Clinical trial NCT05537766: Study of Brexucabtagene Autoleucel in Adults With Rare B-cell Malignancies
Official title: A Phase 2, Open-Label, Multicenter, Basket Study Evaluating the Efficacy of Brexucabtagene Autoleucel in Adults With Rare B-cell Malignancies (ZUMA-25)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Relapsed/Refractory Waldenstrom Macroglobulinemia
Relapsed/Refractory Richter Transformation
Relapsed/Refractory Burkitt Lymphoma
Relapsed/Refractory Hairy Cell Leukemia
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2022-09-13
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 - 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: 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.

Eligibility 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.

Primary outcomes:
measure: 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)
timeFrame: Up to 5 years
measure: Substudy B: Objective Response Rate (ORR) Determined by Central Assessment per the Lugano Classification
timeFrame: Up to 2 years
measure: Substudy C: ORR Determined by Central Assessment per the Lugano Classification
timeFrame: Up to 2 years
measure: Substudy D: ORR Determined by Central Assessment per the Response Criteria Described by Grever and Colleagues
timeFrame: Up to 5 years
Secondary outcomes:
measure: All Substudies (Substudies A, B, C and D): Complete Response (CR) Rate Determined by Central Assessment
timeFrame: Up to 2 years for substudies B and C; Up to 5 years for substudies A and D
measure: All Substudies (Substudies A, B, C and D): Duration of Response (DOR)
timeFrame: Up to 2 years for substudies B and C; Up to 5 years for substudies A and D
measure: All Substudies (Substudies A, B, C and D): Overall Survival (OS)
timeFrame: Up to 2 years for substudies B and C; Up to 5 years for substudies A and D
measure: All Substudies (Substudies A, B, C and D): Progression Free Survival (PFS)
timeFrame: Up to 2 years for substudies B and C; Up to 5 years for substudies A and D
measure: All Substudies (Substudies A, B, C and D): Time to Next Treatment (TTNT)
timeFrame: Up to 2 years for substudies B and C; Up to 5 years for substudies A and D
measure: All Substudies (Substudies A, B, C and D): Time to First Response
timeFrame: Up to 2 years for substudies B and C; Up to 5 years for substudies A and D
measure: All Substudies (Substudies A, B, C and D): Time to Best Response
timeFrame: Up to 2 years for substudies B and C; Up to 5 years for substudies A and D
measure: All Substudies (Substudies A, B, C and D): Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
timeFrame: 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
measure: All Substudies (Substudies A, B, C and D): Percentage of Participants Experiencing Clinically Significant Changes in Safety Laboratory Values
timeFrame: 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
measure: All Substudies (Substudies A, B, C and D): Percentage of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs)
timeFrame: First infusion date of brexucabtagene autoleucel up to 28 days
measure: All Substudies (Substudies A, B, C and D): Percentage of Participants With Positive Anti-brexucabtagene autoleucel Antibodies
timeFrame: First infusion date Up to 2 years for substudies B and C; First infusion date Up to 5 years for substudies A and D
measure: All Substudies (Substudies A, B, C and D): Percentage of Participants With Replication-competent Retrovirus (RCR) in Peripheral Blood Mononuclear Cells (PBMCs)
timeFrame: Baseline, Month 12
measure: 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
timeFrame: Baseline, up to 24 months
measure: 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
timeFrame: Baseline, Up to 24 months
measure: Substudy A: ORR Determined by Central Assessment
timeFrame: Up to 5 years
measure: Substudy A: Combined CR and VGPR Rate Determined by Investigator Assessment
timeFrame: Up to 5 years
measure: Substudy A: PR Rate Determined by Central Assessment
timeFrame: Up to 5 years
measure: Substudy A: VGPR Rate Determined by Central Assessment
timeFrame: Up to 5 years
measure: Substudy B: ORR Determined by Investigator Assessment per the Lugano Classification
timeFrame: Up to 2 years
measure: Substudy B: ORR Determined by Central Assessment per the Lugano Classification
timeFrame: Up to 2 years
measure: Substudy B: ORR Determined by Investigator per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 Criteria
timeFrame: Up to 2 years
measure: Substudy C: ORR Determined by Investigator Assessment per the Lugano Classification
timeFrame: Up to 2 years
measure: Substudy D: ORR Determined by Investigator Assessment
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope (City of Hope National Medical Center)
state: California
city: Stanford
country: United States
facility: Stanford Cancer Institute
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Centre
state: District of Columbia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center - James Cancer HospitalS
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Vienna
country: Austria
facility: Medical University of Vienna, Department of Internal Medicine I, Div. of Hematology
city: Paris
country: France
facility: Hopital de la Pitie Salpetriere
city: Toulouse Cedex 09
country: France
facility: Centre hospitalier de Toulouse - Hematology department
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Koln
country: Germany
facility: Universitatsklinikum Koln
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero - Universitaria di Bologna
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Perugia
country: Italy
facility: Azienda Ospedale di Perugia - Ospedale S. Maria della Misericordia
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Bellinzona
country: Switzerland
facility: Istituto Oncologico Della Svizzera Italiana (IOSI)
Study officials:
affiliation: Kite, A Gilead Company
name: Kite Study Director
role: STUDY_DIRECTOR
References: