Phase II Multicenter Trial of anti-B Cell Maturation Antigen Chimeric Antigen Receptor T Cell Therapy for Multiple Myeloma Patients with Sub-Optimal Response After Autologous Hematopoietic Cell Transplantation and Maintenance Lenalidomide
This study is designed as a Phase II, multicenter, single arm trial to assess anti-B Cell Maturation Antigen (BCMA) chimeric antigen receptor (CAR) T-cells (bb2121) to improve post autologous hematopoietic cell transplant (HCT) responses among patients with multiple myeloma (MM).
Primary Objective: The primary objective of this trial is to evaluate the efficacy of BCMA CAR T cell therapy to improve the response in patients who received an upfront autologous HCT and lenalidomide maintenance Clinical Secondary Objective: Clinical secondary objectives include: Assessment of disease progression, best disease response as described by conversion to MRD negativity and upgrade in clinical disease response, non-relapse mortality, progression free survival, incidence of CRS, incidence of prolonged cytopenias, and incidence of neurotoxicity. Exploratory Objectives: Exploratory objectives to be described include: Incidence of toxicities greater than or equal to grade 3 per CTCAE version 5.0, incidence of infections per protocol-specific MOP, feasibility of reinitiating maintenance, overall survival, disease response, CAR T-cell Expansion, CAR T-cell persistence, BCMA expression, immune reconstitution
Cell Therapy; Chemotherapy (NOS); Therapy (NOS)
CC-5013 (Lenalidomide); Diphenhydramine (); Lenalidomide (Revlimid); acetaminophen (); bb2121 (); cyclophosphamide (); cytoxan (cyclophosphamide); fludarabine (Fludarabine phosphate)
- Inclusion Criteria:
- Age greater than or equal to 18 years
- Must meet the criteria for symptomatic MM requiring therapy (Appendix A) prior to initiating initial systemic anti-myeloma treatment.
- Must have received initial systemic anti- myeloma therapy consisting of induction therapy and consolidation with high-dose melphalan (>140 mg/m2 ) followed by an auto HCT (minimum cell dose of 2x106 CD34+ cells/kg (actual body weight) within 12 months from initiation of systemic anti-myeloma therapy.
- Must have additional stored stem cells greater than or equal to 2x106 CD34+ cells per kg actual body weight.
- Must be less than or equal to 12 months after autologous HCT at the time of enrollment.
- Must have initiated maintenance therapy with lenalidomide-based regimen within 6 months after the auto HCT and have received at least 3 months of maintenance prior to enrollment.
- Must have tolerated a minimum dose of lenalidomide 5 mg/day for 21 days of a 28-day cycle for greater than 2 cycles without having to stop due to toxicities.
- Must have a VGPR or less (Section 3.1) in reference to time time of initiation of initial systemic anti-myeloma therapy at study enrollment.
- Must have Karnofsky performance greater than or equal to 70.
- Must have recovered to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding Grade 2 neuropathy.
- Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 without filgrastim use in the prior 14 days.
- Platelet count greater than 100,000/mm3 (without platelet transfusion in the previous 7 days or thrombopoietin mimetics in the previous 28 days).
- Hemoglobin greater than 9 g/dL (without red blood cell transfusion in the previous 7 days).
- Creatinine Clearance (CrCl) greater than or equal to 60 mL/min, measured or estimated by Cockcroft-Gault equation.
- Corrected serum calcium less than or equal to 13.5 mg/dL.
- Oxygen saturation greater than 92% on room air.
- Hepatic Function: a. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x upper limit of normal (ULN) b. Serum total bilirubin less than or equal to 2 x ULN. Patients who have been diagnosed with Gilbert's disease are permitted to exceed the defined bilirubin value of 2 x ULN
- International ratio (INR) or partial thromboplastin time (PTT) less than 1.5 x ULN
- Cardiac Function: left ventricular ejection fraction greater than 45% by echocardiogram or MUGA.
- Must be willing and able to adhere to the study visit schedule and other protocol requirements including regulatory requirement of a 15 year follow up using the CIBMTR long term follow up mechanism.
- Female patients of childbearing potential (FCBP1 ) must: a. Have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL prior to enrollment b. Agree to use, and be able to comply with, TWO acceptable methods of birth control (Appendix C), one highly effective method and one additional effective (barrier) method AT THE SAME TIME, from screening through at least 1 year following bb2121 infusion or 4 weeks following discontinuation of lenalidomide, whichever is later. c. Agree to abstain from breastfeeding from screening through at least 1 year following bb2121 infusion or 4 weeks following discontinuation of lenalidomide, whichever is later.
- Male patients must: a. Agree to use a condom during sexual contact with a pregnant female or a FCBP, even if he has undergone a successful vasectomy, from screening through at least 1 year following bb2121 infusion or 4 weeks following discontinuation of lenalidomide whichever is later b. Must not donate sperm from screening through at least 1 year following bb2121 infusion or 4 weeks following discontinuation of lenalidomide whichever is later.
- Exclusion Criteria:
- Patients with a prior allogeneic hematopoietic cell.
- Female of childbearing potential (FCBP) is a female who: (a) has achieved menarche at some point, (2) has not undergone a hysterectomy or bilateral oophorectomy or (3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
- Patients with disease progression (see Section 3.1.2 for disease progression definition) at any time prior to enrollment.
- Patients receiving any of the following less than 14 days prior to enrollment: (a) Plasmapheresis (b) Major surgery (as defined by the investigator) (c) Radiation therapy other than local therapy for MM-associated bone lesions (d) Use of any systemic anti-myeloma drug therapy (with the exception of lenalidomide maintenance) (e) Any investigational agents (f) Corticosteroids (Physiologic replacement, topical, intranasal and inhaled steroids are permitted)
- Patients with known Central Nervous System (CNS) involvement with MM.
- Patients with a prior organ transplant requiring systemic immunosuppressive therapy.
- Patients who previously experienced toxicities related to lenalidomide resulting in permanent treatment discontinuation.
- Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with an immunomodulatory agent (IMiD).
- Patients unwilling to take DVT prophylaxis while on lenalidomide maintenance.
- Patients with history of greater than or equal to Grade 2 hemorrhage within 30 days of enrollment.
- Patient requiring ongoing treatment with chronic, therapeutic dosing of anticoagulants (e.g. Warfarin, low molecular weight heparin, Factor Xa inhibitors).
- Patients with 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.
- Patients with active or history of plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis.
- Patients with purely non-secretory MM [prior to starting systemic therapy, absence of a monoclonal protein (M protein) in serum as measured by electrophoresis and immunofixation and the absence of Bence Jones protein in the urine defined by use of conventional electrophoresis and immunofixation techniques and the absence of involved serum free light chain greater than 100mg/L]. Patients with light chain MM detected in the serum by free light chain assay are eligible.
- Patients with a history of Class III or IV congestive heart failure (CHF) or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or hemodynamically significant ventricular arrhythmia within the previous 6 months prior to starting study treatment.
- Patients with ongoing treatment with chronic immunosuppressants (e.g. cyclosporine or systemic steroids at any dose). Physiologic replacement, intermittent topical, inhaled or intranasal corticosteroids are allowed.
- Patients with active clinically significant autoimmune disease, defined as a history of requiring systemic immunosuppressive therapy and at ongoing risk for potential disease exacerbation. Patients with a history of autoimmune thyroid disease, asthma, or limited skin manifestations are potentially eligible.
- Other criteria apply
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