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Safety and Efficacy of bb2121 (Ide-cel) Combinations in Multiple Myeloma (KarMMa-7)

  • Clinicaltrials.gov identifier

    NCT04855136

  • Recruitment Status

    Recruiting

  • First Posted

    April 22, 2021

  • Last update posted

    September 16, 2021

Study Description

Brief summary:

This is a global, open-label, multi-arm, multi-cohort, multi-center, phase 1/2 study to determine the safety, tolerability, efficacy, PK of bb2121 in combination with other therapies in adult subjects with R/RMM. The following combinations will be - Arm A will test bb2121 in combination with CC-220 (± low-dose dexamethasone) - Arm B will test bb2121 in combination with BMS-986405 (JSMD194) - Arm C will test bb2121 in combination with one of the following standard triplet regimens: 1) Daratumumab (DARA) in combination with pomalidomide (POM) and low-dose dexamethasone (DPd); 2) Pomalidomide (POM) in combination with bortezomib (BTZ) and low-dose dexamethasone (PVd) Combination agents being tested may be administered before, concurrently with and/or following (ie, maintenance) bb2121 infusion. The study will consist of 2 parts: dose finding (Phase 1) and dose expansion (Phase 2). Dose expansion may occur in one or more arms.

  • Condition or Disease:Multiple Myeloma
  • Intervention/Treatment: Biological: BB2121
    Drug: CC-220
    Drug: BMS-986405
    Drug: Pomalidomide
    Drug: Dexamethasone
    Drug: Bortezomib
  • Phase: Phase 1/Phase 2

Detailed Description

N/A

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 415 participants
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: An Exploratory Phase 1/2 Trial to Determine Recommended Phase 2 Dose (RP2D), Safety and Preliminary Efficacy of bb2121 (Ide-cel) Combinations in Subjects With Relapsed/Refractory Multiple Myeloma (KarMMa-7)
  • Actual Study Start Date: June 2021
  • Estimated Primary Completion Date: November 2024
  • Estimated Study Completion Date: April 2026

Arms and interventions

Arm Intervention/treatment
Experimental: Arm A- bb2121 in combination with CC-220 (± low-dose dexamethasone)
bb2121 will be administered at a target dose of 450 x 10^6 CAR+T cells. The combination agent will be administered at different doses and/ or schedules, depending on dose limiting toxicity (DLT) evaluation.
Biological: BB2121
CAR T Cell Therapy

Drug: CC-220
Cereblon (CRBN) E3 ligase modulatory compound (CELMoD)
Experimental: Arm B- bb2121 in combination with BMS-986405 (JSMD194)
bb2121 will be administered at a target dose of 450 x 10^6 CAR+T cells. The combination agent will be administered during Month 1 starting from the day of bb2121 infusion.
Biological: BB2121
CAR T Cell Therapy

Drug: BMS-986405
gamma secretase inhibitor (GSI)
Experimental: Arm C-bb2121 in combination with Daratumumab+pomalidomide+low-dose dexamethasone or POM +bortezomib
bb2121 will be administered at a target dose of 450 x 10^6 CAR+T cells. The combination agents will be administered as follow: Cohort 1 (DPd) DARA, POM and dexamethasone at M3D1 until disease progression. Cohort 2 (PVd) POM, BTZ and dexamethasone at M3D1 until disease progression
Biological: BB2121
CAR T Cell Therapy

