Phase 1 Dose-Escalation and Dose-Expansion Study of the Safety and Efficacy of CS1 CAR-T (WS-CART-CS1) in Subjects With Multiple Myeloma
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 25
- Locations
- 1
- Primary Endpoint
- Part A: Frequency and severity of treatment-emergent adverse events
Overview
Brief Summary
Despite recent therapeutic advances, multiple myeloma (MM) remains an incurable disease. Although survival has improved, there are nevertheless diminishing durations of response to each subsequent line of therapy. This highlights the need for further therapeutic innovation. BCMA-targeting CAR-T cells show impressive response rates; however, their median duration of response is disappointing. The investigators propose that CS1(SLAMF7)-targeting CAR-T cells will fill a gap in the MM armamentarium.
CS1 is an attractive target in MM because it is expressed in most patients. Elotuzumab (Empliciti®), an approved anti-CS1 antibody, has proven the clinical efficacy of this target. CAR-T cells are an ideal modality to target CS1, given that two approved treatments, ide-cel (idecabtagene vicleucel, AbecmaTM) and cilta-cel (ciltacabtagene autoleucel, Carvykti™), have proven the potential for cellular immunotherapy in MM.
The investigators are testing the safety and preliminary anti-myeloma efficacy of WS-CART-CS1, a CAR-T cell therapy targeting CS1.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Relapsed or refractory multiple myeloma after 3 or more prior lines of therapy, including proteasome inhibitor (e.g. bortezomib or carfilzomib), anti-CD38 therapy (e.g. daratumumab), and anti-BCMA therapies (e.g. BCMA bispecific antibodies or BCMA CAR-T)
- •Measurable disease, defined as meeting at least one of the following criteria:
- •Serum M-protein ≥ 0.5 g/dL
- •Urine M-protein ≥ 200 mg/24 h
- •In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase) must be \>10 mg/dL for consideration of defining progression before enrollment
- •A biopsy-proven plasmacytoma
- •Bone marrow plasma cells \> 30% of total bone marrow cells
- •At least 18 years of age.
- •ECOG performance status ≤ 1
- •Adequate renal, hepatic, respiratory, and cardiovascular function, as defined below:
Exclusion Criteria
- •Any prior systemic therapy for multiple myeloma within 14 days before planned day of leukapheresis.
- •A history of other malignancy with the exception of treated non-melanomatous skin cancers and malignancies for which all treatment was completed at least 2 years before registration and the subject has no evidence of disease.
- •Currently receiving any other investigational agents.
- •Receipt of any cellular therapy within 8 weeks prior to the planned start of conditioning.
- •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to CS1 CAR-T or other agents used in the study.
- •History of Grade 3 CRS or ICANS with other CAR-Ts (including BCMA CAR).
- •Active hepatitis B, active hepatitis C, any uncontrolled infection, or HIV infection.
- •Ongoing or active infection or other serious underlying medical condition that would impair the ability to receive protocol treatment.
- •Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
Arms & Interventions
Part A Dose Escalation: WS-CART-CS1
- Undergo apheresis procedure for WS-CART-CS1 manufacturing.
- Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician.
- Lymphodepleting chemotherapy on days -5, -4, and -3.
- Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused.
- Part A is the dose escalation portion of the study with the starting dose of 0.5 x 10^6 cells/kg of WS-CART-CS1.
Intervention: WS-CART-CS1 (Biological)
Part A Dose Escalation: WS-CART-CS1
- Undergo apheresis procedure for WS-CART-CS1 manufacturing.
- Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician.
- Lymphodepleting chemotherapy on days -5, -4, and -3.
- Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused.
- Part A is the dose escalation portion of the study with the starting dose of 0.5 x 10^6 cells/kg of WS-CART-CS1.
Intervention: Lymphodepleting chemotherapy (Drug)
Part B Dose Expansion: WS-CART-CS1
- Undergo apheresis procedure for WS-CART-CS1 manufacturing.
- Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician.
- Lymphodepleting chemotherapy on days -5, -4, and -3.
- Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused.
- Part B is the dose expansion portion of the study. The dose of WS-CART-CS1 will be determined in Part A of the study.
Intervention: WS-CART-CS1 (Biological)
Part B Dose Expansion: WS-CART-CS1
- Undergo apheresis procedure for WS-CART-CS1 manufacturing.
- Anti-multiple myeloma therapy may be given after leukapheresis and up to one week prior to the start of lymphodepleting chemotherapy at the discretion of the treating physician.
- Lymphodepleting chemotherapy on days -5, -4, and -3.
- Three days following the last dose of lymphodepleting chemotherapy (on Day 0), WS-CART-CS1 will be infused.
- Part B is the dose expansion portion of the study. The dose of WS-CART-CS1 will be determined in Part A of the study.
Intervention: Lymphodepleting chemotherapy (Drug)
Outcomes
Primary Outcomes
Part A: Frequency and severity of treatment-emergent adverse events
Time Frame: From leukapheresis through 24 months after WS-CART-CS1 infusion (approximately 24 months and 1 week)
-Graded by CTCAE v 5.0.
Part A: Frequency of dose-limiting toxicities (DLTs)
Time Frame: From WS-CART-CS1 infusion through 28 days
DLTs are defined as any Grade 3 to 5 toxicity occurring within the 28 days post infusion of WS-CART-CS1 determined to be at least possibly related to WS-CART-CS1. There are some exceptions to this and there are listed in the study protocol.
Part B: Frequency and severity of treatment-emergent adverse events
Time Frame: From leukaphereis through 24 months after WS-CART-CS1 infusion (approximately 24 months and 1 week)
-Graded by CTCAE v 5.0.
Secondary Outcomes
- Part A MTD and Part B: Disease-specific objective response rate (ORR)(Within 3 months of WS-CART-CS1 infusion)
- Part A MTD and Part B: Minimal residual disease (MRD) negativity in the marrow(Week 12)
- Part A MTD and Part B: Duration of response (DoR)(-From response 24 months after WS-CART-CS1 infusion (estimated to be 24 months))
- Part A MTD and Part B: Progression-free survival (PFS)(From WS-CART-CS1 infusion through completion of follow-up (estimated to be 15 years))
- Part A MTD and Part B: Overall survival (OS)(From WS-CART-CS1 infusion through completion of follow-up (estimated to be 15 years))