Clinical trial NCT03651128: Efficacy and Safety Study of bb2121 Versus Standard Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM)
Official title: A Phase 3, Multicenter, Randomized, Open-label Study to Compare the Efficacy and Safety of bb2121 Versus Standard Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) (KarMMa-3)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
bb2121
Relapsed and Refractory Multiple Myeloma
High Risk Multiple Myeloma
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2018-08-29
Enrollment: 381
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of bb2121 versus standard regimens in subjects with relapsed and refractory multiple myeloma (RRMM).

The study is anticipated to randomize approximately 381 subjects with RRMM. Approximately 254 subjects will be randomized to Treatment Arm A and approximately 127 subjects will be randomized to Treatment Arm B.


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. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements within this protocol and for a subject randomized to Treatment Arm A, subject agrees to continued follow-up for up to 15 years as mandated by the regulatory guidelines for gene therapy trials.
4. Subject has documented diagnosis of MM and 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 (100 mg/L) and abnormal serum immunoglobulin kappa lambda free light chain ratio
5. Subject has received at least 2 but no greater than 4 prior MM regimens.
6. Subject has received prior treatment with DARA, a proteasome inhibitor- and an immunomodulatory compound-containing regimen for at least 2 consecutive cycles.
7. Subject must be refractory to the last treatment regimen. Refractory is defined as documented progressive disease during or within 60 days (measured from the last dose of any drug within the regimen) of completing treatment with the last anti-myeloma regimen before study entry.
8. Subject achieved a response (minimal response \[MR\] or better) to at least 1 prior treatment regimen.
9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
10. Recovery to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding alopecia and Grade 2 peripheral neuropathy.
11. Adequate vascular access for leukapheresis
12. Females of childbearing potential (FCBP) must:

    a. Have negative pregnancy test(s) as verified by the Investigator. This applies even if the subject practices true abstinence from heterosexual contact.

    b. Either practice true abstinence from heterosexual contact or agree to use, and be able to comply with, effective measures of contraception without interruption.

    c. Agree to abstain from breastfeeding during study participation. d. Refrain from tissue donation including egg cell donation or any other tissue/blood/organ donations.
13. Male subjects must:

    a. Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, even if he has undergone a successful vasectomy.

    b. Refrain from tissue donation including sperm or any other tissue/blood/organ donations.
14. Only subjects that would be considered for any of the 5 proposed standard regimens (DPd, DVd, IRd, Kd, or EPd), as judged by the investigator, should be included in the study.

Exclusion Criteria:

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

1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject has nonsecretory multiple myeloma (MM).
5. Subject has any of the following laboratory abnormalities:

   a. Absolute neutrophil count (ANC) \< 1,000/μL b. Platelet count: \< 75,000/μL in subjects in whom \< 50% of bone marrow nucleated cells are plasma cells and platelet count \< 50,000/μL in subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells (it is not permissible to transfuse a subject to reach this level) c. Hemoglobin \< 8 g/dL (\< 4.9 mmol/L) (it is not permissible to transfuse a subject to reach this level) d. Serum creatinine clearance (CrCl) \< 45 mL/min e. Corrected serum calcium \> 13.5 mg/dL (\> 3.4 mmol/L) f. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 × upper limit of normal (ULN) g. Serum total bilirubin \> 1.5 × ULN or \> 3.0 mg/dL for subjects with documented Gilbert's syndrome h. International normalized ratio (INR) or activated partial thromboplastin time (aPTT) \> 1.5 × ULN, or history of Grade ≥ 2 hemorrhage within 30 days, or subject requires ongoing treatment with chronic, therapeutic dosing of anticoagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors)
6. Subject has inadequate pulmonary function defined as oxygen saturation (SaO2) \< 92% on room air.
7. Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years • Basal cell carcinoma of the skin

