Clinical trial NCT03430011: Study Evaluating the Safety and Efficacy of JCARH125 in Subjects With Relapsed and/or Refractory Multiple Myeloma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Keywords: JCARH125
chimeric antigen receptor
multiple myeloma
CAR T cells
B-cell maturation antigen
BCMA
autologous T-cell therapy
immunotherapy
Lead sponsor: Juno Therapeutics, a Subsidiary of Celgene
Sponsor class: INDUSTRY
First posted: 2018-02-12
Enrollment: 165
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicity (DLT) in Phase 1
timeFrame: From day 1 to day 22 following JCARH125 infusion (Up to 21 days)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity in Phase 1 and Phase 1 Anakinra
timeFrame: From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days)
measure: Number of Participants With Clinically Significant Laboratory Abnormalities by Severity in Phase 1 and Phase 1 Anakinra
timeFrame: From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days)
measure: Number of Participants Receiving Prophylactic Anakinra With Grade ≥2 Cytokine Release Syndrome (CRS) in Phase 1 and Phase 1 Anakinra
timeFrame: From first infusion to up to aproximately 61 months
measure: Time to Onset of Grade ≥2 Cytokine Release Syndrome (CRS) in Phase 1 and Phase 1 Anakinra
timeFrame: From JCARH125 infusion to the first onset of Grade ≥2 CRS (Up to approximately 61 months)
measure: Number of Participants Receiving Prophylactic Anakinra With no Cytokine Release Syndrome (CRS) Occurring on Days 1-3 in Phase 1 Anakinra
timeFrame: Day 1, 2, 3
measure: Overall Response Rate (ORR) in Phase 2 and Phase 2a
timeFrame: 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:
measure: Maximum Observed Concentration (Cmax)
timeFrame: From JCARH125 infusion through the day 29 visit
measure: Time to Maximum Observed Concentration (Tmax)
timeFrame: From JCARH125 infusion through the day 29 visit
measure: Area Under the Concertation-Time Curve (AUC) From Time Day 1 to Day 29 [AUC (0-28 Days)]
timeFrame: From JCARH125 infusion through 28 days after the infusion
measure: Number of Participants With Pharmacokinetics Persistence
timeFrame: Day 29, 60, 90, 180, 270, 365, 545, 730
measure: Overall Response Rate (ORR) in Phase 1 and Phase 1 Anakinra
timeFrame: 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)
measure: Complete Response Rate (CRR)
timeFrame: 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)
measure: Duration of Response (DoR) in Phase 2 and 2a
timeFrame: From first response to the date of progression or death due to any cause, whichever occurs first (Up to approixmately 61 months)
measure: Duration of Complete Response (DoCR) in Phase 2 and 2a
timeFrame: From first response to the date of progression or death due to any cause, whichever occurs first (Up to approixmately 61 months)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Severity in Phase 2 and Phase 2a
timeFrame: From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days)
measure: Number of Participants With Clinically Significant Laboratory Abnormalities by Severity in Phase 2 and Phase 2a
timeFrame: From the time of JCARH125 infusion to 90 days following the infusion (Up to 90 days)
measure: Overall Survival (OS) in Phase 2 and Phase 2a
timeFrame: Form date of first infusion to the date of death due to any reason (Up to apprixamtely 61 months)
measure: Progression Free Survival (PFS) in Phase 2 and Phase 2a
timeFrame: Form date of first infusion to the date of disease progression, or death, due to any reason (Up to approximately 61 months)
measure: Time to Response (TTR) in Phase 2 and Phase 2a
timeFrame: Form date of first infusion to the date of disease progression, or death, due to any reason (Up to approximately 61 months)
measure: Time to Complete Response (TTCR) in Phase 2 and Phase 2a
timeFrame: Form date of first infusion to the date of disease progression, or death, due to any reason (Up to approximately 61 months)
measure: Change From Baseline in the Total Score of European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) in Phase 2
timeFrame: Baseline and visit 24 month
measure: Change From Baseline in the Total Score of European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ-MY20) in Phase 2
timeFrame: Baseline and visit 24 month
measure: Change From Baseline (EQ-5D-5L) Index Score in Phase 2
timeFrame: Baseline and visit 24 month
measure: Duration of Hospitalization From JCARH125 Administration in Phase 2
timeFrame: From JCARH125 infusion to up to approximately 61 months
measure: Reasons for Hospitalization From JCARH125 Administration in Phase 2
timeFrame: From JCARH125 infusion to up to approximately 61 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Local Institution - 0006
state: Alabama
city: Duarte
country: United States
facility: Local Institution - 0007
state: California
city: Los Angeles
country: United States
facility: Local Institution - 0059
state: California
city: San Francisco
country: United States
facility: Local Institution - 0010
state: California
city: Denver
country: United States
facility: Local Institution - 0060
state: Colorado
city: Atlanta
country: United States
facility: Local Institution - 0042
state: Georgia
city: New Lenox
country: United States
facility: Local Institution - 0016
state: Illinois
city: Indianapolis
country: United States
facility: Local Institution - 0061
state: Indiana
city: Westwood
country: United States
facility: Local Institution - 0053
state: Kansas
city: Baltimore
country: United States
facility: Local Institution - 0009
state: Maryland
city: Boston
country: United States
facility: Local Institution - 0005
state: Massachusetts
city: Detroit
country: United States
facility: Local Institution - 0062
state: Michigan
city: Rochester
country: United States
facility: Local Institution - 0054
state: Minnesota
city: Hackensack
country: United States
facility: Local Institution - 0038
state: New Jersey
city: Buffalo
country: United States
facility: Local Institution - 0013
state: New York
city: New York
country: United States
facility: Local Institution - 0001
state: New York
city: Portland
country: United States
facility: Local Institution - 0058
state: Oregon
city: Seattle
country: United States
facility: Local Institution - 0023
state: Washington
city: Seattle
country: United States
facility: Local Institution - 0018
state: Washington
city: Milwaukee
country: United States
facility: Local Institution - 0055
state: Wisconsin
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: