Clinical trial NCT03601078: An Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma and in Subjects With High-Risk Multiple Myeloma
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
bb2121
Relapsed and Refractory Multiple Myeloma
High Risk Multiple Myeloma
Phase 2
Multi-cohort
Open-label
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2018-07-26
Enrollment: 264
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Overall response rate (ORR)- Cohort 1
timeFrame: Up to approximately 5 years
measure: Complete response (CR) rate - Cohort 1b, 2a, 2b, 2c, and Cohort 3
timeFrame: Up to approximately 5 years
Secondary outcomes:
measure: Complete response (CR) rate - Cohort 1
timeFrame: Up to approximately 5 years
measure: Overall response rate (ORR) - Cohort 1b, 2a, b, c and Cohort 3
timeFrame: Up to approximately 5 years
measure: Very good partial response (VGPR) rate - Cohort 2c
timeFrame: Up to approximately 5 years
measure: Time to response (TTR)
timeFrame: Up to approximately 5 years
measure: Duration of response (DoR)
timeFrame: Up to approximately 5 years
measure: Progression-free survival (PFS)
timeFrame: Up to approximately 5 years
measure: Time to progression (TTP)
timeFrame: Up to approximately 5 years
measure: Overall survival (OS)
timeFrame: Up to approximately 5 years
measure: Adverse Events (AEs)
timeFrame: Up to approximately 5 years
measure: Percentage of participants who received lenalidomide maintenance for the first 3 cycles following bb2121 infusion with at least 75% dose compliance - Cohort 3
timeFrame: Up to 3 months
measure: Pharmacokinetics - Cmax
timeFrame: Minimum 5 years after bb2121 infusion
measure: Pharmacokinetics - tmax
timeFrame: Minimum 5 years after bb2121 infusion
measure: Pharmacokinetics - AUC
timeFrame: Minimum 5 years after bb2121 infusion
measure: Pharmacokinetics - tlast
timeFrame: Minimum 5 years after bb2121 infusion
measure: Pharmacokinetics - AUC0-28days
timeFrame: Minimum 5 years after bb2121 infusion
measure: Immunogenicity
timeFrame: Minimum of 2 years after bb2121 infusion
measure: Subject-reported outcomes as measured by European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC-QLQ-C30)
timeFrame: Minimum 5 years after bb2121 infusion
measure: Subject-reported outcomes as measured by EuroQoL Group EQ-5D-5L Health Questionnaire
timeFrame: Minimum 5 years after bb2121 infusion
measure: Subject-reported outcomes as measured by EORTC-QLQ-MY20
timeFrame: Minimum 5 years after bb2121 infusion
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona - Scottsdale
state: Arizona
city: San Francisco
country: United States
facility: University Of California San Francisco Medical Center
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Omaha
country: United States
facility: University Of Nebraska
state: Nebraska
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Mt Sinai Medical Center - NY
state: New York
city: New York
country: United States
facility: Columbia University Medical Center/New York-Presbyterian Hospital
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Nashville
country: United States
facility: Tennessee Oncology PLLC
state: Tennessee
city: Dallas
country: United States
facility: University Of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center The University of Texas
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Inst
state: Washington
city: Milwaukee
country: United States
facility: Froedtert Hospital BMT Medical College of Wisconsin
state: Wisconsin
city: Poitiers
country: France
facility: Local Institution - 404
city: Hamburg
country: Germany
facility: Local Institution - 506
city: Würzburg
country: Germany
facility: Local Institution - 505
city: Bologna
country: Italy
facility: Local Institution - 603
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Salamanca
country: Spain
facility: Local Institution - 704
city: London
country: United Kingdom
facility: Kings College Hospital NHS Foundation Trust
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: