Clinical trial NCT05032820: MM CAR-T to Upgrade Response BMTCTN1902
Official title: Phase II Multicenter Trial of Anti-BCMA CAR T-Cell Therapy for MM Patients With Sub-Optimal Response After Auto HCT and Maintenance Len. BMTCTN1902
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
CAR T-cells
Anti-Myeloma Agents
lenalidomide
Maintenance Therapy
Hematologic Disorders
Infusion
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Blood and Marrow Transplant Clinical Trials Network
name: National Cancer Institute (NCI)
name: National Marrow Donor Program
name: Celgene a wholly owned subsidiary of BMS
First posted: 2021-09-02
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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 purpose: TREATMENT

Brief summary: 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).

Detailed description: After meeting the eligibility criteria and enrolling on the trial, patients will undergo leukapheresis for collection of autologous lymphocytes, which will be sent to BMS/Celgene manufacturing facilities. Once cells have been manufactured, patients will then proceed to lymphodepleting chemotherapy with cyclophosphamide 300mg/m\^2 and fludarabine 30mg/m\^2 for 3 consecutive days followed by the infusion of BCMA CAR T-cells at a target dose of 450 x10\^6 cells. Maintenance lenalidomide, starting at 5mg a day for 21 days of a 28-day cycle will be initiated at a minimum of at least 30 days, but no later than 180 days after the CAR T-cell infusion and will continue until the patient reaches 12 months post CAR T-cell infusion and continue free of progression

Eligibility criteria: Inclusion Criteria:

1. Age greater than or equal to 18.00 years
2. Patients must meet the criteria for symptomatic MM requiring therapy (Appendix A) prior to initiating initial systemic anti-myeloma treatment.
3. Patients must have received initial systemic anti- myeloma therapy consisting of induction therapy and consolidation with high-dose melphalan (\>140 mg/m\^2 ) followed by an auto HCT (minimum cell dose of 2x10\^6 CD34+ cells/kg (actual body weight) within 12 months from initiation of systemic anti-myeloma therapy.
4. Patient must have additional stored stem cells greater than or equal to 2x10\^6 CD34+ cells per kg actual body weight.
5. Patients must be less than or equal to 12 months after autologous HCT at the time of enrollment.
6. Patients 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.
7. Patients 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.
8. Patients 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.
9. Patients must have Karnofsky performance greater than or equal to 70.
10. Patients must have recovered to Grade 1 or baseline of any non-hematologic toxicities due to prior treatments, excluding Grade 2 neuropathy.
11. Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 without filgrastim use in the prior 14 days.
12. Platelet count greater than 100,000/mm\^3 (without platelet transfusion in the previous 7 days or thrombopoietin mimetics in the previous 28 days).
13. Hemoglobin greater than 9 g/dL (without red blood cell transfusion in the previous 7 days).
14. Creatinine Clearance (CrCl) greater than or equal to 60 mL/min, measured or estimated by Cockcroft-Gault equation.
15. Corrected serum calcium less than or equal to 13.5 mg/dL.
16. Oxygen saturation greater than 92% on room air.
17. 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
18. International ratio (INR) or partial thromboplastin time (PTT) less than 1.5 x ULN
19. Cardiac Function: left ventricular ejection fraction greater than 45% by echocardiogram or MUGA.
20. Patients 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.
21. 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.
22. 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:

1. Patients with a prior allogeneic hematopoietic cell.
2. Female of childbearing potential (FCBP) is a female who:

   * has achieved menarche at some point,
   * has not undergone a hysterectomy or bilateral oophorectomy or
   * 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).
3. Patients with disease progression (see Section 3.1.2 for disease progression definition) at any time prior to enrollment.
4. Patients receiving any of the following less than 14 days prior to enrollment:

   1. Plasmapheresis
   2. Major surgery (as defined by the investigator)
   3. Radiation therapy other than local therapy for MM-associated bone lesions
   4. Use of any systemic anti-myeloma drug therapy (with the exception of lenalidomide maintenance)
   5. Any investigational agents
   6. Corticosteroids (Physiologic replacement, topical, intranasal and inhaled steroids are permitted)
5. Patients with known Central Nervous System (CNS) involvement with MM.
6. Patients with a prior organ transplant requiring systemic immunosuppressive therapy.
7. Patients who previously experienced toxicities related to lenalidomide resulting in permanent treatment discontinuation.
8. Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with an immunomodulatory agent (IMiD).
9. Patients unwilling to take DVT prophylaxis while on lenalidomide maintenance.
10. Patients with history of greater than or equal to Grade 2 hemorrhage within 30 days of enrollment.
11. Patient requiring ongoing treatment with chronic, therapeutic dosing of anticoagulants (e.g. Warfarin, low molecular weight heparin, Factor Xa inhibitors).
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. Patients seropositive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or C, or acute hepatitis A. If any history of exposure to hepatitis B or C then DNA PCR should be negative.
19. Patients with previous history of treatment with any gene therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA targeted therapy.
20. Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in situ. Cancer treated with curative intent less than 5 years prior to enrollment will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs. Cancer treated with curative intent greater than 5 years prior to enrollment is allowed.
21. Female patients who are pregnant (positive beta-HCG), or breastfeeding, or who intend to become pregnant during participation in the study.
22. Patient with known allergy or hypersensitivity to any of the study medications, their analogues, or excipients in the various formulations of any agent.
23. Patient with serious medical of psychiatric illness likely to interfere with participation on this clinical study.
24. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
25. Patients unwilling or unable to provide informed consent 25. Patients unable or unwilling to return to the transplant center for treatment and follow up.

Primary outcomes:
measure: Efficacy of BCMA CAR-T cell therapy
timeFrame: 6 months
Secondary outcomes:
measure: Assessment of Disease progression
timeFrame: 1 Year
measure: Best Disease Response
timeFrame: 1 Year
measure: Non relapse Mortality
timeFrame: 1 Year
measure: Progression free survival
timeFrame: 1 Year
measure: Incidence of Cytokine Release Syndrome
timeFrame: 1 year
measure: Incidence of prolonged cytopenias
timeFrame: 1 Year
measure: Incidence of neurotoxicity
timeFrame: 1 Year
Other outcomes:
measure: Exploratory Objective 1: Incidence of toxicities greater than or equal to grade 3 per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
timeFrame: 1 Year
measure: Exploratory Objective 2: incidence of infections per protocol-specific Manual of Procedures (MOP)
timeFrame: 1 Year
measure: Exploratory Objective 3: maintenance feasibility
timeFrame: 1 Year
measure: Exploratory Objective 2: overall survival
timeFrame: 1 Year
measure: Exploratory Objective 2: CAR Tcell expansion
timeFrame: 1 Year
measure: Exploratory Objective 2: CAR T-cell persistence
timeFrame: 1 Year
measure: Exploratory Objective 2: BCMA expression
timeFrame: 1 Year
measure: Exploratory Objective 2: immune reconstitution
timeFrame: 1 Year
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford Hospital and Clinics
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Buffalo
country: United States
facility: Roswell Park Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania Hospital Center
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College and Medicine
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin Hospitals and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: Marcelo C Pasquini, MD, MS
role: STUDY_DIRECTOR
affiliation: University of Pennsylvannia
name: Alfred Garfall, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Sergio Giralt, MD
role: PRINCIPAL_INVESTIGATOR
References: