Phase I Study to Evaluate Cellular Immunotherapy Using Memory-Enriched T Cells Lentivirally Transduced to Express a CS1-Targeting, Hinge-Optimized, 41BB-Costimulatory Chimeric Antigen Receptor and a Truncated EGFR Following Lymphodepleting Chemotherapy in Adult Patients With CS1+ Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- Cyclophosphamide
- Conditions
- Recurrent Plasma Cell Myeloma
- Sponsor
- City of Hope Medical Center
- Enrollment
- 30
- Locations
- 2
- Primary Endpoint
- Incidence of all other toxicities
- Status
- Recruiting
- Last Updated
- 17 days ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of CS1-chimeric antigen receptor (CAR) T therapy after chemotherapy in treating patients who have CS1 positive multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Immune cells can be engineered to kill multiple myeloma cells by inserting a piece of deoxyribonucleic acid (DNA) into the immune cells using a lentiviral vector such as CS1, that allows them to recognize multiple myeloma cells. These engineered immune cells, CS1-CAR T cells, may kill multiple myeloma cells.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the safety and tolerability of intravenous (i.v.) delivered autologous CS1-CAR T cells for research participants with CS1+ recurrent/refractory multiple myeloma (MM). SECONDARY OBJECTIVES: I. Evaluate the response rates at days 28, 100, and 180 post CAR T cell infusion. II. Measure the persistence of CS1-CAR T cells in blood and marrow. III. Measure phenotype and anti-tumor functionality of CS1-CAR T cells in marrow and blood. IV. Measure the levels of cytokines in blood and marrow, and soluble CS-1 in blood post infusion as a surrogate indicator of CAR T cell activity. V. Evaluate CS-1 expression on MM cancer cells before, during and at progressive disease (PD) to determine antigenic loss. EXPLORATORY OBJECTIVE: I. Describe the percentage of MM cells that express CS-1 surface marker before, during and at PD. OUTLINE: This is a dose-escalation study of CS1-CAR T cells. Patients undergo leukapheresis over 2-4 hours. Beginning 3-4 weeks, patients receive cyclophosphamide intravenously (IV) on days -4 and/or -3 or fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients then undergo CS1-CAR T therapy over 10-15 minutes on day 0. After completion of study treatment, patients are followed up at 1 day, at least every 2 days for up to a minimum of 14 days, weekly for 1 month, monthly for 1 year, then periodically for up to 15 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Documented informed consent of the participant and/or legally authorized representative.
- •Assent, when appropriate, will be obtained per institutional guidelines.
- •Karnofsky Performance Status (KPS) of \>= 70%.
- •Life expectancy \>= 16 weeks.
- •Participant must have a confirmed diagnosis of active MM as defined by the International Myeloma Working Group (IMWG) criteria.
- •Participant must have a confirmed CS1+ MM as evaluated by City of Hope (COH) Pathology Core.
- •Participant must have measurable disease defined as meeting at least one of the criteria below:
- •Serum M-protein \>= 0.5 g/dL.
- •Urine M-protein \>= 200 mg/24 hour.
- •Involved serum free light chain (sFLC) level \>= 10 mg/dL with abnormal kappa/lambda ratio.
Exclusion Criteria
- •Prior allogeneic stem cell transplantation.
- •Autologous transplantation =\< 90 days of enrollment.
- •Growth factors within 14 days of enrollment.
- •Platelet transfusions within 7 days of enrollment.
- •Epstein-Barr virus (EBV) positivity by polymerase chain reaction (PCR) at the time of enrollment
- •Participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy.
- •Participants with known additional malignancy that is progressing or required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
- •Participants with toxicities from prior therapies, with the exception of peripheral neuropathy attributable to bortezomib, that have not recovered to grade =\< 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria or to the subject's prior baseline.
- •Participants with known active hepatitis B or C infection; research participants who are human immunodeficiency virus (HIV) positive based on testing performed within 4 weeks of enrollment; research participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections.
- •Participants with active auto-immune disease, including connective tissue disease, sarcoidosis, multiple sclerosis, inflammatory bowel disease or have a history of severe (as judged by the principal investigator) autoimmune disease that will require prolonged immunosuppressive therapy.
Arms & Interventions
Treatment (leukapheresis, chemotherapy, CS-1 CAR T therapy)
Patients undergo leukapheresis over 2-4 hours. Beginning 3-4 weeks, patients receive cyclophosphamide IV on days -4 and/or -3 or fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients then undergo CS1-CAR T therapy over 10-15 minutes on day 0.
Intervention: Cyclophosphamide
Treatment (leukapheresis, chemotherapy, CS-1 CAR T therapy)
Patients undergo leukapheresis over 2-4 hours. Beginning 3-4 weeks, patients receive cyclophosphamide IV on days -4 and/or -3 or fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients then undergo CS1-CAR T therapy over 10-15 minutes on day 0.
Intervention: CS1-CAR T Therapy
Treatment (leukapheresis, chemotherapy, CS-1 CAR T therapy)
Patients undergo leukapheresis over 2-4 hours. Beginning 3-4 weeks, patients receive cyclophosphamide IV on days -4 and/or -3 or fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients then undergo CS1-CAR T therapy over 10-15 minutes on day 0.
Intervention: Leukapheresis
Treatment (leukapheresis, chemotherapy, CS-1 CAR T therapy)
Patients undergo leukapheresis over 2-4 hours. Beginning 3-4 weeks, patients receive cyclophosphamide IV on days -4 and/or -3 or fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients then undergo CS1-CAR T therapy over 10-15 minutes on day 0.
Intervention: Fludarabine
Outcomes
Primary Outcomes
Incidence of all other toxicities
Time Frame: Up to 15 years
Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Will include cytokine release syndrome (CRS) based on the revised CRS grading system, and heart failure based on New York Heart Association criteria.
Incidence of dose-limiting toxicity (DLT) and all other toxicities
Time Frame: Up to 12 months
Tables will be created to summarize all toxicities and side effects by organ, severity (Common Terminology Criteria for Adverse Events version 5.0), and attribution. Rates and associated 90% confidence limits will be estimated for participants experiencing DLTs.
Opportunistic infections
Time Frame: Up to 15 years
Prolonged lymphopenia (lasting more than 12 weeks)
Time Frame: Up to 15 years
Secondary Outcomes
- Cytokine and soluble CS-1 levels in blood and marrow(Up to 15 years)
- Progression-free survival(At 12 months)
- Disease response(Up to 180 days)
- Expansion/persistence of chimeric antigen receptor (CAR) T cells(At 28 days post CAR T cell infusion)
- Phenotype and anti-tumor functionality of modified T cells in marrow and blood(Up to 15 years)
- Disease free survival (DFS)(At 12 months)
- CS1 expression on multiple myeloma cells(Baseline up to 15 years)