This phase I trial determines the side effects and best dose of B-cell maturation antigen (BCMA)-chimeric antigen receptor (CAR) T-cells when combined with gamma-secretase inhibitor LY3039478 (JSMD194), cyclophosphamide, and fludarabine in treating participants with multiple myeloma that that has come back or remains despite treatment. Placing genes added in the laboratory into immune T-cells may make the T-cells recognize BCMA, a protein on the surface of cancer cells. JSMD194 may enhance the killing of cancer cells by increasing the BCMA expression on multiple myeloma cells, making the targeted BCMA CAR-T treatment more effective. JSMD194 also decreases the amount of BCMA found in the circulation (called soluble BCMA) that is not bound to the myeloma cells. JSMD194 can therefore reduce the potential for soluble BCMA to act as a decoy. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, 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. Giving BCMA CAR T therapy with JSMD194, cyclophosphamide, and fludarabine may work better in treating participants with relapsed or persistent multiple myeloma.
OUTLINE: This is a dose escalation study of BCMA-specific CAR T-cells. Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells intravenously (IV) over 20-30 minutes on day 0 and gamma-secretase inhibitor LY3039478 orally (PO) on days 2, 4, 7, 9, 11, 14, 16, and 18. Patients will also receive JSMD194 orally before the fludarabine and cyclophosphamide to evaluate the effect of this drug alone on multiple myeloma cell BCMA levels. After completion of study treatment, participants are followed up every 6 months for years 1-5 and annually for years 6-15.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
19
Receive CAR T infusion
Given IV
Given IV
Given PO
Correlative studies
Correlative studies
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Maximum tolerated dose (MTD) of chimeric antigen receptor (CAR) T cells
This is defined as the dose associated with a true dose-limiting toxicity (DLT) rate of 25% in each of the cohorts. DLTs are events that occur within the first 28 days following CAR T-cell infusion.
Time frame: Up to 28 days following CAR T-cell infusion
Incidence of general toxicities
This will be measured according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Time frame: Up to 1 year
Objective response rate of complete remission and partial remission
Time frame: Up to 1 year
Progression-free survival
Time frame: Up to 1 year
Overall survival
Time frame: Up to 1 year
Duration of persistence of adoptively transferred B-cell maturation antigen (BCMA) CAR T cells
Time frame: Up to 1 year
Evaluation of the migration of adoptively transferred BCMA CAR T cells
Time frame: Up to 1 year
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