Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma (KarMMa)

• ClinicalTrials.gov Identifier: NCT03361748
• Recruitment Status: Active, not recruiting
• First Posted: December 5, 2017
• Last Update Posted: March 9, 2023
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

Study Description

Brief Summary:

This is an open label, single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of bb2121 in subjects with relapsed and refractory multiple myeloma. A leukapheresis procedure will be performed to manufacture bb2121 chimeric antigen receptor (CAR) modified T cells. Prior to bb2121 infusion subjects will receive lymphodepleting therapy with fludarabine and cyclophosphamide.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Biological: bb2121	Phase 2

Detailed Description:

Anti-myeloma bridging treatment is allowed for disease control while bb2121 is being manufactured.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 149 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter Study to Determine the Efficacy and Safety of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma
• Actual Study Start Date: December 13, 2017
• Estimated Primary Completion Date: November 28, 2024
• Estimated Study Completion Date: November 28, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Administration of bb2121; bb2121 autologous CAR T cells will be infused at a dose ranging from 15 - 450 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy.	Biological: bb2121; : bb2121 consists of autologous T lymphocytes transduced with an anti-BCMA02 CAR lentiviral vector to express a chimeric antigen receptor targeting the human B cell maturation antigen (anti-BCMA CAR).

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma.

Secondary Outcome Measures :

1. Complete Response (CR) Rate [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma
2. Time to Response [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Time from first bb2121 infusion to first documentation of response
3. Duration of Response [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Time from first response to disease progression or death from any cause
4. Progression-free Survival (PFS) [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Time from first bb2121 infusion to first documentation of progressive disease (PD), or death due to any cause, whichever occurs first
5. Time to Progression (TTP) [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Time from first bb2121 infusion to first documentation of PD
6. Overall Survival (OS) [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Time from first bb2121 infusion to time of death due to any cause
7. Adverse Events (AEs) [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Number of participants with adverse events (AEs), severity of adverse events, adverse events of special interest (AESI), and serious adverse events (SAEs)
8. Pharmacokinetics - Cmax [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   The maximum transgene level at Tmax
9. Pharmacokinetics - Tmax [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
   Time to peak transgene level
10. Pharmacokinetics - AUC [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
    Area under the curve of the transgene level
11. Immunogenicity [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
    Development of an anti-CAR antibody response
12. Minimal Residual Disease (MRD) [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
    Proportion of MRD evaluable subjects that are MRD negative
13. Subject-reported outcomes as measured by European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC-QLQ-C30) [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
    Questionnaire will be used as a measure of health-related quality of life
14. Subject-reported outcomes as measured by EuroQoL Group EQ-5D-5L Health Questionnaire [ Time Frame: : Minimum of 24 months post-bb2121 infusion ]
    Is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal
15. Subject-reported outcomes as measured by EORTC-QLQ-MY20 [ Time Frame: Minimum of 24 months post-bb2121 infusion ]
    Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality

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:

Eligibility is determined prior to leukapheresis. Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).

2. Documented diagnosis of multiple myeloma

   • Must have received at least 3 prior MM treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen.
   • Must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen.
   • Must have received a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody.
   • Must be refractory to the last treatment regimen.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

4. Subjects must have measurable disease, including at least one of the criteria below:

   • Serum M-protein greater or equal to 1.0 g/dL
   • Urine M-protein greater or equal to 200 mg/24 h
   • Serum free light chain (FLC) assay: involved FLC level greater or equal to 10 mg/dL (100 mg/L) provided serum FLC ratio is abnormal
5. Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 neuropathy.

Exclusion Criteria:

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

1. Subjects with known central nervous system involvement with myeloma.
2. History or presence of clinically relevant central nervous system (CNS) pathology.
3. Subjects with active or history of plasma cell leukemia.
4. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease
5. Inadequate organ function
6. Ongoing treatment with chronic immunosuppressants
7. Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy
8. Evidence of human immunodeficiency virus (HIV) infection.
9. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV)
10. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) and Hepatitis C virus (HCV)
11. Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months.
12. Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission
13. Pregnant or lactating women.
14. Subject with known hypersensitivity to any component of bb2121 productThe presence of any of the following will exclude a subject from enrollment:

1. Subjects with known central nervous system involvement with myeloma. 2. History or presence of clinically relevant central nervous system (CNS) pathology.

3. Subjects with active or history of plasma cell leukemia. 4. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence of measurable disease 5. Inadequate organ function 6. Ongoing treatment with chronic immunosuppressants 7. Previous history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy 8. Evidence of human immunodeficiency virus (HIV) infection. 9. Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV) and Hepatitis C virus (HCV) 10. Subjects with a history of class III or IV congestive heart failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months. 11. Subjects with second malignancies in addition to myeloma if the second malignancy has required therapy in the last 3 years or is not in complete remission 12. Pregnant or lactating women. 13 Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, or tocilizumab.