Drug: Pomalidomide
immunomodulatory agent

Drug: Dexamethasone
corticosteroids

Drug: Bortezomib
inhibitor of the proteasome

Outcome Measures

  • Primary Outcome Measures: 1. Does Limiting Toxicity (DLT) rates _Phase 1 [ Time Frame: Up to 28 days from start of the combination therapy ]
    Percentage of participants experiencing DLTs
  • 2. Complete Response Rate (CRR)_ Phase 2 [ Time Frame: Up to 24 months ]
    Proportion of participants who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by investigator's review
  • Secondary Outcome Measures: 1. Incidence of Adverse Event (AEs) [ Time Frame: Up to 24 months after the last participant received any study treatment ]
    An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.
  • 2. Overall Response Rate (ORR) [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Proportion of participants who achieved PR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed investigator's review
  • 3. Progression-free Survival (PFS) [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Time from first study treatment (whichever is given earlier) start date to the date of either first observation of progressive disease or death due to any cause
  • 4. Overall Survival (OS) [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Time from first study treatment (whichever is given earlier) start date to death due to any cause
  • 5. Time to response (TTR) [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Time from first study treatment start date to the first date of documented response (PR or better)
  • 6. Duration of Response (DoR) [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Time from first documentation of response (PR or better) to first documentation of PD or death due to any cause
  • 7. Time to next antimyeloma treatment (TTNT) [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Time from first study treatment (whichever is given earlier) start date to first day when participant receives another antimyeloma treatment
  • 8. Progression-free survival after next antimyeloma therapy (PFS2) [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Time from first study treatment (whichever is given earlier) start date to documentation of PD on the next-line treatment or death from any cause, whichever is first.
  • 9. Feasibility of maintenance therapy in combination with bb2121 [ Time Frame: Up to 4 months after bb2121 infusion in the respective cohort ]
    Cumulative incidence of the maintenance therapy starting from bb2121 infusion with death as the competing risk
  • 10. Pharmacokinetics - Cmax_Phase 1 and 2 [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Maximum transgene level
  • 11. Pharmacokinetics - Tmax_Phase 1 and 2 [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Time to maximum observed transgene level
  • 12. Pharmacokinetics - AUC_Phase 1 and 2 [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Area under the curve of transgene level
  • 13. Pharmacokinetics - AUC0-28days _Phase 1 and 2 [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Area under the curve of transgene level from time 0 to 28 days
  • 14. Pharmacokinetics - Tlast _Phase 1 and 2 [ Time Frame: Up to 24 months after the last participant received any study treatment in the respective cohort ]
    Time of last measurable transgene level

Eligibility Criteria

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

Criteria

Inclusion Criteria: Participants must satisfy the following criteria to be enrolled in the study: - Participant has documented diagnosis of MM and measurable disease, defined as: 1. M-protein (serum protein electrophoresis [sPEP] or urine protein electrophoresis [uPEP]): sPEP ≥ 0.5 g/dL or uPEP ≥ 200 mg/24 hours and/or 2. Light chain MM without measurable disease in the serum or urine: Serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free light chain ratio - Participant has received: 1. at least 3 prior MM regimens for Arm A Cohort 1 and Arm B 2. at least 1 but no greater than 3 prior MM regimens for Arm A Cohort 2 and Arm C. - Arm A Cohort 1 and Arm B: Participant has received prior treatment with an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody-containing regimen for at least 2 consecutive cycles. - Arm A Cohort 2 and Arm C: Participant has received prior treatment with an immunomodulatory agent for at least 2 consecutive cycles. - Evidence of PD during or within 6 months (measured from the last dose of any drug within the regimen) of completing treatment with the last antimyeloma regimen before study entry. - Participant achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen. - Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion Criteria: The presence of any of the following will exclude a participant from enrollment: - Participant has non-secretory MM or has history of or active plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis. - Participant has any of the following laboratory abnormalities: 1. ANC and Platelets count as reported below 2. Hemoglobin < 8 g/dL (< 4.9 mmol/L) (transfusion is not permitted within 21 days of screening) 3. Creatinine clearance (CrCl) as reported below 4. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L) 5. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 ×upper limit of normal (ULN) 6. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for participants with documented Gilbert's syndrome 7. International normalized ratio (INR) or activated partial thromboplastin time (aPTT) 1.5 × ULN, or history of Grade ≥ 2 hemorrhage within 30 days, or participant requires ongoing treatment with chronic, therapeutic dosing of anticoagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors) - Participant has inadequate pulmonary function defined as oxygen saturation (SaO2) < 92% on room air. - Participant has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal. - Prior exposure to CC-220 (± low-dose dexamethasone) as part of their most recent antimyeloma treatment regimen (Arm A). - Prior exposure to, BMS-986405 (JSMD194) (Arm B). - Prior exposure to DARA in combination with POM with or without dexamethasone (DP±d) as part of their most recent antimyeloma treatment regimen (Arm C Cohort 1). - Prior exposure to POM in combination with BTZ with or without dexamethasone (PV± d as part of their most recent antimyeloma treatment regimen (Arm C Cohort 2). - Previous history of an allogeneic hematopoietic stem cell transplantation, treatment with any gene therapy-based therapeutic for cancer, investigational cellular therapy for cancer or BCMA targeted therapy. - Treatment Arm A Cohort 1 and Arm B: participant has received autologous stem cell transplantation (ASCT) within 12 weeks prior to leukapheresis. - Treatment Arms A Cohort 2 and Arm C: participant has received autologous stem cell transplantation (ASCT) within 12 months prior to leukapheresis.