   • Squamous cell carcinoma of the skin
   * Carcinoma in situ of the cervix
   * Carcinoma in situ of the breast
   * Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[TNM\] clinical staging system) or prostate cancer that can be treated with curative intent
8. Subject has active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome or amyloidosis.
9. Subject with known central nervous system (CNS) involvement with myeloma.
10. Subject has clinical evidence of pulmonary leukostasis and disseminated intravascular coagulation.
11. Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) 50% of predicted normal.
12. Subject has a history or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
13. Subject was treated with DARA in combination with POM with or without dex (DP±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DPd as bridging therapy but may receive DVd, IRd, Kd or EPdas bridging as per Investigator's discretion if randomized to Treatment Arm A.
14. Subject was treated with DP±d as part of their most recent anti-myeloma treatment regimen, cannot receive DPd if randomized to Treatment Arm B but may receive DVd, IRd, Kd, or EPd as per Investigator's discretion.
15. Subject was treated with DARA in combination with BTZ with or without dexamethasone (DV±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DVd as bridging therapy but may receive DPd, IRd, Kd, or EPd as bridging as per Investigator's discretion if randomized to Treatment Arm A.
16. Subject was treated with DV±d as part of their most recent anti-myeloma treatment regimen, cannot receive DVd if randomized to Treatment Arm B but may receive DPd, IRd, Kd, or EPd as per Investigator's discretion.
17. Subject was treated with IXA in combination with LEN with or without dexamethasone (IR±d) as part of their most recent anti-myeloma treatment regimen, cannot receive IRd as bridging therapy but may receive DPd, DVd, Kd, or EPd as bridging as per Investigator's discretion if randomized to Treatment Arm A.
18. Subject was treated with IR±d as part of their most recent anti-myeloma treatment regimen, cannot receive IRd if randomized to Treatment Arm B but may receive DPd, DVd, Kd, or EPd as per Investigator's discretion.
19. Previous history of an allogeneic hematopoietic stem cell transplantation, treatment with any gene therapy-based therapeutic for cancer, investigational cellular therapy for cancer or BCMA targeted therapy.
20. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks prior to randomization.
21. Subject has received any of the following within the last 14 days prior to randomization:

    a. Plasmapheresis b. Major surgery (as defined by the Investigator) c. Radiation therapy other than local therapy for myeloma-associated bone lesions d. Use of any investigational agents and systemic anti-myeloma drug therapy
22. Echocardiogram (ECHO) or multigated acquisition (MUGA) with left ventricular ejection fraction (LVEF) \< 45%.
23. Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are allowed.
24. Subject is positive for human immunodeficiency virus (HIV-1 and HIV-2), chronic or active hepatitis B or active hepatitis A or C.
25. Subject has uncontrolled systemic fungal, bacterial, viral or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial treatment) or requiring IV antimicrobials for management.
26. Subject has 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 randomization.
27. Hypersensitivity to DARA, thalidomide, lenalidomide, POM, BTZ, IXA, CFZ, ELO or dexamathasone. This includes rash ≥ Grade 3 during prior thalidomide, POM or lenalidomide therapy.
28. Subject with known hypersensitivity to any component of bb2121 product, cyclophosphamide, fludarabine, and/or tocilizumab or hypersensitivity to the excipients contained in the formulation of DARA, POM, LEN, IXA, BTZ, CFZ, ELO or dexamethasone.
29. Subject is a female who is pregnant, nursing, or breastfeeding
30. For a subject randomized to Treatment Arm B and will be on a POM- or LEN-containing regimen; unable or unwilling to undergo protocol required thromboembolism prophylaxis.

28 Subject is intolerant to bortezomib, or has acute diffuse infiltrative pulmonary and pericardial disease, subject cannot receive DVd as bridging therapy if randomized to Treatment Arm A or cannot receive DVd if randomized to Treatment Arm B.

31. Subject was treated with K±d as part of their most recent anti-myeloma treatment regimen, cannot receive Kd if randomized to Treatment Arm B but may receive DPd, DVd, IRd or EPd as per Investigator's discretion.

32. Subject was treated with EP±d as part of their most recent anti-myeloma treatment regimen, cannot receive EPd if randomized to Treatment Arm B but may receive DPd, DVd, Kd or IRd as per Investigator's discretion.

