A Phase I Study of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells in Combination With JSMD194, a Small Molecule Inhibitor of Gamma Secretase, in Patients With Relapsed or Persistent Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- Fludarabine
- Conditions
- Recurrent Plasma Cell Myeloma
- Sponsor
- Fred Hutchinson Cancer Center
- Enrollment
- 19
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD) of chimeric antigen receptor (CAR) T cells
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief 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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Eastern Cooperative Oncology Group (ECOG) performance status score =\< 2
- •Have measurable disease by International Myeloma Working Group (IMWG) criteria based on one or more of the following findings:
- •Serum monoclonal immunoglobulin (M-protein) \>= 1 g/dL
- •Urine M-protein \>= 200 mg/24 hour
- •Involved serum free light chain (sFLC) level \>= 10 mg/dL with abnormal kappa/lambda ratio
- •Measurable biopsy-proven plasmacytomas (\>= 1 lesion that has a single diameter \>= 2 cm)
- •Bone marrow plasma cells \>= 30%
- •Have a diagnosis of multiple myeloma (MM); the MM diagnosis must be confirmed by internal pathology review of a fresh biopsy specimen at the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance (FHCRC/SCCA)
- •Have relapsed or treatment refractory disease with \>= 10% CD138+ malignant plasma cells immunohistochemistry (IHC) on BM core biopsy, either:
- •Following autologous stem-cell transplantation (ASCT)
Exclusion Criteria
- •History of another primary malignancy that requires intervention beyond surveillance or that has not been in remission for at least 1 year (the following are exempt from the 1-year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, curatively treated superficial bladder cancer and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear)
- •Active hepatitis B, hepatitis C at the time of screening
- •Patients who are human immunodeficiency virus (HIV) seropositive
- •Subjects with uncontrolled active infection
- •\> 1 hospital admission for infection in prior 6 months
- •Presence of acute or chronic graft-versus-host disease (GVHD) unless limited to skin involvement and managed with topical steroid therapy alone
- •History of any one of the following cardiovascular conditions within the past 6 months: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease as determined by the principal investigator (PI) or designee
- •History of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis, active central nervous system MM involvement and/or carcinomatous meningitis; subjects with previously treated central nervous systems involvement may participate, provided they are free of disease in the CNS (documented by flow cytometry performed on the cerebrospinal fluid \[CSF\] within 14 days of enrollment) and have no evidence of new sites of CNS activity
- •Pregnant or breastfeeding females
- •Allogeneic hematopoietic stem cell transplantation (HSCT) or donor lymphocyte infusion within 90 days of leukapheresis
Arms & Interventions
Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells IV over 20-30 minutes on day 0 and LY3039478 PO on days 2, 4, 7, 9, 11, 14, 16, and 18.
Intervention: Fludarabine
Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells IV over 20-30 minutes on day 0 and LY3039478 PO on days 2, 4, 7, 9, 11, 14, 16, and 18.
Intervention: BCMA-specific CAR-expressing T Lymphocytes
Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells IV over 20-30 minutes on day 0 and LY3039478 PO on days 2, 4, 7, 9, 11, 14, 16, and 18.
Intervention: Cyclophosphamide
Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells IV over 20-30 minutes on day 0 and LY3039478 PO on days 2, 4, 7, 9, 11, 14, 16, and 18.
Intervention: Gamma-Secretase Inhibitor LY3039478
Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells IV over 20-30 minutes on day 0 and LY3039478 PO on days 2, 4, 7, 9, 11, 14, 16, and 18.
Intervention: Laboratory Biomarker Analysis
Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells IV over 20-30 minutes on day 0 and LY3039478 PO on days 2, 4, 7, 9, 11, 14, 16, and 18.
Intervention: Pharmacokinetic Study
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD) of chimeric antigen receptor (CAR) T cells
Time Frame: Up to 28 days following CAR T-cell infusion
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.
Incidence of general toxicities
Time Frame: Up to 1 year
This will be measured according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Secondary Outcomes
- Objective response rate of complete remission and partial remission(Up to 1 year)
- Progression-free survival(Up to 1 year)
- Overall survival(Up to 1 year)
- Duration of persistence of adoptively transferred B-cell maturation antigen (BCMA) CAR T cells(Up to 1 year)
- Evaluation of the migration of adoptively transferred BCMA CAR T cells(Up to 1 year)