Contacts and Locations

Locations

United States, California

Local Institution - 108

San Francisco, California, United States, 94143

United States, Georgia

Local Institution - 103

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Local Institution - 107

Boston, Massachusetts, United States, 02114

Local Institution - 106

Boston, Massachusetts, United States, 02215

United States, Minnesota

Local Institution - 105

Rochester, Minnesota, United States, 55905

United States, New Jersey

Local Institution - 102

Hackensack, New Jersey, United States, 07601

United States, New York

Local Institution - 109

New York, New York, United States, 10029

United States, Tennessee

Local Institution - 101

Nashville, Tennessee, United States, 37203

United States, Texas

Local Institution - 104

Dallas, Texas, United States, 75390

Belgium

Local Institution - 201

Leuven, Belgium, B-3000

Canada, Ontario

Local Institution - 301

Toronto, Ontario, Canada, M5G 2M9

France

Local Institution - 402

Lille, France, 59037

Local Institution - 401

Nantes, France, 44093

Germany

Local Institution - 502

Heidelberg, Germany, 69120

Local Institution - 503

Tübingen, Germany, 72076

Local Institution - 501

Würzburg, Germany, 97080

Italy

Local Institution - 602

Bergamo, Italy, 24128

Local Institution - 601

Bologna, Italy, 40138

Japan

Local Institution - 803

Isehara City, Kanagawa, Japan, 259-1193

Local Institution - 801

Shibuya-ku, Japan, 150-8935

Local Institution - 802

Shimotsuke, Japan, 329-0498

Local Institution - 804

Shinjuku City, Japan, 162-8666

Spain

Local Institution - 702

Badalona (Barcelona), Spain, 08916

Local Institution - 701

Pamplona, Spain, 31008

Sponsors and Collaborators

Celgene

Investigators

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

More Information

Additional Information:

BMS Clinical Trial Information 

BMS Clinical Trial Patient Recruiting 

Publications:

Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, Liedtke M, Rosenblatt J, Maus MV, Turka A, Lam LP, Morgan RA, Friedman K, Massaro M, Wang J, Russotti G, Yang Z, Campbell T, Hege K, Petrocca F, Quigley MT, Munshi N, Kochenderfer JN. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019 May 2;380(18):1726-1737. doi: 10.1056/NEJMoa1817226.

Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, Raje N, Lin Y, Siegel D, Oriol A, Moreau P, Yakoub-Agha I, Delforge M, Cavo M, Einsele H, Goldschmidt H, Weisel K, Rambaldi A, Reece D, Petrocca F, Massaro M, Connarn JN, Kaiser S, Patel P, Huang L, Campbell TB, Hege K, San-Miguel J. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Feb 25;384(8):705-716. doi: 10.1056/NEJMoa2024850.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shah N, Mojebi A, Ayers D, Cope S, Dhanasiri S, Davies FE, Hari P, Patel P, Hege K, Dhanda D. Indirect treatment comparison of idecabtagene vicleucel versus conventional care in triple-class exposed multiple myeloma. J Comp Eff Res. 2022 Jul;11(10):737-749. doi: 10.2217/cer-2022-0045. Epub 2022 Apr 29.

Sharma P, Kanapuru B, George B, Lin X, Xu Z, Bryan WW, Pazdur R, Theoret MR. FDA Approval Summary: Idecabtagene Vicleucel for Relapsed or Refractory Multiple Myeloma. Clin Cancer Res. 2022 May 2;28(9):1759-1764. doi: 10.1158/1078-0432.CCR-21-3803.

Delforge M, Shah N, Miguel JSF, Braverman J, Dhanda DS, Shi L, Guo S, Yu P, Liao W, Campbell TB, Munshi NC. Health-related quality of life with idecabtagene vicleucel in relapsed and refractory multiple myeloma. Blood Adv. 2022 Feb 22;6(4):1309-1318. doi: 10.1182/bloodadvances.2021005913.

Da Via MC, Dietrich O, Truger M, Arampatzi P, Duell J, Heidemeier A, Zhou X, Danhof S, Kraus S, Chatterjee M, Meggendorfer M, Twardziok S, Goebeler ME, Topp MS, Hudecek M, Prommersberger S, Hege K, Kaiser S, Fuhr V, Weinhold N, Rosenwald A, Erhard F, Haferlach C, Einsele H, Kortum KM, Saliba AE, Rasche L. Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma. Nat Med. 2021 Apr;27(4):616-619. doi: 10.1038/s41591-021-01245-5. Epub 2021 Feb 22.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT03361748
• Other Study ID Numbers: BB2121-MM-001; U1111-1202-5554 ( Other Identifier: WHO ); 2017-002245-29 ( EudraCT Number )
• First Posted: December 5, 2017
• Last Update Posted: March 9, 2023
• Last Verified: March 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Celgene:

Multiple Myeloma; Efficacy and Safety; BB2121; CAR T Cell; BCMA; Relapsed and Refractory

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Idecabtagene vicleucel; Antineoplastic Agents, Immunological; Antineoplastic Agents