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

NCT03430011 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: H125001
• Study Type: interventional
• Target: 165
• Locations: 1 country
• Sites: 20

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.

Conditions

Multiple Myeloma

Keywords

JCARH125; chimeric antigen receptor; multiple myeloma; CAR T cells; B-cell maturation antigen; BCMA; autologous T-cell therapy; immunotherapy

Outcome Measures

Primary Outcomes (7)

• Number of Participants With Dose-Limiting Toxicity (DLT) in Phase 1

  DLT is defined as adverse events (AEs) that occur within 21 days following JCARH125 infusion and meet any of the following criteria: * Treatment-emergent Grade ≥3 allergic reactions related to JCARH125; * Treatment-emergent Grade 3 seizures, regardless of attribution, that do not resolve to Grade ≤2 within 3 days in participants who have no evidence of central nervous system (CNS) involvement of Multiple Myeloma or other CNS pathology; * Treatment-emergent autoimmune toxicity Grade ≥3, regardless of attribution (excluding B-cell aplasia); * Treatment-emergent Grade 3 CRS that does not resolve to Grade ≤2 within 72 hours; * Any other treatment-emergent Grade 3 AE related to JCARH125 that does not resolve to Grade ≤2 within 7 days; * Any treatment-emergent Grade 4 AE related to JCARH125 that does not resolve to Grade ≤2 within 7 days; * Treatment-emergent Grade 4 Cytokine Release Syndrome of any duration; * Any treatment-emergent Grade 5 toxicity not due to the underlying malignancy

  From day 1 to day 22 following JCARH125 infusion (Up to 21 days)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity in Phase 1 and Phase 1 Anakinra

  TEAE is defined as an AE that starts any time from initiation of JCARH125 administration through and including 90 days following the JCARH125 infusion graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Any AE occurring after the initiation of another anticancer treatment will not be considered a TEAE. Grade 3=Severe; Grade 4=Life-threatening; and Grade 5=death.

  From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days)

• Number of Participants With Clinically Significant Laboratory Abnormalities by Severity in Phase 1 and Phase 1 Anakinra

  Clinically significant laboratory abnormalities are assessed by investigator and are reported as treatment-emergent adverse event (TEAE). TEAE is defined as an AE that starts any time from initiation of JCARH125 administration through and including 90 days following the JCARH125 infusion graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Any AE occurring after the initiation of another anticancer treatment is not considered a TEAE. Grade 3=Severe; Grade 4=Life-threatening.

  From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days)

• Number of Participants Receiving Prophylactic Anakinra With Grade ≥2 Cytokine Release Syndrome (CRS) in Phase 1 and Phase 1 Anakinra

  Number of participants receiving prophylactic anakinra with grade ≥ 2 CRS relative to the number of participants treated at the recommended Phase 2 dose (RP2D) in the Phase 1 dose escalation portion of the trial with grade ≥ 2 CRS. CRS grade is defined by the most severe symptom (excluding fever). Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening

  From first infusion to up to aproximately 61 months

• Time to Onset of Grade ≥2 Cytokine Release Syndrome (CRS) in Phase 1 and Phase 1 Anakinra

  Time to first onset of Grade ≥2 CRS in participants receiving prophylactic anakinra relative to onset of Grade ≥ 2 CRS in participants treated at the RP2D(s) in the Phase 1 dose escalation portion of the trial. Time to onset is calculated from the latest JCARH125 infusion prior to the first onset of Grade \>= 2 CRS. CRS grade is defined by the most severe symptom (excluding fever). Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening

  From JCARH125 infusion to the first onset of Grade ≥2 CRS (Up to approximately 61 months)

• Number of Participants Receiving Prophylactic Anakinra With no Cytokine Release Syndrome (CRS) Occurring on Days 1-3 in Phase 1 Anakinra

  The number of participants receiving prophylactic anakinra with no CRS occurring on study days 1, 2, or 3. CRS grade is defined by the most severe symptom (excluding fever). Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening

