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

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Biological: JCARH125; Biological: JCARH125 + anakinra

• Study Type: Interventional
• Enrollment (Actual): 169
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 10016
      • Local Institution - 0006
  • California
    • Duarte, California, United States, 91010
      • Local Institution - 0007
    • Los Angeles, California, United States, 90095-1678
      • Local Institution - 0059
    • San Francisco, California, United States, 94158
      • Local Institution - 0010
  • Colorado
    • Denver, Colorado, United States, 80218
      • Local Institution - 0060
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Local Institution - 0042
  • Illinois
    • New Lenox, Illinois, United States, 60451
      • Local Institution - 0016
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Local Institution - 0061
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Local Institution - 0053
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Local Institution - 0009
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Local Institution - 0005
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Local Institution - 0062
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Local Institution - 0054
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Local Institution - 0038
  • New York
    • Buffalo, New York, United States, 14263
      • Local Institution - 0013
    • New York, New York, United States, 10065
      • Local Institution - 0001
  • Oregon
    • Portland, Oregon, United States, 97201-3098
      • Local Institution - 0058
  • Washington
    • Seattle, Washington, United States, 98109
      • Local Institution - 0018
    • Seattle, Washington, United States, 98104
      • Local Institution - 0023
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Local Institution - 0055

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. 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):

   1. Autologous stem cell transplant
   2. A regimen that included an immunomodulatory agent (eg, thalidomide, lenalidomide, pomalidomide) and a proteasome inhibitor (eg, bortezomib, carfilzomib, ixazomib), either alone or in combination
   3. 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.

2. Subjects must have measurable disease.
3. Subject must be willing to provide fresh bone marrow biopsy samples during Screening (and prior to study treatment, if required).
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
5. Adequate renal, bone marrow, hepatic, pulmonary, and cardiac function

6. 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:

   1. 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.
   2. Subjects who have received prior BCMA-directed T-cell engager therapy.
   3. Subjects who have received prior BCMA-directed antibody-drug conjugate therapy.

Exclusion Criteria:

1. Subjects with known active or history of CNS involvement by malignancy
2. 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
3. Subjects who are considered eligible to receive and have not refused an autologous stem cell transplant
4. 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.
5. 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])
6. Prior CAR T-cell or other genetically-modified T-cell therapy (not applicable for subjects enrolled in Phase 2a cohorts)
7. Prior treatment with a BCMA-targeted agent (not applicable for subjects enrolled in Phase 2a cohorts)
8. 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
9. 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.
10. 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
11. Subjects with known hypersensitivity to E Coli-derived proteins (only applicable to subjects in Phase 1 Anakinra Cohort)
12. History of severe immediate hypersensitivity reaction to any of the protocol-mandated or recommended agents used in this study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: JCARH125; Subjects will receive a course of lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by a single dose of JCARH125	Biological: JCARH125; 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).
Experimental: JCARH125 + anakinra; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Juno Therapeutics, a Subsidiary of Celgene
• Investigators: Study Director: Ronald Dubowy, MD, Bristol-Myers Squibb

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2018
• Primary Completion (Actual): March 30, 2023
• Study Completion (Actual): March 30, 2023

Study Registration Dates

• First Submitted: February 6, 2018
• First Submitted That Met QC Criteria: February 9, 2018
• First Posted (Actual): February 12, 2018

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: immunotherapy; JCARH125; multiple myeloma; BCMA; CAR T cells; chimeric antigen receptor; B-cell maturation antigen; autologous T-cell therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: H125001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No