KarMMa-4: A Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (NDMM)

Sponsor
Celgene (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT04196491
Collaborator
(none)
13
20
1
42.6
0.7
0

Study Details

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 Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
13 participants
Allocation:
N/A
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 27, 2020
Anticipated Primary Completion Date :
Dec 14, 2023
Anticipated Study Completion Date :
Dec 14, 2023

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
CAR-T Cell Therapy
Other Names:
  • ide-cel
  • Drug: Fludarabine
    Lymphodepleting Chemotherapy

    Drug: Cyclophosphamide
    Lymphodepleting Chemotherapy

    Drug: Lenalidomide
    Maintenance Therapy

    Outcome Measures

    Primary Outcome Measures

    1. Dose-limiting toxicity (DLT) rates [Up to completion of DLT period after last 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) [Approximately 2 years after last 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 [Approximately 2 years after last 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) [Approximately 2 years after last 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) [Approximately 2 years after last 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) [Approximately 2 years after last 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 [Approximately 2 years after last subject bb2121 infused]

      Is defined as time to start lenalidomide maintenance therapy post-bb2121 infusion

    6. Feasibility of initiating maintenance [Approximately 2 years after last subject bb2121 infused]

      Number of subjects starting the maintenance or on maintenance between D90 and D110

    7. Progression-free Survival (PFS) [Approximately 2 years after last 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) [Approximately 2 years after last subject bb2121 infused]

      Is defined as time from bb2121 infusion date to time of death due to any cause

    9. Pharmacokinetics - Cmax [Approximately 2 years after last subject bb2121 infused]

      Maximum transgene level

    10. Pharmacokinetics - Tmax [Approximately 2 years after last subject bb2121 infused]

      Time to peak transgene level

    11. Pharmacokinetics - AUC [Approximately 2 years after last subject bb2121 infused]

      Area under the curve of the transgene level

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    1. 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

    1. Subject has Eastern Cooperative Oncology Group performance ≤ 1

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

    2. Subject has any of the following laboratory abnormalities:

    3. Absolute neutrophil count < 1,000/μL

    4. Platelet count < 50,000 mm3

    5. Hemoglobin < 8 g/dL (< 4.9 mmol/L)

    6. Serum creatinine clearance < 45 mL/min

    7. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)

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

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

    10. INR or aPTT > 1.5 × ULN

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

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

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

    14. Subjects has moderate or severe pulmonary hypertension

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

    16. Subject has not recovered from induction therapy-related toxicities (non-hematologic) to < grade 1 CTCAE at the time of screening

    17. Subject has prior history of deep vein thrombosis or pulmonary embolus (PE) within 6 months of starting study treatment

    18. Subject has cardiac conditions such as:

    19. Echocardiogram or multi gated acquisition assessment of left ventricular ejection fraction < 45%

    20. Subject has a history of clinically significant cardiovascular disease or clinically significant ECG abnormalities

    21. Subject has Pulmonary conditions such as:

    22. Subject has known chronic obstructive pulmonary with a forced expiratory vol in 1 sec 50% of predicted normal.

    23. Inadequate pulmonary function defined as oxygen saturation < 92 % on room air

    24. Subject needs ongoing treatment with chronic immunosuppressants

    25. Subject has history of primary immunodeficiency

    26. Subject is seropositive for human immunodeficiency virus, chronic or active hepatitis B or active hepatitis A or C

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic Phoenix Scottsdale Arizona United States 85259
    2 UCLA School of Medicine Los Angeles California United States 90095
    3 University of California San Francisco (UCSF) San Francisco California United States 94143
    4 Colorado Blood Cancer Institute Denver Colorado United States 80218
    5 Mayo Clinic - Jacksonville Jacksonville Florida United States 32224
    6 Winship Cancer Institute of Emory University Atlanta Georgia United States 30322
    7 Northside Hospital, The Blood &Marrow Transplant Group of Georgia (BMTGA) Atlanta Georgia United States 30342
    8 Massachusetts General Hospital Boston Massachusetts United States 02114
    9 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02215
    10 Hackensack University Medical Center Hackensack New Jersey United States 07601
    11 NYU Langone Medical Center New York New York United States 10016
    12 Icahn School of Medicine at Mount Sinai Medical Center New York New York United States 10029
    13 Levine Cancer Institute Charlotte North Carolina United States 28204
    14 Oregon Health & Science University (OHSU) Portland Oregon United States 97239
    15 University of Pennsylvania - Abramson Cancer Center Philadelphia Pennsylvania United States 19104
    16 Sarah Cannon Research Institute Center for Blood Cancers Nashville Tennessee United States 37203
    17 UT Southwestern Medical Center Dallas Texas United States 75390
    18 The University of Texas - MD Anderson Cancer Center Houston Texas United States 77030
    19 Fred Hutchinson Cancer Research Center Seattle Washington United States 75390
    20 Froedtert Hospital and Medical College of Wisconsin Milwaukee Wisconsin United States 53226

    Sponsors and Collaborators

    • Celgene

    Investigators

    • Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Celgene
    ClinicalTrials.gov Identifier:
    NCT04196491
    Other Study ID Numbers:
    • BB2121-MM-004
    • U1111-1243-5088
    First Posted:
    Dec 12, 2019
    Last Update Posted:
    Jul 8, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Celgene
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 8, 2022