as the proportion of participants who achieve a best response of either CR or partial response (PR). | Up to 2 years | 
| Substudy C: ORR Determined by Central Assessment per the Lugano Classification | ORR is defined as the proportion of participants who achieve a best response of either CR or PR. | Up to 2 years | 
| Substudy D: ORR Determined by Central Assessment per the Response Criteria Described by Grever and Colleagues | ORR is defined as the proportion of participants who achieve either CR or PR. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Substudies (Substudies A, B, C and D): Complete Response (CR) Rate Determined by Central Assessment | CR rate is defined as proportion of participants who achieve CR. | Up to 2 years for substudies B and C; Up to 5 years for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Duration of Response (DOR) | DOR is defined as time from first objective response to disease progression per indication specific response criteria or death from any cause. | Up to 2 years for substudies B and C; Up to 5 years for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Overall Survival (OS) | OS is defined as the time from enrollment or brexucabtagene autoleucel infusion to death from any cause. | Up to 2 years for substudies B and C; Up to 5 years for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Progression Free Survival (PFS) | PFS is defined as the time from enrollment or brexucabtagene autoleucel infusion to disease progression per indication specific response criteria or death from any cause. | Up to 2 years for substudies B and C; Up to 5 years for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Time to Next Treatment (TTNT) | TTNT defined as the time from enrollment or brexucabtagene autoleucel infusion to the initiation of subsequent anticancer treatment. | Up to 2 years for substudies B and C; Up to 5 years for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Time to First Response | Time to first response is defined as the time from enrollment or brexucabtagene autoleucel infusion to first objective response. | Up to 2 years for substudies B and C; Up to 5 years for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Time to Best Response | Time to best response is defined as the time from enrollment or brexucabtagene autoleucel infusion to best objective response. | Up to 2 years for substudies B and C; Up to 5 years for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) |  | First infusion date up to 2 years plus 30 days for substudies B and C; First infusion date up to 5 years plus 30 days for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Percentage of Participants Experiencing Clinically Significant Changes in Safety Laboratory Values |  | First infusion date up to 2 years plus 30 days for substudies B and C; First infusion date up to 5 years plus 30 days for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Percentage of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) | Dose-limiting toxicity is defined as protocol-defined brexucabtagene autoleucel-related events with onset within the first 28 days following brexucabtagene autoleucel infusion. | First infusion date of brexucabtagene autoleucel up to 28 days | 
| All Substudies (Substudies A, B, C and D): Percentage of Participants With Positive Anti-brexucabtagene autoleucel Antibodies |  | First infusion date Up to 2 years for substudies B and C; First infusion date Up to 5 years for substudies A and D | 
| All Substudies (Substudies A, B, C and D): Percentage of Participants With Replication-competent Retrovirus (RCR) in Peripheral Blood Mononuclear Cells (PBMCs) |  | Baseline, Month 12 | 
| All Substudies (Substudies A, B, C and D): Change From Baseline in the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire-30 (EORTC QLQ-C30) Score | The EORTC-QLQ-C30 is a multi-item questionnaire measuring the following content five (5) multi-item functional scales, six (6) multi-item symptom scales, one (1) global health status scale, and one (1) global health-related quality of life (HRQoL) each scale is measured from 0 to 100 after a linear transformation. Higher scores for functioning scales and for the Global Health Status or Global HRQoL scales indicate a higher level of functioning and a better HRQoL respectively, whereas higher scores in symptom scales represent a higher level of symptoms. | Baseline, up to 24 months | 
| All Substudies (Substudies A, B, C and D): Changes From Baseline in the European Quality of Life Five Dimensions Five Levels Questionnaire (EQ-5D-5L) Score | The EQ-5D-5L questionnaire is a generic measure of health status that provides a simple descriptive profile and a single index value. The EQ-5D-5L comprises 2 components: a questionnaire covering 5 dimensions and a tariff of values based upon direct valuations of health states using a visual analog scale (VAS). Rating gets recorded on a vertical VAS in which the endpoints are labeled best imaginable health state is 100 (on the top) and worst imaginable health state is 0 (on the bottom). Higher scores of EQ VAS indicate better health. | Baseline, Up to 24 months | 
| Substudy A: ORR Determined by Central Assessment | ORR is defined as the proportion of participants who achieve a best response of CR, VGPR, or PR. | Up to 5 years | 
| Substudy A: Combined CR and VGPR Rate Determined by Investigator Assessment | Combined rate is defined as the proportion of participants who achieve either CR or VGPR. | Up to 5 years | 
| Substudy A: PR Rate Determined by Central Assessment | PR rate is defined as proportion of participants who achieve PR. | Up to 5 years | 
| Substudy A: VGPR Rate Determined by Central Assessment | VGPR rate is defined as proportion of participants who achieve VGPR. | Up to 5 years | 
| Substudy B: ORR Determined by Investigator Assessment per the Lugano Classification | ORR is defined as the proportion of participants who achieve a best response of either CR or PR. | Up to 2 years | 
| Substudy B: ORR Determined by Central Assessment per the Lugano Classification | ORR is defined as the proportion of participants who achieve a best response of either CR or PR, in subgroups by clonal relationship to the underlying CLL. Clonality will be assessed by central assessment. | Up to 2 years | 
| Substudy B: ORR Determined by Investigator per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 Criteria | ORR is defined as the proportion of participants who achieve a best response of either CR, complete response with incomplete marrow recovery (CRi) or PR. | Up to 2 years | 
| Substudy C: ORR Determined by Investigator Assessment per the Lugano Classification | ORR is defined as the proportion of participants who achieve a best response of either CR or PR. | Up to 2 years | 
| Substudy D: ORR Determined by Investigator Assessment | ORR is defined as the proportion of participants who achieve either CR or PR. | Up to 5 years |