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Efficacy and Safety Study of bb2121 Versus Standard Triplet Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) (KarMMa-3)

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ClinicalTrials.gov Identifier: NCT03651128
Recruitment Status : Not yet recruiting
First Posted : August 29, 2018
Last Update Posted : October 25, 2018
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:

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

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.


Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: bb2121 Drug: Daratumumab Drug: Pomalidomide Drug: Dexamethasone Drug: Bortezomib Drug: Ixazomib Drug: Lenalidomide Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 381 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3, Multicenter, Randomized, Open-label Study to Compare the Efficacy and Safety of bb2121 Versus Standard Triplet Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) (KarMMa-3)
Estimated Study Start Date : November 30, 2018
Estimated Primary Completion Date : June 9, 2025
Estimated Study Completion Date : June 9, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: Arm A - Administration of bb2121
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
Drug: bb2121
bb2121

Experimental: Arm B- standard regimens as per Investigator's discretion

The participants will receive one of following regimens

  • Daratumumab (DARA) in combination with pomalidomide (POM) and low-dose dexamethasone (dex) (DPd)
  • DARA in combination with bortezomib (BTZ) and low-dose dex (DVd)
  • Ixazomib (IXA) in combination with lenalidomide (LEN) and low-dose dex (IRd)
Drug: Daratumumab
Daratumumab

Drug: Pomalidomide
Pomalidomide

Drug: Dexamethasone
Dexamethasone

Drug: Bortezomib
Bortezomib

Drug: Ixazomib
Ixazomib

Drug: Lenalidomide
Lenalidomide




Primary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to the first documentation of progressive disease based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma assessed by an independent response committee (IRC) or death due to any cause, whichever occurs first.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to time of death due to any cause

  2. Event-free Survival (EFS) [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to the first documentation of progressive disease, first day when subject receives another anti-myeloma treatment or death due to any cause, whichever occurs first

  3. Overall Response Rate (ORR) [ Time Frame: Minimum of 5 years from randomization ]
    Percentage of subjects who achieved partial response (PR) or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC

  4. Minimal Residual Disease (MRD) [ Time Frame: Minimum of 5 years from randomization ]
    Percentage of MRD evaluable subjects that are MRD negative (defined at a minimum of 1 in 10^5 nucleated cells) using flow cytometry (EuroFlow) and next generation sequencing (NGS)

  5. Complete Response (CR) Rate [ Time Frame: Minimum of 5 years from randomization ]
    Percentage of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as assessed by an IRC

  6. Duration of Response (DOR) [ Time Frame: Minimum of 5 years from randomization ]
    Time from first documentation of response (PR or better) to first documentation of disease progression or death from any cause, whichever occurs first

  7. Time to Response (TTR) [ Time Frame: Minimum of 5 years from randomization ]
    TTR is calculated as the time from randomization to the initial documented response (PR or better) based on IMWG guideline for responders

  8. Adverse Events (AEs) [ Time Frame: Minimum of 5 years from randomization ]
    Number of participants with adverse events

  9. Pharmacokinetics- Cmax [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Maximum peak in bb2121 chimeric antigen receptor (CAR) T cells

  10. Pharmacokinetics- tmax [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Time to peak of bb2121 CAR T cells

  11. Pharmacokinetics- AUC [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Area under the curve of CAR T cells

  12. Pharmacokinetics- t-last [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Time to last measurable CAR T cells

  13. Pharmacokinetics- AUC0-28days [ Time Frame: Minimum 5 years after bb2121 infusion ]
    Area under the curve of CAR T cells from time zero to Day 28

  14. 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 5 years from randomization ]
    Questionnaire will be used as a measure of health-related quality of life

  15. 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 [ Time Frame: Minimum of 5 years from randomization ]
    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

  16. Subject-reported outcomes as measured by European Quality of Life Multiple Myeloma Module (EORTC-QLQ-MY20) [ Time Frame: Minimum of 5 years from randomization ]
    Is a 20-item myeloma module intended for use among patients varying in disease stage and treatment modality

  17. Time to next antimyeloma treatment [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to first day when subject receives another anti-myeloma treatment

  18. Progression-free survival after next line therapy (PFS2) [ Time Frame: Minimum of 5 years from randomization ]
    Time from randomization to second objective disease progression or death from any cause, whichever is first



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 prior MM regimens.
  6. Subject has received prior treatment with 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.

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:

    1. Absolute neutrophil count (ANC) < 1,000/μL
    2. 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)
    3. Hemoglobin < 8 g/dL (< 4.9 mmol/L) (it is not permissible to transfuse a subject to reach this level)
    4. Serum creatinine clearance (CrCl) < 45 mL/min
    5. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
    6. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN)
    7. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert's syndrome
    8. 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 with the exception of the following non-invasive malignancies:

    • 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 (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 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 or IRd as 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 or IRd as per Investigator's discretion.
  15. Subject was treated with DARA in combination with BTZ with or without dex (DV±d) as part of their most recent anti-myeloma treatment regimen, cannot receive DVd as bridging therapy but may receive DPd or IRd 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 or IRd as per Investigator's discretion.
  17. Subject was treated with IXA in combination with LEN with or without dex (IR±d) as part of their most recent anti-myeloma treatment regimen, cannot receive IRd as bridging therapy but may receive DPd or DVd 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 or DVd 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 B-cell maturation antigen (BCMA) targeted therapy.
  20. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks prior to randomization.
  21. Subject used any investigational agents within 28 days prior to randomization.
  22. Subject has received any of the following within the last 14 days prior to randomization:

    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
  23. Echocardiogram (ECHO) or multigated acquisition (MUGA) with left ventricular ejection fraction (LVEF) < 45%.
  24. Ongoing treatment with chronic immunosuppressants (eg, cyclosporine or systemic steroids at any dose). Intermittent topical, inhaled or intranasal corticosteroids are allowed.
  25. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C.
  26. 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.
  27. 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.
  28. Hypersensitivity to DARA, thalidomide, lenalidomide, POM, BTZ, IXA or dex. This includes rash ≥ Grade 3 during prior thalidomide, POM or lenalidomide therapy.
  29. 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 or dex.
  30. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study.
  31. 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.
  32. Subject is intolerant to bortezomib, subject cannot receive DVd as bridging therapy if randomized

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03651128


Contacts
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations
United States, Tennessee
Sarah Cannon Research Institute Center for Blood Not yet recruiting
Nashville, Tennessee, United States, 37203:
Sponsors and Collaborators
Celgene
Investigators
Study Director: Steven Novick, MD Celgene

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT03651128     History of Changes
Other Study ID Numbers: BB2121-MM-003
U1111-1217-9988 ( Registry Identifier: WHO )
2018-001023-38 ( EudraCT Number )
First Posted: August 29, 2018    Key Record Dates
Last Update Posted: October 25, 2018
Last Verified: October 2018

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

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
Dexamethasone acetate
Dexamethasone
Lenalidomide
Pomalidomide
Ixazomib
Daratumumab
Bortezomib
Thalidomide
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids