Safety and Efficacy of CS1 CAR-T (WS-CART-CS1) in Subjects With Multiple Myeloma

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

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 Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Biological: WS-CART-CS1; Drug: Lymphodepleting chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Armin Ghobadi, M.D.; Phone Number: 314-747-2743; Email: arminghobadi@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Sub-Investigator: Feng Gao, M.D., Ph.D.
      • Sub-Investigator: Ramzi Abboud, M.D.
      • Sub-Investigator: Mark A Schroeder, M.D.
      • Sub-Investigator: John F DiPersio, M.D., Ph.D.
      • Sub-Investigator: Keith Stockerl-Goldstein, M.D.
      • Sub-Investigator: Ravi Vij, M.D.
      • Principal Investigator: Armin Ghobadi, M.D.
      • Contact: Armin Ghobadi, M.D.; Phone Number: 314-747-2743; Email: arminghobadi@wustl.edu
      • Sub-Investigator: Matthew J Christopher, M.D., Ph.D.
      • Sub-Investigator: Zachary D Crees, M.D.
      • Sub-Investigator: Mark A Fiala, MSW, Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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:

  • Renal function:

    • calculated creatinine clearance ≥ 50 mL/min/1.73 m2 OR
    • radioisotope glomerular filtration rate ≥ 50 mL/min/1.73 m2 OR
    • normal serum creatinine based on age/gender per institutional normal range

  • Hepatic function:

    • ALT (SGPT) ≤ 5 x ULN for age
    • Total bilirubin ≤ 2.0 x IULN (unless the patient has Grade 1 bilirubin elevation due to Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin)

  • Respiratory function:

    • Minimum level of pulmonary reserve defined as oxygen saturation > 91% measured by pulse oximetry on room air

  • Cardiovascular function:

    • LVEF ≥ 45% confirmed by echocardiogram or MUGA within 28 days of screening
• The effects of CS1 CAR-T on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (at least 2 forms of contraception, including one barrier method) prior to study entry and for 12 months after CS1 CAR-T infusion. If a female subject or female partner of a male subject becomes pregnant during therapy or within 12 months following WS-CART-CS1 infusion, the investigator must be notified in order to facilitate outcome follow-up.
• Ability to understand and willingness to sign an IRB-approved written informed consent document (or that of legally authorized representative, if applicable).

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Biological: WS-CART-CS1; -Subject will be hospitalized for 7 days; Drug: Lymphodepleting chemotherapy; Cyclophosphamide 500 mg/m^2 IV on Days -5, -4, and -3; Fludarabine 30 mg/m^2 IV on Days -5, -4, and -3
Experimental: 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.	Biological: WS-CART-CS1; -Subject will be hospitalized for 7 days; Drug: Lymphodepleting chemotherapy; Cyclophosphamide 500 mg/m^2 IV on Days -5, -4, and -3; Fludarabine 30 mg/m^2 IV on Days -5, -4, and -3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Frequency and severity of treatment-emergent adverse events	Graded by CTCAE v 5.0.; Adverse events will be tracked at the time of leukapheresis through 28 days post leukapheresis, to capture any AEs related to leukapheresis only.; Adverse events will then be collected beginning with lymphodepletion chemotherapy and continue through Day 100 post WS-CART-CS1 infusion or until initiation of another anticancer therapy, whichever occurs first.; After Day 100, only targeted AEs will be reported through 24 months after WS-CART-CS1 infusion or until disease progression or relapse, whichever occurs first. Targeted AEs include and are limited to secondary malignancies, CRS, ICANS, prolonged cytopenia (defined as Grade 3 neutropenia or thrombocytopenia lasting more than 28 days after WS-CART-CS1 infusion), and SAEs or SUSARs that are not attributable to progressive disease or extraneous causes.	From leukapheresis through 24 months after WS-CART-CS1 infusion (approximately 24 months and 1 week)
Part A: Frequency of dose-limiting toxicities (DLTs)	DLTs are defined in the protocol.	From WS-CART-CS1 infusion through 28 days
Part B: Frequency and severity of treatment-emergent adverse events	Graded by CTCAE v 5.0.; Adverse events will be tracked at the time of leukapheresis through 28 days post leukapheresis, to capture any AEs related to leukapheresis only.; Adverse events will then be collected beginning with lymphodepletion chemotherapy and continue through Day 100 post WS-CART-CS1 infusion or until initiation of another anticancer therapy, whichever occurs first.; After Day 100, only targeted AEs will be reported through 24 months after WS-CART-CS1 infusion or until disease progression or relapse, whichever occurs first. Targeted AEs include and are limited to secondary malignancies, CRS, ICANS, prolonged cytopenia (defined as Grade 3 neutropenia or thrombocytopenia lasting more than 28 days after WS-CART-CS1 infusion), and SAEs or SUSARs that are not attributable to progressive disease or extraneous causes.	From leukaphereis through 24 months after WS-CART-CS1 infusion (approximately 24 months and 1 week)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A MTD and Part B: Disease-specific objective response rate (ORR)	-Defined as stringent complete response (sCR), plus complete response (CR), plus very good partial response (VGPR), plus partial response (PR), plus minimal response (MR) in MM within 3 months of infusion using the International Myeloma Working Group (IMWG) response criteria in MM.	Within 3 months of WS-CART-CS1 infusion
Part A MTD and Part B: Minimal residual disease (MRD) negativity in the marrow	-Based on next-generation flow (NGF), next-generation sequencing (NGS), or both	Week 12
Part A MTD and Part B: Progression-free survival (PFS)	-PFS is measured from Day 0 to time of relapse, progression or death, whichever occurs first.	From WS-CART-CS1 infusion through completion of follow-up (estimated to be 15 years)
Part A MTD and Part B: Overall survival (OS)	-OS is defined as the time from start of treatment (Day 0) to time of death.	From WS-CART-CS1 infusion through completion of follow-up (estimated to be 15 years)
Part A MTD and Part B: Duration of response (DoR)	-DoR for subjects who respond to treatment is measured from the time measurement criteria are met for response (whichever is first recorded) until the first date that relapse or progression is objectively documented.	-From response 24 months after WS-CART-CS1 infusion (estimated to be 24 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Paula C. & Rodger O. Riney Blood Cancer Research
• Investigators: Principal Investigator: Armin Ghobadi, M.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2024
• Primary Completion (Estimated): August 31, 2029
• Study Completion (Estimated): August 31, 2040

Study Registration Dates

• First Submitted: December 15, 2023
• First Submitted That Met QC Criteria: December 15, 2023
• First Posted (Actual): December 29, 2023

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Chimeric Antigen Receptor; CS1
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Multiple Myeloma
• Other Study ID Numbers: 202404090

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No