  Day 1, 2, 3

• Overall Response Rate (ORR) in Phase 2 and Phase 2a

  ORR is defined as stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), according to IMWG criteria. Participants without any reported disease response assessments will be considered non-responders. sCR=complete response plus normal free light chain ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry; CR=negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in bone marrow aspirates. When the only method to measure disease is by serum FLC levels, CR can be defined as a normal FLC ratio of 0.26 to 1.65; VGPR=serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein level plus urine M-protein level \< 100 mg/24 h; PR=≥ 50% reduction of serum M protein plus reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg/24 h

  From the time of the JCARH125 infusion until disease progression, end of study, or the start of another anticancer therapy or stem cell transplant (Up to aproximately 61 months)

Secondary Outcomes (19)

• Maximum Observed Concentration (Cmax)

  From JCARH125 infusion through the day 29 visit

• Time to Maximum Observed Concentration (Tmax)

  From JCARH125 infusion through the day 29 visit

• Area Under the Concertation-Time Curve (AUC) From Time Day 1 to Day 29 [AUC (0-28 Days)]

  From JCARH125 infusion through 28 days after the infusion

• Number of Participants With Pharmacokinetics Persistence

  Day 29, 60, 90, 180, 270, 365, 545, 730

• Overall Response Rate (ORR) in Phase 1 and Phase 1 Anakinra

  From the time of the JCARH125 infusion until disease progression, end of study, or the start of another anticancer therapy or stem cell transplant (Up to 61 approximately months)

Study Arms (2)

JCARH125

EXPERIMENTAL

Subjects will receive a course of lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by a single dose of JCARH125

Biological: JCARH125

JCARH125 + anakinra

EXPERIMENTAL

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

Interventions

JCARH125 BIOLOGICAL

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).

JCARH125

JCARH125 + anakinra BIOLOGICAL

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.

JCARH125 + anakinra

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Juno Therapeutics, a Subsidiary of Celgene: lead

Study Sites (20)

Local Institution - 0006

Birmingham, Alabama, 10016, United States

Location

Local Institution - 0007

Duarte, California, 91010, United States

Location

Local Institution - 0059

Los Angeles, California, 90095-1678, United States

Location

Local Institution - 0010

San Francisco, California, 94158, United States

Location

Local Institution - 0060

Denver, Colorado, 80218, United States

Location

Local Institution - 0042

Atlanta, Georgia, 30322, United States

Location

Local Institution - 0016

New Lenox, Illinois, 60451, United States

Location

Local Institution - 0061

Indianapolis, Indiana, 46202, United States

Location

Local Institution - 0053

Westwood, Kansas, 66205, United States

Location

Local Institution - 0009

Baltimore, Maryland, 21231, United States

Location

Local Institution - 0005

Boston, Massachusetts, 02114, United States

Location

Local Institution - 0062

Detroit, Michigan, 48201, United States

Location

Local Institution - 0054

Rochester, Minnesota, 55905, United States

Location

Local Institution - 0038

Hackensack, New Jersey, 07601, United States

Location

Local Institution - 0013

Buffalo, New York, 14263, United States

Location

Local Institution - 0001

New York, New York, 10065, United States

Location

Local Institution - 0058

Portland, Oregon, 97201-3098, United States

Location

Local Institution - 0023

Seattle, Washington, 98104, United States

Location

Local Institution - 0018

Seattle, Washington, 98109, United States

Location

Local Institution - 0055

Milwaukee, Wisconsin, 53226, United States

Location

Related Links

• BMS Clinical Trial Information

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Interleukin 1 Receptor Antagonist Protein

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

1-855-907-3286

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2018
• First Posted: February 12, 2018
• Study Start: February 1, 2018
• Primary Completion: March 30, 2023
• Study Completion: March 30, 2023
• Last Updated: May 24, 2024
• Results First Posted: May 24, 2024

Record last verified: 2024-04

Locations

US (20)