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A Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (NDMM)

  • Clinicaltrials.gov identifier

    NCT04196491

  • Recruitment Status

    Recruiting

  • First Posted

    December 12, 2019

  • Last update posted

    May 18, 2021

Study Description

Brief summary:

This is a multicenter, open-label, phase 1, single arm study intended to determine the optimal target dose and safety of bb2121 in subjects with HR (R-ISS Stage III per IMWG criteria) NDMM. Subjects should have received 3 Cycles of standard induction therapy prior to undergoing leukapheresis procedure to collect autologous mononuclear cells for manufacture of the drug product (bb2121). Following manufacture of the drug product, subjects will receive fourth cycle of induction therapy followed by lymphodepleting therapy with fludarabine and cyclophosphamide prior to bb2121 infusion. Maintenance therapy is recommended for all subjects who have received bb2121 infusion and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later.

  • Condition or Disease:Multiple Myeloma
  • Intervention/Treatment: Biological: bb2121 carfilzomib
    Drug: Fludarabine
    Drug: Cyclophosphamide
    Drug: Lenalidomide
  • Phase: Phase 1

Detailed Description

N/A

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 60 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase 1, Open-label, Multicenter Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (KarMMa-4)
  • Actual Study Start Date: May 2020
  • Estimated Primary Completion Date: January 2025
  • Estimated Study Completion Date: January 2025

Arms and interventions

Arm Intervention/treatment
Experimental: Dose Escalation
bb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 800 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy with a planned starting dose of 450 x 10^6 CAR+ T cells. Lenalidomide maintenance therapy is recommended for all patients and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later
Biological: bb2121 carfilzomib
CAR-T Cell Therapy

Drug: Fludarabine
Lymphodepleting Chemotherapy

Drug: Cyclophosphamide
Lymphodepleting Chemotherapy

Drug: Lenalidomide
Maintenance Therapy

Outcome Measures

  • Primary Outcome Measures: 1. Dose-limiting toxicity (DLT) rates [ Time Frame: Up to approximately 2 years after first subject bb2121 infused ]
    DLTs will be assessed during the DLT interval (ie, within 21 days immediately after bb2121 infusion). DLTs are defined as any bb2121 related Grade 3 to 5 toxicity.
  • 2. Adverse Events (AEs) [ Time Frame: Up to approximately 5 years after first subject bb2121 infused ]
    An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject 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 subject'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.
  • Secondary Outcome Measures: 1. Proportion of subjects who achieved Complete Response (CR) Rate [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Is defined as proportion of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma for multiple myeloma will be determined by an Investigator assessment.
  • 2. Overall Response Rate (ORR) [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Is defined as proportion of subjects who achieved PR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as determined by an Investigator assessment
  • 3. Duration of Response (DoR) [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Is defined as time from first documentation of response (PR or better) to first documentation of progressive disease (PD) or death from any cause, whichever occurs first, for responders.
  • 4. Time to Complete Response (TCR) [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Is defined as time from bb2121 infusion date to first documentation of CR for responders (Complete Response (CR) or better).
  • 5. Time to start maintenance [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Is defined as time to start lenalidomide maintenance therapy post-bb2121 infusion
  • 6. Feasibility of initiating maintenance [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Number of subjects starting the maintenance or on maintenance between D90 and D110
  • 7. Progression-free Survival (PFS) [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Is defined as time from bb2121 infusion date to first documentation of PD, or death due to any cause, whichever occurs first.
  • 8. Overall Survival (OS) [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Is defined as time from bb2121 infusion date to time of death due to any cause
  • 9. Pharmacokinetics - Cmax [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Maximum transgene level
  • 10. Pharmacokinetics - Tmax [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Time to peak transgene level
  • 11. Pharmacokinetics - AUC [ Time Frame: Approximately 2.5 years after first subject bb2121 infused ]
    Area under the curve of the 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:

Subjects must satisfy all of the following criteria to be enrolled in the study:

1. Subject is newly diagnosed and has symptomatic Multiple Myeloma (MM) prior to
initiating induction anti-myeloma therapy

2. Subject is ≥ 18 years of age at the time of initial diagnosis of MM

3. Subject has measurable disease at initial diagnosis by

- M-protein and/or

- Light chain MM without measurable disease in the serum or urine

4. Subject has high-risk MM at the time of initial diagnosis of MM per R-ISS Stage III as
defined by IMWG:

- ISS Stage III and cytogenetic abnormalities with t(4; 14) and/or del(17p); and/or
t(14:16) by iFISH; or;

- ISS Stage III and serum LDH > ULN

5. Subject has Eastern Cooperative Oncology Group performance ≤ 1

6. Subjects has received ≤ to 3 cycles of the following induction anti-myeloma therapy
prior to enrollment:

- Cycle 1: one of the following regimens (RVd, KRd, CyBorD, D-RVd and D-KRd)

- Cycle 2 to Cycle 3: either KRd or RVd (Cycle 3 must be without dexamethasone)

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment: The presence
of any of the following will exclude a subject from enrollment:

At initial diagnosis, screening and prior to initiation of induction therapy for MM:

1. Subject has non-secretory MM

During Screening:

2. Subject received any treatments for MM other than up to 3 cycles of induction therapy
per protocol

3. Subject has any of the following laboratory abnormalities:

1. Absolute neutrophil count < 1,000/μL 2. Platelet count < 50,000 mm3 3. Hemoglobin < 8 g/dL (< 4.9 mmol/L) 4. Serum creatinine clearance 13.5 mg/dL (> 3.4 mmol/L)

6. Serum aspartate aminotransferase or alanine aminotransferase > 2.5 × upper limit
of normal

7. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented
Gilbert's syndrome

8. INR or aPTT > 1.5 × ULN

4. Subject has history or presence of clinically significant CNS pathology

5. Subjects has high risk for developing deep vein thrombosis or pulmonary embolus and
are unable or unwilling to undergo anti-thrombotic therapy

6. Subject has peripheral neuropathy of > Grade 2 severity according to the NCI CTCAE
Version 4.03 with bortezomib based induction regimen

7. Subjects has moderate or severe pulmonary hypertension

8. Subject has intolerance to components of induction regimen (KRd or RVd) or has any
contraindication to one or the other drug

9. Subject has not recovered from induction therapy-related toxicities (non-hematologic)
to < grade 1 CTCAE at the time of screening 10. Subject has prior history of deep vein thrombosis or pulmonary embolus (PE) within 6 months of starting study treatment 11. Subject has cardiac conditions such as: 1. Echocardiogram or multi gated acquisition assessment of left ventricular ejection fraction < 45% 2. Subject has a history of clinically significant cardiovascular disease or clinically significant ECG abnormalities 12. Subject has Pulmonary conditions such as: 1. Subject has known chronic obstructive pulmonary with a forced expiratory vol in 1 sec 50% of predicted normal. 2. Inadequate pulmonary function defined as oxygen saturation < 92 % on room air 13. Subject needs ongoing treatment with chronic immunosuppressants 14. Subject has history of primary immunodeficiency 15. Subject is seropositive for human immunodeficiency virus, chronic or active hepatitis B or active hepatitis A or C

Contacts and Locations

Contacts

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

Locations

United States, Arizona
Mayo Clinic Phoenix
Scottsdale

United States, California
UCLA School of Medicine
Los Angeles

United States, California
University of California San Francisco (UCSF)
San Francisco

United States, Colorado
Colorado Blood Cancer Institute
Denver

United States, Florida
Mayo Clinic - Jacksonville
Jacksonville

United States, Georgia
Winship Cancer Institute of Emory University
Atlanta

United States, Georgia
Northside Hospital, The Blood &Marrow Transplant Group of Georgia (BMTGA)
Atlanta

United States, Massachusetts
Massachusetts General Hospital
Boston

United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston

United States, New Jersey
Hackensack University Medical Center
Hackensack

United States, New York
NYU Langone Medical Center
New York

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

United States, North Carolina
Levine Cancer Institute
Charlotte

United States, Oregon
Oregon Health & Science University (OHSU)
Portland

United States, Pennsylvania
University of Pennsylvania - Abramson Cancer Center
Philadelphia

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

United States, Texas
UT Southwestern Medical Center
Dallas

United States, Washington
Fred Hutchinson Cancer Research Center
Seattle

United States, Wisconsin
Froedtert Hospital and Medical College of Wisconsin
Milwaukee

Sponsors and Collaborators

Celgene

Investigators

Study Director: Suresh Shelat, MD, PhD Celgene/BMS

More Information

  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT04196491 History of Changes
  • Other Study ID Numbers: BB2121-MM-004, U1111-1243-5088
  • First Posted: December 12, 2019 Key Record Dates
  • Last Update Posted: May 18, 2021
  • Last Verified: May 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: Multiple Myeloma
    Newly diagnosed multiple myeloma
    BB2121
    KarMMa-4
    Phase I
    NDMM
    High Risk
    R-ISS III
    KRd
    RVd
    Dara-KRd
    Dara-RVd
    CyBorD
    BCMA
  • Additional relevant MeSH terms: Multiple Myeloma Neoplasms, Plasma Cell