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

  • Clinicaltrials.gov identifier

    NCT03430011

  • Recruitment Status

    Active, not recruiting

  • First Posted

    February 12, 2018

  • Last update posted

    March 12, 2021

Study Description

Brief summary:

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.

  • Condition or Disease:Multiple Myeloma
  • Intervention/Treatment: Biological: JCARH125
    Biological: JCARH125 + anakinra
  • Phase: Phase 1/Phase 2

Detailed Description

N/A

Study Design

  • Study Type: Interventional
  • Actual Enrollment: 169 participants
  • Allocation: Non-Randomized
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: 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
  • Actual Study Start Date: February 2018
  • Estimated Primary Completion Date: January 2022
  • Estimated Study Completion Date: June 2023

Arms and interventions

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.

Outcome Measures

  • Primary Outcome Measures: 1. Phase 1: Incidence of dose-limiting toxicities (DLTs) [ Time Frame: 21 days ]
    Proportion of subjects with adverse events meeting DLT criteria
  • 2. Phase 1: Incidence and severity of adverse events [ Time Frame: 2 years ]
    Proportion of subjects with adverse events overall and by severity grade
  • 3. Phase 1: Incidence and severity of clinically significant laboratory abnormalities [ Time Frame: 2 years ]
    Proportion of subjects with clinically significant laboratory abnormalities overall and by severity grade
  • 4. Phase 1 Anakinra Cohort only: Incidence and severity of Grade 2 or higher cytokine release syndrome (CRS) [ Time Frame: 2 years ]
    Proportion of subjects with Grade 2 or higher CRS
  • 5. Phase 1 Anakinra Cohort only: Percentage of subjects with no CRS on Days 1, 2, or 3 following JCARH125 infusion [ Time Frame: 2 years ]
    Proportion of subjects with no CRS on Days 1, 2, or 3 following JCARH125 infusion
  • 6. Phase 1 Anakinra Cohort only: Time to onset of Grade 2 or higher CRS [ Time Frame: 2 years ]
    Median time to onset of Grade 2 or higher CRS
  • 7. Phase 2: Overall response rate [ Time Frame: 2 years ]
    Proportion of subjects with a partial response or better by International Myeloma Working Group (IMWG) criteria
  • Secondary Outcome Measures: 1. Phase 1 and Phase 2: Maximum concentration (Cmax) of JCARH125 in the blood [ Time Frame: 2 years ]
  • 2. Phase 1 and Phase 2: Time to maximum concentration (Tmax) of JCARH125 in the blood [ Time Frame: 2 years ]
  • 3. Phase 1 and Phase 2: Area under the concentration vs time curve (AUC) of JCARH125 in the blood [ Time Frame: 2 years ]
  • 4. Phase 1 and Phase 2: Duration of persistence of JCARH125 CAR T cells in the blood [ Time Frame: 2 years ]
  • 5. Phase 1: Overall response rate [ Time Frame: 2 years ]
    Proportion of subjects with a partial response (PR) or better by IMWG criteria
  • 6. Phase 1 and Phase 2: Complete response (CR) rate [ Time Frame: 2 years ]
    Proportion of subjects with a CR by IMWG criteria
  • 7. Phase 2: Duration of response [ Time Frame: 2 years ]
    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
  • 8. Phase 2: Duration of CR [ Time Frame: 2 years ]
    Time from first sCR or CR to the earlier date of PD or death due to any cause
  • 9. Phase 2: incidence and severity of adverse events [ Time Frame: 2 years ]
    Proportion of subjects with adverse events overall and by severity grade
  • 10. Phase 2: Incidence and severity of clinically significant laboratory abnormalities [ Time Frame: 2 years ]
    Proportion of subjects with clinically significant laboratory abnormalities overall and by severity grade
  • 11. Phase 2: Overall survival [ Time Frame: 2 years ]
    Time from JCARH125 infusion until death
  • 12. Phase 2: Progression-free survival [ Time Frame: 2 years ]
    Time from JCARH125 infusion until the earliest of date of death or disease progression as assessed by IMWG criteria
  • 13. Phase 2: Time to response [ Time Frame: 2 years ]
    Time from JCARH125 infusion to first documentation of PR or better
  • 14. Phase 2: Time to CR [ Time Frame: 2 years ]
    Time from JCARH125 infusion to first documentation of CR or better
  • 15. Phase 2 (excluding Phase 2a): Changes in measures of health-related quality of life (HRQoL) [ Time Frame: 2 years ]
    Change from baseline in HRQoL
  • 16. Phase 2 (excluding Phase 2a): Numbers of days in the intensive care unit (ICU) [ Time Frame: 2 years ]
  • 17. Phase 2 (excluding Phase 2a): Number of non-ICU inpatient days [ Time Frame: 2 years ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Locations

United States, Alabama
University of Alabama
Birmingham

United States, California
City of Hope Comprehensive Cancer Center
Duarte

United States, California
University of California, Los Angeles
Los Angeles

United States, California
University of California
San Francisco

United States, Colorado
SCRI - Colorado Blood Cancer Institute
Denver

United States, Georgia
Winship Cancer Institute at Emory University
Atlanta

United States, Illinois
The University of Chicago Medicine
Chicago

United States, Kansas
Kansas University Medical Center
Westwood

United States, Maryland
Johns Hopkins Hospital
Baltimore

United States, Massachusetts
Massachusetts General Hospital
Boston

United States, Michigan
Karmanos Cancer Institute Wayne State
Detroit

United States, Minnesota
Mayo Clinic
Rochester

United States, New Jersey
Hackensack University Medical Center
Hackensack

United States, New York
Roswell Park Cancer Institute
Buffalo

United States, New York
Memorial Sloan Kettering Cancer Center
New York

United States, Oregon
Oregon Health & Science University
Portland

United States, Texas
Methodist Hospital
San Antonio

United States, Washington
Swedish Cancer Institute
Seattle

United States, Washington
Fred Hutchinson Cancer Research Center
Seattle

United States, Wisconsin
Froedtert Hospital Medical College Wisconsin
Milwaukee

Sponsors and Collaborators

Juno Therapeutics, a Subsidiary of Celgene

Investigators

Study Director: Ronald Dubowy, MD Bristol-Myers Squibb

More Information

  • Responsible Party: Juno Therapeutics, a Subsidiary of Celgene
  • ClinicalTrials.gov Identifier: NCT03430011 History of Changes
  • Other Study ID Numbers: H125001
  • First Posted: February 12, 2018 Key Record Dates
  • Last Update Posted: March 12, 2021
  • Last Verified: March 2021
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Undecided
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Juno Therapeutics, a Subsidiary of Celgene: B-cell maturation antigen
    JCARH125
    multiple myeloma
    BCMA
    autologous T-cell therapy
    immunotherapy
    CAR T cells
    chimeric antigen receptor
  • Additional relevant MeSH terms: Multiple Myeloma Neoplasms, Plasma Cell