Study Evaluating the Safety and Efficacy of JCARH125 in Subjects With Relapsed and/or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This is an open-label, multicenter, Phase 1/2 study to determine the safety and efficacy of JCARH125, a CAR T-cell product that targets B-cell maturation antigen (BCMA), in adult subjects with relapsed and/or refractory multiple myeloma. The study will include a Phase 1 part to determine the recommended dose of JCARH125 in subjects with relapsed and/or refractory multiple myeloma, followed by a Phase 2 part to further evaluate the safety and efficacy of JCARH125 at the recommended dose. The safety and tolerability of JCARH125 in subjects who receive prophylactic treatment with anakinra will be evaluated in a separate Phase 1 cohort. The antitumor activity of JCARH125 in subjects who have been previously treated with BCMA-directed therapy will be evaluated in separate Phase 2a cohorts.

Official Title
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Protocol H125001: An Open-Label Phase 1/2 Study of JCARH125, BCMA-targeted Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: JCARH125
* Biological: JCARH125 + anakinra


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of multiple myeloma (MM) with relapsed and/or refractory (R/R) disease. Participants must have received at least 3 prior anti-myeloma treatment regimens. Participants must have previously received all of the following therapies and must be refractory to the last line of therapy prior to entering the study (not applicable to Phase 2a): Autologous stem cell transplant A regimen that included an immunomodulatory agent (eg, thalidomide, lenalidomide, pomalidomide) and a proteasome inhibitor (eg, bortezomib, carfilzomib, ixazomib), either alone or in combination Anti-CD38 (eg, daratumumab) as part of a combination regimen or as a monotherapy Subjects who have received prior allogeneic stem cell transplant or donor lymphocyte infusion at least 100 days before enrollment with no signs of acute or chronic graft-versus-host disease (GVHD) will be considered eligible. Subjects who were not candidates to receive one or more of the above treatments (ie, contraindicated) are eligible. Subjects must have measurable disease. Subject must be willing to provide fresh bone marrow biopsy samples during Screening (and prior to study treatment, if required). Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Adequate renal, bone marrow, hepatic, pulmonary, and cardiac function Phase 2a cohorts only - Subjects with R/R MM who have been previously treated with prior BCMA-directed anti-myeloma therapy, achieved at least a partial response (PR) and progressed on the following treatment: Subjects who have received prior BCMA-directed CAR T-cell therapy. The last CAR T-cell therapy must have been received at least 6 months prior to JCARH125 screening. Subjects who have received prior BCMA-directed T-cell engager therapy. Subjects who have received prior BCMA-directed antibody-drug conjugate therapy. Exclusion Criteria: Subjects with known active or history of CNS involvement by malignancy Subjects with solitary plasmacytoma; active or history of plasma cell leukemia (PCL); Waldenstrom's macroglobulinemia; Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasmaproliferative disorder, Skin changes (POEMS) syndrome; or symptomatic amyloidosis Subjects who are considered eligible to receive and have not refused an autologous stem cell transplant History of another primary malignancy that has not been in remission for at least 3 years. The following are exempt from the 3-year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear, and in situ breast cancer that has been completely resected. Require systemic immunosuppressive therapies (eg, calcineurin inhibitors, methotrexate, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-IL-6 or anti-IL-6 receptor [IL-6R]) Prior CAR T-cell or other genetically-modified T-cell therapy (not applicable for subjects enrolled in Phase 2a cohorts) Prior treatment with a BCMA-targeted agent (not applicable for subjects enrolled in Phase 2a cohorts) History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis Untreated or active infection at time of initial screening, at the time of leukapheresis, within 72 hrs before lymphodepletion, or 5 days before JCARH125 infusion. History of any of the following cardiovascular conditions within 6 months of screening: Class III or IV heart failure as defined by the New York Heart Association (NYHA), myocardial infarction, unstable angina, uncontrolled or symptomatic atrial arrhythmias, any ventricular arrhythmias, or other clinically significant cardiac disease Subjects with known hypersensitivity to E Coli-derived proteins (only applicable to subjects in Phase 1 Anakinra Cohort) History of severe immediate hypersensitivity reaction to any of the protocol-mandated or recommended agents used in this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JCARH125<br>Subjects will receive a course of lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by a single dose of JCARH125 | Biological: JCARH125<br>* Participants will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of JCARH125. During JCARH125 production, participants may receive bridging chemotherapy for disease control. Following successful generation of JCARH125 product, participants will receive a course of lymphodepleting chemotherapy followed by one dose of JCARH125 administered intravenously (IV).<br>|
