BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma
Summary
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.
Timeline
- Start
- 2018-05-23
- Primary completion
- 2022-04-20
- Completion
- 2022-04-20
Publications
- Cowan AJ, Pont MJ, Sather BD, Turtle CJ, Till BG, Libby EN 3rd, Coffey DG, Tuazon SA, Wood B, Gooley T, Wu VQ, Voutsinas J, Song X, Shadman M, Gauthier J, Chapuis AG, Milano F, Maloney DG, Riddell SR, Green DJ. gamma-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial. Lancet Oncol. 2023 Jul;24(7):811-822. doi: 10.1016/S1470-2045(23)00246-2.
- Pont MJ, Hill T, Cole GO, Abbott JJ, Kelliher J, Salter AI, Hudecek M, Comstock ML, Rajan A, Patel BKR, Voutsinas JM, Wu Q, Liu L, Cowan AJ, Wood BL, Green DJ, Riddell SR. gamma-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019 Nov 7;134(19):1585-1597. doi: 10.1182/blood.2019000050.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | BCMA-specific CAR T-cells | Cell therapy | 50 cells | Intravenous |
| Subject | BCMA-specific CAR T-cells | Cell therapy | 150 cells | Intravenous |
| Subject | BCMA-specific CAR T-cells | Cell therapy | 300 cells | Intravenous |
| Subject | BCMA-specific CAR T-cells | Cell therapy | 450 cells | Intravenous |
| Subject | crenigacestat | Small molecule | 25 mg | Oral |
| Background | Cyclophosphamide | Other / unclassified | — | Intravenous |
| Background | Fludarabine | Small molecule | — | Intravenous |