Contacts and Locations

Contacts

Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@bms.com

Locations

United States, Alabama
University of Alabama Birmingham
Birmingham

United States, California
University of California, San Francisco- California
San Francisco

United States, Florida
Mayo Clinic - Jacksonville
Jacksonville

United States, Georgia
Winship Cancer Institute of Emory University
Atlanta

United States, Georgia
Northside Hospital, Inc
Atlanta

United States, Illinois
Northwestern University
Chicago

United States, Maryland
University of Maryland - Greenebaum Comprehensive Cancer Center
Baltimore

United States, Massachusetts
Massachusetts General Hospital
Boston

United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston

United States, New Jersey
The Cancer Center at Hackensack University Medical Center
Hackensack

United States, New York
New York University Langone
New York

United States, New York
Weill Cornell Medicine / New York Presbyterian Hospital
New York

United States, New York
Icahn School of Medicine at Mount Sinai Medical Center
New York

United States, New York
Columbia University Medical Center
New York

United States, North Carolina
Levine Cancer Institute
Charlotte

United States, North Carolina
Duke University Medical Center
Durham

United States, Pennsylvania
Kimmel Cancer Center Thomas Jefferson Univ
Philadelphia

United States, Tennessee
Sarah Cannon Research Institute Center for Blood Cancers
Nashville

United States, Texas
University of Texas Southwestern Medical Center
Dallas

United States, Texas
The University of Texas - MD Anderson Cancer Center
Houston

United States, Washington
Fred Hutchinson Cancer Research Center
Seattle

United States, Wisconsin
University of Wisconsin Medical School
Madison

Spain
Clinica Universidad de Navarra
Pamplona

Spain
Universitario de Salamanca - Hospital Clinico
Salamanca

Sponsors and Collaborators

Celgene

Investigators

Study Director: Gianfranco Pittari, Md, PhD Celgene Corporation

More Information

  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT04855136 History of Changes
  • Other Study ID Numbers: BB2121-MM-007, 2020-003248-10
  • First Posted: April 22, 2021 Key Record Dates
  • Last Update Posted: September 16, 2021
  • Last Verified: September 2021
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Yes
  • Plan Description: Information relating to our policy on data sharing and the process for requesting data can be found at the following link: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/
  • Supporting Materials: Study Protocol, Statistical Analysis Plan (SAP), Informed Consent Form (ICF), Clinical Study Report (CSR), Analytic Code
  • Time Frame: See Plan Description
  • Access Criteria: See Plan Description
  • URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Celgene: BTZ
    POM
    DARA
    Phase II
    Phase I
    KarMMa-7
    CAR T
    PVd
    DPd
    BMS-986405
    JSMD194
    CC-220
    ide-cel
    BB2121
    Relapsed/Refractory Multiple Myeloma
  • Additional relevant MeSH terms: Neoplasms, Plasma Cell Multiple Myeloma