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

Multiple Myeloma Clinical Trial

— KarMMa-2  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03601078
• Other study ID #: BB2121-MM-002
• Secondary ID: U1111-1216-42092
• Status: Recruiting
• Phase: Phase 2
• Start date: December 13, 2018
• Est. completion date: December 30, 2030

Study information

• Verified date: February 2024
• Source: Celgene
• Contact: BMS Study Connect Contact Center www.BMSStudyConnect.com
• Phone: 855-907-3286
• Email: Clinical.Trials[@]bms.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a multi-cohort, open-label, multicenter Phase 2 study to evaluate the efficacy and safety of bb2121 in participants with relapsed and refractory multiple myeloma (RRMM) (Cohort 1), in participants with RRMM who receive bridging therapy with talquetamab (Cohort 1b), in participants with multiple myeloma (MM) having progressed within 18 months of initial treatment with autologous stem cell transplantation (ASCT) (Cohort 2a) and without ASCT (Cohort 2b) or, in participants with inadequate response post ASCT during initial treatment (Cohort 2c) and the efficacy and safety of bb2121 used in combination with lenalidomide maintenance in participants with suboptimal response post ASCT (Cohort 3). Approximately 264 participants will be enrolled into one of three cohorts. Cohort 1 (including cohort 1b) will enroll approximately 126 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.

Description:

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 264
• Est. completion date: December 30, 2030
• Est. primary completion date: July 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

3. 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 Cohort 3

• 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

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

5. 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:

1. Plasmapheresis

2. Major surgery (as defined by the investigator)

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

4. Use of any systemic anti-myeloma drug therapy

3. Subject with known central nervous system involvement with myeloma

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

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

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

7. 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

8. Ongoing treatment with chronic immunosuppressants

9. 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

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

11. Subject has history of primary immunodeficiency

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

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

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

15. Pregnant or lactating women

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

17. Prior history of deep venous thrombosis (DVT) or pulmonary embolus (PE) within 6 months prior to consent (For Cohort 3)

18. For Cohort 1b, previous treatment with any G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D) targeted therapy or T-cell engagers

19. For Cohort 1b, known allergies, hypersensitivity, or intolerance to talquetamab or its excipients

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

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)

Drug:
• Lenalomide
Specified dose on specified days
• Talquetamab
Specified dose on specified days

Locations

Country	Name	City	State
France	Local Institution - 404	Poitiers
Germany	Local Institution - 506	Hamburg
Germany	Local Institution - 505	Würzburg
Italy	Local Institution - 603	Bologna
Spain	Local Institution - 703	Pamplona
Spain	Local Institution - 704	Salamanca
United Kingdom	Local Institution - 801	London
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Local Institution - 0802	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University Of Texas Southwestern Medical Center	Dallas	Texas
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	MD Anderson Cancer Center The University of Texas	Houston	Texas
United States	Froedtert Hospital BMT Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Sarah Cannon Research Inst	Nashville	Tennessee
United States	Columbia University Medical Center/New York-Presbyterian Hospital	New York	New York
United States	Mt Sinai Medical Center - NY	New York	New York
United States	University Of Nebraska	Omaha	Nebraska
United States	Washington University	Saint Louis	Missouri
United States	University Of California San Francisco Medical Center	San Francisco	California
United States	Mayo Clinic in Arizona - Scottsdale	Scottsdale	Arizona
United States	Swedish Cancer Inst	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  France,  Germany,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response rate (ORR)- Cohort 1	Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator	Up to approximately 5 years
Primary	Complete response (CR) rate - Cohort 1b, 2a, 2b, 2c, and Cohort 3	Percentage of subjects who achieved CR or stringent CR according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator	Up to approximately 5 years
Secondary	Complete response (CR) rate - Cohort 1	Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator	Up to approximately 5 years
Secondary	Overall response rate (ORR) - Cohort 1b, 2a, b, c and Cohort 3	Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator	Up to approximately 5 years
Secondary	Very good partial response (VGPR) rate - Cohort 2c	Percentage of subjects who achieved VGPR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by the investigator	Up to approximately 5 years
Secondary	Time to response (TTR)	Time from first bb2121 infusion to first documentation of response (PR or greater) [Cohorts 1 and 2]; time from first dose of lenalidomide pre-leukapheresis to first documentation of response [Cohort 3 only]	Up to approximately 5 years
Secondary	Duration of response (DoR)	Time from first documentation of response (PR or greater) to first documentation of progressive disease (PD) or death from any cause, whichever occurs first	Up to approximately 5 years
Secondary	Progression-free survival (PFS)	Time from first bb2121 infusion to first documentation of PD, or death due to any cause, whichever occurs first (Cohorts 1 and 2); time from first dose of lenalidomide pre-leukapheresis to first documentation of PD, or death due to any cause, whichever occurs first (Cohort 3 only)	Up to approximately 5 years
Secondary	Time to progression (TTP)	Time from first bb2121 infusion to first documentation of PD (Cohorts 1 and 2); time from first dose of lenalidomide pre-leukapheresis to first documentation of PD (Cohort 3 only)	Up to approximately 5 years
Secondary	Overall survival (OS)	Time from first bb2121 infusion to time of death due to any cause (Cohorts 1 and 2); time from first dose of lenalidomide pre-leukapheresis to time of death due to any cause (Cohort 3 only)	Up to approximately 5 years
Secondary	Adverse Events (AEs)	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.	Up to approximately 5 years
Secondary	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
Secondary	Pharmacokinetics - Cmax	Maximum expansion of bb2121 chimeric antigen receptor (CAR) T cells	Minimum 5 years after bb2121 infusion
Secondary	Pharmacokinetics - tmax	Time to peak of bb2121 CAR T cells	Minimum 5 years after bb2121 infusion
Secondary	Pharmacokinetics - AUC	Area under the curve of CAR T cells	Minimum 5 years after bb2121 infusion
Secondary	Pharmacokinetics - tlast	Time to last measurable CAR T cells	Minimum 5 years after bb2121 infusion
Secondary	Pharmacokinetics - AUC0-28days	Area under the curve of CAR T cells from time zero to Day 28	Minimum 5 years after bb2121 infusion
Secondary	Immunogenicity	Development of an anti-CAR antibody response	Minimum of 2 years after bb2121 infusion
Secondary	Subject-reported outcomes as measured by European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC-QLQ-C30)	Questionnaire will be used as a measure of health-related quality of life	Minimum 5 years after bb2121 infusion
Secondary	Subject-reported outcomes as measured by EuroQoL Group EQ-5D-5L Health Questionnaire	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	Minimum 5 years after bb2121 infusion
Secondary	Subject-reported outcomes as measured by EORTC-QLQ-MY20	Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality	Minimum 5 years after bb2121 infusion

External Links

•   BMS Clinical Trial Information
•   BMS Clinical Trial Patient Recruiting