Study of Brexucabtagene Autoleucel in Adults With Rare B-cell Malignancies (ZUMA-25)

Gilead Sciences

Status and phase: Terminated; Phase 2

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

Treatments: Drug: Fludarabine; Biological: Brexucabtagene Autoleucel; Drug: Cyclophosphamide

Study type: Interventional

Funder types: Industry

Identifiers

NCT05537766

2022-501259-10 (Other Identifier)

KT-US-568-0138

2022-501260-18 (Other Identifier)

2022-501262-21 (Other Identifier)

2022-501261-46 (Other Identifier)

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 19 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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19 participants in 4 patient groups

Substudy A (Relapsed/Refractory Waldenstrom Macroglobulinemia): Brexucabtagene Autoleucel

Experimental group

Description:

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.

Treatment:

Drug: Cyclophosphamide

Biological: Brexucabtagene Autoleucel

Drug: Fludarabine

Substudy B (Relapsed/Refractory Richter Transformation): Brexucabtagene Autoleucel

Experimental group

Description:

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. This arm is no longer recruiting.

Treatment:

Drug: Cyclophosphamide

Biological: Brexucabtagene Autoleucel

Drug: Fludarabine

Substudy C (Relapsed/Refractory Burkitt Lymphoma): Brexucabtagene Autoleucel

Experimental group

Description:

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.

Treatment:

Drug: Cyclophosphamide

Biological: Brexucabtagene Autoleucel

Drug: Fludarabine

Substudy D (Relapsed/Refractory hairy cell leukemia): Brexucabtagene Autoleucel

Experimental group

Description:

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.

Treatment:

Drug: Cyclophosphamide

Biological: Brexucabtagene Autoleucel

Drug: Fludarabine