A Randomized Phase II Trial of Consolidation Therapy Following CD19 CAR T-Cell Treatment for Relapsed/Refractory Diffuse Large B-Cell Lymphoma or Grade IIIB Follicular Lymphoma
Overview
- Phase
- Phase 2
- Intervention
- Axicabtagene Ciloleucel
- Conditions
- Diffuse Large B-Cell Lymphoma
- Sponsor
- SWOG Cancer Research Network
- Enrollment
- 396
- Locations
- 169
- Primary Endpoint
- Progression free survival (PFS)
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This phase II trial tests whether mosunetuzumab and/or polatuzumab vedotin helps benefit patients who have received chemotherapy (fludarabine and cyclophosphamide) followed by chimeric antigen receptor (CAR) T-cell therapy (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel) for diffuse large B-cell lymphoma that has come back (recurrent) or that does not respond to treatment (refractory) or grade IIIb follicular lymphoma. Mosunetuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Polatuzumab vedotin is a monoclonal antibody, called polatuzumab, linked to a drug called vedotin. Polatuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, and delivers vedotin to kill them. Chemotherapy drugs, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving mosunetuzumab and/or polatuzumab vedotin after chemotherapy and CAR T-cell therapy may be more effective at controlling or shrinking the cancer than not giving them.
Detailed Description
PRIMARY OBJECTIVES: I. To compare the progression-free survival in participants with relapsed/refractory large B-cell lymphoma or follicular lymphoma grade 3B with stable disease (SD) or partial remission (PR) on first imaging response by central review (day +30 positron emission tomography \[PET\]/computed tomography \[CT\] scan) after commercial CD19 CAR T-cell therapy who are randomized to receive each consolidation therapy versus those that receive no consolidation therapy (i.e. control). Ia. Specifically, to compare the progression free survival (PFS) of 1) mosunetuzumab consolidation to no consolidation, 2) polatuzumab vedotin consolidation to no consolidation, 3) mosunetuzumab + polatuzumab vedotin to no consolidation. SECONDARY OBJECTIVES: I. To compare overall survival (OS) in participants randomized to each consolidation treatment arm versus control. II. To compare the complete remission (CR) conversion rate up to one year in participants randomized to each consolidation arm versus control. III. To evaluate the treatment-related adverse events in participants randomized to each consolidation arm. IV. To evaluate the association between total metabolic tumor volume (TMTV), standardized uptake value (SUV) max, and sum product (SPD) of diameters by PET-CT at first imaging response with complete remission conversion up to one year in participants randomized to each consolidation arm as well as those randomized to control. V. To evaluate the overall response rate (ORR), CR rate, PFS, and OS of participants randomized to Arm 4 (observation) who have lymphoma progression within 12 months of CAR T-cell infusion and subsequently 'cross-over' to receive treatment with mosunetuzumab + polatuzumab vedotin. VI. To estimate overall survival for all patients registered to this study. VII. To assess the difference in overall survival between participants who achieved CR at first imaging (day +30) versus those who did not achieve CR at first imaging. BANKING OBJECTIVES: I. To bank specimens for future correlative studies. II. To bank PET-CT images for future correlative studies. OUTLINE: STEP I: Patients receive lymphodepleting chemotherapy consisting of fludarabine intravenously (IV) and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study. STEP II: Patients are randomized to 1 of 4 arms. ARM I: Patients receive mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. ARM II: Patients receive polatuzumab vedotin IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. ARM III: Patients receive polatuzumab vedotin IV and mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. ARM IV: Patients undergo observation on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. Patients with subsequent progression within 12 months of CAR T-cell therapy may crossover to Arm III.
Investigators
Eligibility Criteria
Inclusion Criteria
- •STEP 1: REGISTRATION: Participants must have a histologically confirmed diagnosis of diffuse large B-cell lymphoma or follicular lymphoma grade 3b or primary mediastinal large B-cell lymphoma (PMBCL)
- •STEP 1: REGISTRATION: Participants with transformed DLBCL must have transformed DLBCL from follicular or marginal zone lymphoma
- •STEP 1: REGISTRATION: Participant must have bi-dimensionally measurable systemic disease (at least one lesion with longest diameter \> 1.5 cm)
- •STEP 1: REGISTRATION: Participants with secondary central nervous system (CNS) lymphoma (parenchymal, spinal cord, meningeal, cerebrospinal fluid involvement) must be asymptomatic from their CNS disease
- •STEP 1: REGISTRATION: Participants must be registered for step 1 after they have signed institutional consent for CAR T-cell leukapheresis but prior to the start of lymphodepleting (LD) chemotherapy for commercial CAR T-cell product
- •STEP 1: REGISTRATION: In the opinion of the enrolling physician, participants must be felt to be a candidate for CAR T-cell therapy with plans to be treated with Food and Drug Administration (FDA) approved commercially available CD19 CAR T-cell construct.
- •Participants must qualify for commercially approved CD19 CAR T-cell therapy per FDA package insert.
- •If the CAR T-cell product does not meet parameters to be given as an FDA approved product (i.e. does not meet specification criteria mandated by FDA and is infused under an expanded access protocol \[EAP\] or single participant investigational new drug \[IND\]) the participant will be taken off of study and no longer be eligible for step 2 randomization
- •STEP 1: REGISTRATION: Participants are permitted to receive or have received 'bridging therapy' after CAR T-cell leukapheresis. However, participants must not receive polatuzumab vedotin, and/or mosunetuzumab as part of bridging therapy.
- •Bridging therapy is defined as lymphoma directed therapy administered between leukapheresis and the start of LD chemotherapy. This includes cytotoxic chemotherapy (e.g.: bendamustine and rituximab \[BR\], rituximab, gemcitabine and oxaliplatin \[R-gem/ox\]), radiation, corticosteroids, as well as novel therapies such as BTK inhibitors (e.g.: Ibrutinib), immunomodulators (e.g.: lenalidomide), monoclonal antibodies (e.g.: rituximab, obinutuzumab, tafasitamab) antibody drug conjugates (e.g: loncastuximab), checkpoint inhibitors (e.g.: pembrolizumab, nivolumab), clinical trial treatments, etc.
Exclusion Criteria
- Not provided
Arms & Interventions
Step I (lymphodepleting chemotherapy)
Patients receive lymphodepleting chemotherapy consisting of fludarabine IV and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study.
Intervention: Axicabtagene Ciloleucel
Step I (lymphodepleting chemotherapy)
Patients receive lymphodepleting chemotherapy consisting of fludarabine IV and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study.
Intervention: Cyclophosphamide
Step I (lymphodepleting chemotherapy)
Patients receive lymphodepleting chemotherapy consisting of fludarabine IV and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study.
Intervention: Fludarabine
Step I (lymphodepleting chemotherapy)
Patients receive lymphodepleting chemotherapy consisting of fludarabine IV and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study.
Intervention: Lisocabtagene Maraleucel
Step I (lymphodepleting chemotherapy)
Patients receive lymphodepleting chemotherapy consisting of fludarabine IV and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study.
Intervention: Positron Emission Tomography
Step I (lymphodepleting chemotherapy)
Patients receive lymphodepleting chemotherapy consisting of fludarabine IV and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study.
Intervention: Tisagenlecleucel
Step II Arm III (polatuzumab vedotin, mosunetuzumab)
Patients receive polatuzumab vedotin IV and mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Biospecimen Collection
Step II Arm I (mosunetuzumab)
Patients receive mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Biospecimen Collection
Step II Arm I (mosunetuzumab)
Patients receive mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Computed Tomography
Step II Arm I (mosunetuzumab)
Patients receive mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Mosunetuzumab
Step II Arm I (mosunetuzumab)
Patients receive mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Positron Emission Tomography
Step II Arm II (polatuzumab vedotin)
Patients receive polatuzumab vedotin IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Biospecimen Collection
Step II Arm II (polatuzumab vedotin)
Patients receive polatuzumab vedotin IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Computed Tomography
Step II Arm II (polatuzumab vedotin)
Patients receive polatuzumab vedotin IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Polatuzumab Vedotin
Step II Arm II (polatuzumab vedotin)
Patients receive polatuzumab vedotin IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Positron Emission Tomography
Step II Arm III (polatuzumab vedotin, mosunetuzumab)
Patients receive polatuzumab vedotin IV and mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Computed Tomography
Step II Arm III (polatuzumab vedotin, mosunetuzumab)
Patients receive polatuzumab vedotin IV and mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Mosunetuzumab
Step II Arm III (polatuzumab vedotin, mosunetuzumab)
Patients receive polatuzumab vedotin IV and mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Polatuzumab Vedotin
Step II Arm III (polatuzumab vedotin, mosunetuzumab)
Patients receive polatuzumab vedotin IV and mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study.
Intervention: Positron Emission Tomography
Step II Arm IV (observation)
Patients undergo observation on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. Patients with subsequent progression within 12 months of CAR T-cell therapy may crossover to Arm III.
Intervention: Biospecimen Collection
Step II Arm IV (observation)
Patients undergo observation on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. Patients with subsequent progression within 12 months of CAR T-cell therapy may crossover to Arm III.
Intervention: Computed Tomography
Step II Arm IV (observation)
Patients undergo observation on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. Patients with subsequent progression within 12 months of CAR T-cell therapy may crossover to Arm III.
Intervention: Patient Observation
Step II Arm IV (observation)
Patients undergo observation on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. Patients with subsequent progression within 12 months of CAR T-cell therapy may crossover to Arm III.
Intervention: Positron Emission Tomography
Outcomes
Primary Outcomes
Progression free survival (PFS)
Time Frame: From date of randomization to date of first observation of progressive disease or death due to any cause, assessed up to 2 years
Will compare PFS in participants with relapsed/refractory large B-cell lymphoma or follicular lymphoma grade 3B with stable disease (SD) or partial remission (PR) on first imaging response (day +30 positron emission tomography \[PET\]/computed tomography \[CT\] scan) after commercial CD19 chimeric antigen receptor (CAR) T-cell therapy who are randomized to receive each consolidation therapy versus those that receive no consolidation therapy (i.e. control). Specifically, will compare the PFS of 1) mosunetuzumab consolidation to no consolidation, 2) polatuzumab vedotin consolidation to no consolidation, 3) mosunetuzumab + polatuzumab vedotin to no consolidation. Will analyze results by arm rather than assuming no-interactions in some factorial analyses. Will follow multi-step hypothesis testing procedure of Freidlin and Korn to compare the arms within this randomized Phase II study. Each of the primary comparisons has 81% power using a stratified logrank test at one-sided alpha of 0.05.
Secondary Outcomes
- Conversion of CR(Up to 2 years)
- Overall survival (OS)(From date of randomization to date of death due to any cause, assessed up to 2 years)
- Complete remission (CR) conversion rate(Up to 1 year after randomization)
- Incidence of adverse events(Up to 2 years)
- Association between total metabolic tumor volume (TMTV), standardized uptake value (SUV) max, and sum product (SPD) of diameters(Up to 2 years)