KarMMa-2: An Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma and in Subjects With High-Risk Multiple Myeloma

• Sponsor: Celgene (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT03601078
• Collaborator: (none)
• Enrollment: 235
• Locations: 50
• Arms: 2
• Anticipated Duration (Months): 144.6
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study is a multi-cohort, open-label, multicenter Phase 2 study to evaluate the efficacy and safety of bb2121 in subjects with relapsed and refractory MM (Cohort 1), in subjects with MM having progressed within one 18 months of initial treatment including autologous stem cell transplantation (ASCT) (Cohort 2a), and without ASCT (Cohort 2b) or, in subjects with inadequate response post ASCT during initial treatment (Cohort 2c). Approximately 235 subjects will be enrolled into one of three cohorts. Cohort 1 will enroll approximately 97 RRMM subjects with ≥ 3 prior anti-myeloma treatment regimens. Cohort 2a will enroll approximately 39 MM subjects, with 1 prior anti-myeloma therapy including ASCT and with early relapse. Cohort 2b will enroll approximately 39 MM subjects with 1 prior anti-myeloma therapy not including ASCT and with early relapse. Cohort 2c will enroll approximately 30 MM subjects with inadequate response to ASCT during their initial anti-myeloma therapy. The cohorts will start in parallel and independently. Cohort 3 will enroll approximately 30 newly diagnosed multiple myeloma (NDMM) participants with suboptimal response to ASCT.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Biological: bb2121; Drug: Lenalomide	Phase 2

Detailed Description

Anti-myeloma bridging treatment is allowed for disease control while bb2121 is being manufactured for cohorts 1, 2a and 2b only.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 235 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multi-cohort, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma and in Subjects With Clinical High-Risk Multiple Myeloma (KarMMa-2)
• Actual Study Start Date: Dec 13, 2018
• Anticipated Primary Completion Date: Dec 18, 2023
• Anticipated Study Completion Date: Dec 30, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: bb2121 in relapsed and refractory multiple myeloma patients bb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 450 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy	Biological: bb2121; bb2121 consists of autologous T lymphocytes transduced with an anti-BCMA CAR lentiviral vector to express a chimeric antigen receptor targeting the human B cell maturation antigen (anti-BCMA CAR); Other Names: BMS-986395
Experimental: BB2121 with lenalidomide in newly diagnosed multiple myeloma	Biological: bb2121; bb2121 consists of autologous T lymphocytes transduced with an anti-BCMA CAR lentiviral vector to express a chimeric antigen receptor targeting the human B cell maturation antigen (anti-BCMA CAR); Other Names: BMS-986395 ; Drug: Lenalomide; Specified dose on specified days; Other Names: Revlimid®

Outcome Measures

Primary Outcome Measures

1. Overall response rate (ORR)- Cohort 1 [Up to approximately 5 years]

   Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator

2. Complete response (CR) rate - Cohort 2a , b, c and Cohort 3 [Up to approximately 5 years]

   Percentage of subjects who achieved CR or stringent CR according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator

Secondary Outcome Measures

1. Complete response (CR) rate - Cohort 1 [Up to approximately 5 years]

   Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator

2. Overall response rate (ORR) - Cohort 2a, b, c and Cohort 3 [Up to approximately 5 years]

   Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator

3. Very good partial response (VGPR) rate - Cohort 2c [Minimum of 2 years after bb2121 infusion]

   Percentage of subjects who achieved VGPR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator

4. Time to response (TTR) [Minimum of 2 years after bb2121 infusion]

   Time from first bb2121 infusion to first documentation of response (PR or greater)

5. Duration of response (DoR) [Minimum of 2 years after bb2121 infusion]

   Time from first documentation of response (PR or greater) to first documentation of progressive disease (PD) or death from any cause, whichever occurs first

6. Progression-free survival (PFS) [Minimum of 2 years after bb2121 infusion]

   Time from first bb2121 infusion to first documentation of PD, or death due to any cause, whichever occurs first

7. Time to progression (TTP) [Minimum of 2 years after bb2121 infusion]

   Time from first bb2121 infusion to first documentation of PD

8. Overall survival (OS) [Minimum of 2 years after bb2121 infusion]

   Time from first bb2121 infusion to time of death due to any cause

9. Adverse Events (AEs) [Minimum 5 years after bb2121 infusion]

   Type, frequency, seriousness and severity of adverse events (AEs), adverse events of special interest (AESIs) (including cytokine release syndrome, neurotoxicity and infection), and relationship of AE to study drug.

10. Percentage of participants who received lenalidomide maintenance for the first 3 cycles following bb2121 infusion with at least 75% dose compliance - Cohort 3 [Up to 3 months]

11. Pharmacokinetics - Cmax [Minimum 5 years after bb2121 infusion]

    Maximum expansion of bb2121 chimeric antigen receptor (CAR) T cells

12. Pharmacokinetics - tmax [Minimum 5 years after bb2121 infusion]

    Time to peak of bb2121 CAR T cells

13. Pharmacokinetics - AUC [Minimum 5 years after bb2121 infusion]

    Area under the curve of CAR T cells

14. Pharmacokinetics - tlast [Minimum 5 years after bb2121 infusion]

    Time to last measurable CAR T cells

15. Pharmacokinetics - AUC0-28days [Minimum 5 years after bb2121 infusion]

    Area under the curve of CAR T cells from time zero to Day 28

16. Immunogenicity [Minimum of 2 years after bb2121 infusion]

    Development of an anti-CAR antibody response

17. Subject-reported outcomes as measured by European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC-QLQ-C30) [Minimum 5 years after bb2121 infusion]

    Questionnaire will be used as a measure of health-related quality of life

18. Subject-reported outcomes as measured by EuroQoL Group EQ-5D-5L Health Questionnaire [Minimum 5 years after 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

19. Subject-reported outcomes as measured by EORTC-QLQ-MY20 [Minimum 5 years after bb2121 infusion]

    Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality

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 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. For Cohorts 1 and 2 only, participant has measurable disease, defined as:

• M-protein (serum protein electrophoresis [sPEP] or urine protein electrophoresis [uPEP]): sPEP ≥ 0.5 g/dL or uPEP ≥ 200 mg/24 hours and/or

• Light chain MM without measurable disease in the serum or urine: Serum immunoglobulin free light chain ≥ 10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio

1. Subjects with one of the following cohort specific requirements:

Cohort 1 RRMM subjects with ≥ 3 prior anti-myeloma treatment regimens:

• Subject must have received at least 3 prior anti-myeloma treatment regimens. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen

• Subject must have undergone at least 2 consecutive cycles of treatment for each regimen, unless PD was the best response to the regimen

• Subject must have received prior treatment with a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody

• Subject has evidence of PD on or within 60 days of the most recent prior treatment regimen

• Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen

Cohort 2 subjects with 1 prior anti-myeloma treatment regimen:

• Subject must have received only 1 prior anti-myeloma treatment regimen. Note: induction with or without hematopoietic stem cell transplant and with or without maintenance therapy is considered a single regimen

• Subject must have the following HR factors:

• Early relapse defined as:

Cohort 2a: PD < 18 months since date of start of initial therapy. Initial therapy must contain induction, ASCT (single or tandem) and lenalidomide containing maintenance.

Cohort 2b: PD < 18 months since date of start or initial therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone Cohort 2c: Subject must have received minimum 3 cycles of induction therapy which must contain at minimum, a proteasome inhibitor, an immunomodulatory agent and dexamethasone. Subjects must have had ASCT (single or tandem AND < VGPR (excluding PD) at first assessment between 70 to 110 days after last ASCT, with initial therapy without consolidation and maintenance. Cohort 3 participants with newly diagnosed MM (NDMM) who received only induction and ASCT, without subsequent consolidation or maintenance Subject with NDMM who have received only induction and ASCT, without subsequent consolidation or maintenance Cohort 3

• With NDMM who have received only induction and ASCT, without subsequent consolidation or maintenance

• Must have received 4 to 6 cycles of induction therapy which must contain at minimum, a proteasome inhibitor and an immunomodulatory agent and must have had single ASCT within 6 months prior to consent

• Must have achieved documented PR or VGPR at first post-ASCT assessment approximately 100 days after ASCT and this response must be maintained at screening

• Per Investigator's assessment, subject must be a candidate for single-agent lenalidomide maintenance

1. Subject must have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

2. Subject must have 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. Subject used any investigational agents within 14 days prior to leukapheresis or, for Cohort 3, within 14 days prior to consent

2. Subject received any of the following within the last 14 days prior to leukapheresis or, for Cohort 3, within 14 days prior to consent:

3. Plasmapheresis

4. Major surgery (as defined by the investigator)

5. Radiation therapy other than local therapy for myeloma associated bone lesions

6. Use of any systemic anti-myeloma drug therapy

7. Subject with known central nervous system involvement with myeloma

8. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation

9. History or presence of clinically relevant central nervous system (CNS) pathology

10. Subject with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, or clinically significant amyloidosis

11. Inadequate organ function Subject with a history of Class III or IV congestive heart failure (CHF) or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 6 months prior to starting study treatment

12. Ongoing treatment with chronic immunosuppressants

13. 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

14. Subject has received ASCT within 12 weeks prior to leukapheresis

15. Subject has history of primary immunodeficiency

16. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C

17. Subject has uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment

18. Subject with prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years

19. Pregnant or lactating women

20. Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic in Arizona - Scottsdale	Scottsdale	Arizona	United States	85259
3	UCSF Medical Center	San Francisco	California	United States	94142
4	University Of California San Francisco Medical Center	San Francisco	California	United States	94142
5	Moffitt Cancer Center	Tampa	Florida	United States	33612
6	Moffitt Cancer Center	Tampa	Florida	United States	33612
7	Emory University	Atlanta	Georgia	United States	30322
8	Emory University	Atlanta	Georgia	United States	30322
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02117
10	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215-5450
11	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215-5450
12	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
13	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
14	Washington University	Saint Louis	Missouri	United States	63110
15	Washington University	Saint Louis	Missouri	United States	63110
16	University of Nebraska	Omaha	Nebraska	United States	68198-7680
17	University Of Nebraska	Omaha	Nebraska	United States	68198-7680
18	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
19	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
20	Mt Sinai Medical Center - NY	New York	New York	United States	10029
21	Mt Sinai Medical Center - NY	New York	New York	United States	10029
22	Columbia University Medical Center / New York Presbyterian Hospital	New York	New York	United States	10032
23	Columbia University Medical Center/New York-Presbyterian Hospital	New York	New York	United States	10032
24	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
25	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
26	Levine Cancer Institute	Charlotte	North Carolina	United States	28204
27	Sarah Cannon Research Inst	Nashville	Tennessee	United States	37203
28	Sarah Cannon Research Inst	Nashville	Tennessee	United States	37203
29	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75235
30	University Of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
31	MD Anderson Cancer Center The University of Texas	Houston	Texas	United States	77030
32	MD Anderson Cancer Center The University of Texas	Houston	Texas	United States	77030
33	Swedish Cancer Inst	Seattle	Washington	United States	98104
34	Swedish Cancer Inst	Seattle	Washington	United States	98104
35	Froedtert Hospital BMT Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226-3522
36	Froedtert Hospital BMT Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226-3522
37	CHU de Poitiers	Poitiers		France	86021
38	Local Institution - 404	Poitiers		France	86021
39	Local Institution - 506	Hamburg		Germany	20246
40	Universitaetsklinkum Hamburg-Eppendorf	Hamburg		Germany	20246
41	Local Institution - 505	Würzburg		Germany	97080
42	Universitatsklinikum Würzburg	Würzburg		Germany	97080
43	Azienda Ospedaliero Universitaria Di Bologna - Policlinico S.Orsola Malpighi	Bologna		Italy	40138
44	Local Institution - 603	Bologna		Italy	40138
45	Clinica Universitaria de Navarra	Pamplona		Spain	31008
46	Local Institution - 703	Pamplona		Spain	31008
47	Hospital Universitario de Salamanca	Salamanca		Spain	37007
48	Local Institution - 704	Salamanca		Spain	37007
49	King's College HospitalGKT School of Medicine	London		United Kingdom	SE5 9RS
50	Local Institution - 801	London		United Kingdom	SE5 9RS

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: NCT03601078
• Other Study ID Numbers: BB2121-MM-002; U1111-1216-4209; 2018-000264-28
• First Posted: Jul 26, 2018
• Last Update Posted: Jun 24, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Celgene: Multiple Myeloma; bb2121; Relapsed and Refractory Multiple Myeloma; High Risk Multiple Myeloma; Phase 2; Multi-cohort; Open-label
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Lenalidomide

Study Results

No Results Posted as of Jun 24, 2022