| Experimental: JCARH125 + anakinra<br>Subjects will receive a course of lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by prophylactic treatment with anakinra and a single dose of JCARH125 | Biological: JCARH125 + anakinra<br>* Participants will undergo leukapheresis to isolate PBMCs for the production of JCARH125. During JCARH125 production, participants may receive bridging chemotherapy for disease control. Following successful generation of JCARH125 product, participants will receive a course of lymphodepleting chemotherapy followed by two doses of anakinra administered subcutaneously and one dose of JCARH125 administered IV. Subjects receive anakinra for 5 consecutive days following JCARH125 infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Incidence of dose-limiting toxicities (DLTs) | Proportion of subjects with adverse events meeting DLT criteria | 21 days | 
| Phase 1: Incidence and severity of adverse events | Proportion of subjects with adverse events overall and by severity grade | 2 years | 
| Phase 1: Incidence and severity of clinically significant laboratory abnormalities | Proportion of subjects with clinically significant laboratory abnormalities overall and by severity grade | 2 years | 
| Phase 1 Anakinra Cohort only: Incidence and severity of Grade 2 or higher cytokine release syndrome (CRS) | Proportion of subjects with Grade 2 or higher CRS | 2 years | 
| Phase 1 Anakinra Cohort only: Percentage of subjects with no CRS on Days 1, 2, or 3 following JCARH125 infusion | Proportion of subjects with no CRS on Days 1, 2, or 3 following JCARH125 infusion | 2 years | 
| Phase 1 Anakinra Cohort only: Time to onset of Grade 2 or higher CRS | Median time to onset of Grade 2 or higher CRS | 2 years | 
| Phase 2: Overall response rate | Proportion of subjects with a partial response or better by International Myeloma Working Group (IMWG) criteria | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and Phase 2: Maximum concentration (Cmax) of JCARH125 in the blood |  | 2 years | 
| Phase 1 and Phase 2: Time to maximum concentration (Tmax) of JCARH125 in the blood |  | 2 years | 
| Phase 1 and Phase 2: Area under the concentration vs time curve (AUC) of JCARH125 in the blood |  | 2 years | 
| Phase 1 and Phase 2: Duration of persistence of JCARH125 CAR T cells in the blood |  | 2 years | 
| Phase 1: Overall response rate | Proportion of subjects with a partial response (PR) or better by IMWG criteria | 2 years | 
| Phase 1 and Phase 2: Complete response (CR) rate | Proportion of subjects with a CR by IMWG criteria | 2 years | 
| Phase 2: Duration of response | Time from first response (stringent complete response [sCR], CR, very good partial response [VGPR], or PR) to the earlier date of progressive disease (PD) or death due to any cause | 2 years | 
| Phase 2: Duration of CR | Time from first sCR or CR to the earlier date of PD or death due to any cause | 2 years | 
| Phase 2: incidence and severity of adverse events | Proportion of subjects with adverse events overall and by severity grade | 2 years | 
| Phase 2: Incidence and severity of clinically significant laboratory abnormalities | Proportion of subjects with clinically significant laboratory abnormalities overall and by severity grade | 2 years | 
| Phase 2: Overall survival | Time from JCARH125 infusion until death | 2 years | 
| Phase 2: Progression-free survival | Time from JCARH125 infusion until the earliest of date of death or disease progression as assessed by IMWG criteria | 2 years | 
| Phase 2: Time to response | Time from JCARH125 infusion to first documentation of PR or better | 2 years | 
| Phase 2: Time to CR | Time from JCARH125 infusion to first documentation of CR or better | 2 years | 
| Phase 2 (excluding Phase 2a): Changes in measures of health-related quality of life (HRQoL) | Change from baseline in HRQoL | 2 years | 
| Phase 2 (excluding Phase 2a): Numbers of days in the intensive care unit (ICU) |  | 2 years | 
| Phase 2 (excluding Phase 2a): Number of non-ICU inpatient days |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JCARH125, chimeric antigen receptor, multiple myeloma, CAR T cells, B-cell maturation antigen, BCMA, autologous T-cell therapy, immunotherapy