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.
|Trial Phase||Phase 1|
The following criteria is a partial list of reasons why patients may or may not be eligible to participate in this clinical trial. Further evaluation with a medical professional will be required to determine full eligibility.
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December 12, 2021
From June 2018 to March 2021, 18 patients underwent leukapheresis, run-in with JSMD194, and treatment with BCMA CAR T cells. The median age was 65 years, and patients had received a median of 10 prior lines of therapy (range, 4-19). 67% of patients were refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, 72% had high-risk cytogenetic features, and 28% had extramedullary disease. 7/18 (39%) had prior BCMA targeted therapy; other BCMA targeted CAR T cell products had previously been administered to 4/18 patients (22%). All 18 treated patients completed the 5-day run-in with JSMD194. After three oral doses of GSI, increased from a median of 610 to 9563 receptors per cell, or a median of 12-fold (range, 0.2-fold to 157-fold; Figure 1). The only patient that did not demonstrate an increase in BCMA ABC after GSI run-in had previously received BCMA targeted therapy and BCMA expression at screening was virtually absent. 5 patients were treated at 5x107 CAR+ cells, 3 were treated at 15x107 CAR+ cells, 3 were treated at 30x107 CAR+ cells, and 7 were treated at 45x107 CAR+ cells dose levels. Treatment was consistent with other BCMA CAR T therapy, with manageable toxicities. One patient experienced a DLT. 95% of patients experienced cytokine release syndrome (CRS), mostly grade 1-2 (83%), and 66% of patients experienced ICANS, predominantly grades 1-2. The overall response rate was 89%, with 14 patients achieving ≥ VGPR, and 8 patients achieving CR (including 5 with sCR). Deep responses were observed at all dose levels; including the first patient treated on trial at (dose level 1) who has maintained a stringent CR (sCR) for over 35 months and 3 of 5 patients at dose level 1 had no evidence of progressive disease for >18 months. With a median follow-up of 20 months, the median PFS is 11 months (95% CI, 6 mos to not reached). Amongst patients without prior exposure to BCMA targeted therapy (n=11), the median PFS has not been reached, while amongst those previously exposed to BCMA targeted therapy (n=7), the median PFS was 2 months.
December 07, 2019
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