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Minimum of 5 years from randomization
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Minimum of 5 years from randomization
measure: Event-free Survival (EFS)
timeFrame: Minimum of 5 years from randomization
measure: Overall Response Rate (ORR)
timeFrame: Minimum of 5 years from randomization
measure: Minimal Residual Disease (MRD)
timeFrame: Minimum of 5 years from randomization
measure: Complete Response (CR) Rate
timeFrame: Minimum of 5 years from randomization
measure: Duration of Response (DOR)
timeFrame: Minimum of 5 years from randomization
measure: Time to Response (TTR)
timeFrame: Minimum of 5 years from randomization
measure: Adverse Events (AEs)
timeFrame: Minimum of 5 years from randomization
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- t-last
timeFrame: Minimum 5 years after bb2121 infusion
measure: Pharmacokinetics- AUC0-28days
timeFrame: Minimum 5 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 of 5 years from randomization
measure: Subject-reported outcomes as measured by EuroQoL Group European Quality of Life-5 Dimensions health state classifier to 5 Levels (EQ-5D-5L) Health Questionnaire
timeFrame: Minimum of 5 years from randomization
measure: Subject-reported outcomes as measured by European Quality of Life Multiple Myeloma Module (EORTC-QLQ-MY20)
timeFrame: Minimum of 5 years from randomization
measure: Time to next antimyeloma treatment
timeFrame: Minimum of 5 years from randomization
measure: Progression-free survival after next line therapy (PFS2)
timeFrame: Minimum of 5 years from randomization
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Local Institution - 109
state: Alabama
city: Scottsdale
country: United States
facility: Local Institution - 141
state: Arizona
city: Los Angeles
country: United States
facility: Local Institution - 145
state: California
city: Los Angeles
country: United States
facility: Local Institution - 122
state: California
city: Palo Alto
country: United States
facility: Local Institution - 124
state: California
city: Aurora
country: United States
facility: Local Institution - 142
state: Colorado
city: Jacksonville
country: United States
facility: Local Institution - 108
state: Florida
city: Tampa
country: United States
facility: Local Institution - 102
state: Florida
city: Atlanta
country: United States
facility: Local Institution - 131
state: Georgia
city: Atlanta
country: United States
facility: Local Institution - 140
state: Georgia
city: Chicago
country: United States
facility: Local Institution - 139
state: Illinois
city: Indianapolis
country: United States
facility: Local Institution - 100
state: Indiana
city: Westwood
country: United States
facility: Local Institution - 112
state: Kansas
city: Baltimore
country: United States
facility: Local Institution - 104
state: Maryland
city: Boston
country: United States
facility: Local Institution - 134
state: Massachusetts
city: Boston
country: United States
facility: Local Institution - 123
state: Massachusetts
city: Ann Arbor
country: United States
facility: University Of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Local Institution - 125
state: Minnesota
city: Saint Louis
country: United States
facility: Local Institution - 114
state: Missouri
city: Hackensack
country: United States
facility: Local Institution - 138
state: New Jersey
city: New York
country: United States
facility: Local Institution - 119
state: New York
city: New York
country: United States
facility: Local Institution - 115
state: New York
city: New York
country: United States
facility: Local Institution - 135
state: New York
city: Durham
country: United States
facility: Local Institution - 113
state: North Carolina
city: Philadelphia
country: United States
facility: Local Institution - 111
state: Pennsylvania
city: Philadelphia
country: United States
facility: Local Institution - 110
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center William M. Cooper Ambulatory Care Pavillion
state: Pennsylvania
city: Nashville
country: United States
facility: Local Institution - 106
state: Tennessee
city: Dallas
country: United States
facility: Local Institution - 118
state: Texas
city: Dallas
country: United States
facility: Local Institution - 103
state: Texas
city: Houston
country: United States
facility: Local Institution - 132
state: Texas
city: Salt Lake City
country: United States
facility: Local Institution - 136
state: Utah
city: Seattle
country: United States
facility: Local Institution - 105
state: Washington
city: Madison
country: United States
facility: Local Institution - 107
state: Wisconsin
city: Leuven
country: Belgium
facility: Local Institution - 202
city: Calgary
country: Canada
facility: Local Institution - 302
state: Alberta
city: Toronto
country: Canada
facility: Local Institution - 303
state: Ontario
city: Lille Cedex
country: France
facility: Local Institution - 402
city: Nantes
country: France
facility: Local Institution - 403
city: Paris
country: France
facility: Local Institution - 400
city: Toulouse CEDEX 9
country: France
facility: Local Institution - 401
city: Dusseldorf
country: Germany
facility: Local Institution - 513
city: Hamburg
country: Germany
facility: Local Institution - 514
city: Heidelberg
country: Germany
facility: Local Institution - 512
city: Köln
country: Germany
facility: Local Institution - 515
city: Würzburg
country: Germany
facility: Local Institution - 511
city: Bologna
country: Italy
facility: Local Institution - 611
city: Bunkyo-ku
country: Japan
facility: Local Institution - 806
city: Isehara City, Kanagawa
country: Japan
facility: Local Institution - 804
city: Nagoya
country: Japan
facility: Local Institution - 807
city: Shibuya-ku
country: Japan
facility: Local Institution - 805
city: Amsterdam
country: Netherlands
facility: Local Institution - 650
city: Rotterdam
country: Netherlands
facility: Local Institution - 651
city: Oslo
country: Norway
facility: Local Institution - 700
city: Pamplona
country: Spain
facility: Local Institution - 750
city: Salamanca
country: Spain
facility: Local Institution - 751
city: Stockholm
country: Sweden
facility: Local Institution - 800
city: Bern
country: Switzerland
facility: Local Institution - 251
city: Leeds
country: United Kingdom
facility: Local Institution - 850
city: London
country: United Kingdom
facility: Local Institution - 851
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: