Testing Drug Treatments after CAR T-cell Therapy in Patients with Diffuse Large B-cell Lymphoma That Has Come Back or Not Responded to Treatment

Active:	Yes
Cancer Type:	Hematopoietic Malignancies Lymphoma Non-Hodgkin Lymphoma Unknown Primary	NCT ID:	NCT05633615
Trial Phases:	Phase II	Protocol IDs:	S2114 (primary) S2114 NCI-2022-07930
Eligibility:	18 Years and older, Male and Female	Study Type:	Treatment
Study Sponsor:	SWOG
NCI Full Details:	http://clinicaltrials.gov/show/NCT05633615

Summary

This phase II trial tests how mosunetuzumab with or without polatuzumab vedotin works in treating patients undergoing chemotherapy followed by chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma that has come back (recurrent) or does not respond to treatment (refractory) or in patients with grade IIIB follicular lymphoma. Mosunetuzumab is a monoclonal antibody that binds to a protein called CD3, which is found on T cells (a type of white blood cell). It also binds to a protein called CD20, which is found on B cells (another type of white blood cell) and some lymphoma cells. This may help the immune system kill cancer cells. Polatuzumab vedotin is a monoclonal antibody called polatuzumab, linked to an anticancer drug called vedotin. Polatuzumab vedotin attaches to specific molecules (receptors) called CD79B, which is found on B cells and some lymphoma cells and delivers vedotin to kill them. It is a form of targeted therapy and a type of antibody-drug conjugate. Fludarabine is in a class of medications called purine analogs. It stops cells from making DNA and may kill cancer cells. It is a type of antimetabolite. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell’s DNA and may kill cancer cells. It may also lower the body’s immune response. CAR T-cell therapy is a type of treatment in which a patient's T cells 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 with or without polatuzumab vedotin after chemotherapy and CAR T-cell therapy may be more effective at controlling or shrinking relapsed/refractory diffuse large B-cell lymphoma or grade IIIB follicular lymphoma than not giving them.

Objectives

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. 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 days 1-3. Patients then receive tisagenlecleucel IV between days 6-15, axicabtagene ciloleucel IV on day 6 or lisocabtagene maraleucel IV between days 6-11. Patients also undergo PET-CT imaging.

STEP II: Patients are randomized to 1 of 4 arms.

ARM I: Patients receive mosunetuzumab IV over 4 hours on days 1, 8, and 15 of cycle 1, followed by day 1 of each subsequent cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET-CT or CT imaging and collection of blood and tissue samples throughout the study.

ARM II: Patients receive polatuzumab vedotin IV per institutional guidelines on day 1 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET-CT or CT imaging and collection of blood and tissue samples throughout the study.

ARM III: Patients receive polatuzumab vedotin IV per institutional guidelines on day 1 of cycles 2-7 and mosunetuzumab IV over 4 hours on days 1, 8, and 15 of cycle 1, followed by day 1 of each subsequent cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo PET-CT or CT imaging and collection of blood and tissue samples throughout the study.

ARM IV: Patients undergo observation over 90 minutes. Patients also undergo PET-CT or CT imaging and 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.

After completion of study treatment, patients who receive CAR T-cell infusion and who are ineligible for Step 2 randomization will be followed every 3 months for 2 years, then every 6 months until 5 years after Step 1 registration, or progression, or death, whichever occurs first.

Treatment Sites in Georgia

Winship Cancer Institute of Emory University
1365 Clifton Road NE
Building C
Atlanta, GA 30322
404-778-5180
winshipcancer.emory.edu

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