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MM CAR-T to Upgrade Response BMT CTN 1902

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ClinicalTrials.gov Identifier: NCT05032820
Recruitment Status : Not yet recruiting
First Posted : September 2, 2021
Last Update Posted : October 21, 2021
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Celgene a wholly owned subsidiary of BMS
Information provided by (Responsible Party):
Marcelo Pasquini, MD, Medical College of Wisconsin

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).

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Lenalidomide and bb2121 Phase 2

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/m2 and fludarabine 30mg/m2 for 3 consecutive days followed by the infusion of BCMA CAR T-cells at a target dose of 450 x106 cells. Maintenance lenalidomide, starting at 10mg 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
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).
Masking: None (Open Label)
Primary Purpose: Treatment
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. BMT CTN 1902
Estimated Study Start Date : October 2021
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : February 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: Lenalidomide and bb2121
Patients complete apheresis and proceed to lymphodepleting chemotherapy with cyclophosphamide 300mg/m2 and fludarabine 30mg/m2 for 3 consecutive days followed by the infusion of BCMA CAR T-cells at a target dose of 450 x106 cells. Maintenance lenalidomide, starting at 10mg 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.
Drug: Lenalidomide and bb2121
Patients complete apheresis and proceed to lymphodepleting chemotherapy with cyclophosphamide 300mg/m2 and fludarabine 30mg/m2 for 3 consecutive days followed by the infusion of BCMA CAR T-cells at a target dose of 450 x106 cells. Maintenance lenalidomide, starting at 10mg 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.
Other Name: ide-cel, revlimid




Primary Outcome Measures :
  1. Complete Response [ Time Frame: 1 Year ]
    Complete response or better (CR or sCR) as assessed by the 6-month time point after BCMA CAR T-cell therapy in MM patients with suboptimal disease responses after an autologous HCT and lenalidomide maintenance.


Secondary Outcome Measures :
  1. Disease Progression [ Time Frame: 1 Year ]
    Diseases will be assessed by response categories based on the International Myeloma Working Group: Stringent Complete Response (sCR), Complete Remission (CR), Very Good Partial Remission (VGPR), Partial Remission (PR), Minimal Response (MR), Stable Disease (SD).

  2. Best Disease Response [ Time Frame: 1 Year ]
    Proportion of patients achieving upgrade in response following enrollment (SD to MR or greater, MR to PR or greater, or PR to VGPR or greater) and Conversion to MRD negativity. MRD will be assessed by multi-color flow at 10^5 level.

  3. Non-Relapse Mortality [ Time Frame: 1 Year ]
    Non-Relapse Mortality (NRM) is defined as death occurring in a patient from causes other than disease relapse or progression. Disease progression is the competing event for NRM.

  4. Progression Free Survival [ Time Frame: 1 year ]
    Defined as progression of disease or death from any cause. Surviving patients without disease progression will be censored at the date of last contact.

  5. Cytokine Release Syndrome [ Time Frame: 1 Year ]
    Overall incidence of CRS of any grade and grade 3 or 4 CRS post CAR T-cell infusion will be reported on all patients.

  6. Prolonged Cytopenias [ Time Frame: 1 Year ]
    Overall incidence of prolonged cytopenias will be reported. Prolonged cytopenia is defined as failure to achieve ANC greater than 500/mm^3 or platelet count greater than 20,000/mm^3(with or without support) by 30 days post CAR T-cell infusion.

  7. Incidence of Neurotoxicity [ Time Frame: 1 Year ]
    Overall incidence of CAR T-cell related neurotoxicity per the ASBMT immune effector cell associated neurotoxicity syndrome (ICANS) Consensus Grading.


Other Outcome Measures:
  1. Incidence of toxicities greater than or equal to grade 3 per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: 1 Year ]
    All Grade 3 or higher toxicities will be tabulated. The proportion of patients experiencing cytokine release syndrome CRS will be reported including overall and grades 3-4 based on the ASTCT grading.

  2. Incidence of Infections [ Time Frame: 1 Year ]
    Incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each patient.

  3. Maintenance Feasibility [ Time Frame: 1 Year ]
    The feasibility of resuming maintenance following enrollment by 180 days after CAR T-cell infusion will be described. The proportion of patients initiating maintenance at 180 days follow ing bb2121 infusion will be reported.

  4. Overall Survival [ Time Frame: 1 Year ]
    The event is death from any cause. The time to this event is the time from initial enrollment to sdeath, loss to follow-up, or the end of the study, whichever comes first.

  5. CAR T-cell Expansion [ Time Frame: 1 Year ]
    Quantitation of CAR T-cells in peripheral blood will be determined at specified timepoints by quantitative PCR assay, measured in copies/mcg genomic DNA. Peak CAR T-cell expansion will be compared between subjects who are and are not in CR at 12 months, and between subjects who are and are not progression-free at 12 months.

  6. CAR T-cell Persistence [ Time Frame: 1 Year ]

    Quantitation of CAR T-cells in peripheral blood will be determined at specified timepoints by quantitative PCR assay, measured in copies/mcg genomic DNA. Persistence will be measured in 2 ways:

    1. as an area under the curve (AUC) over first 6 months post CAR T-cell infusion; and
    2. as still having detectable CAR T-cells at 6 months post CAR T-cell infusion. AUC6mos and 6-month persistence will be compared between subjects who are and are not in CR at 12 months,and between subjects who are and are not progression-free at 12 months.

  7. Immune Reconstitution [ Time Frame: 1 Year ]
    The cellular composition of marrow (T-Cells, B-Cells, Natural Killer Cells, dendritic cells, and myeloid derived suppressor cells) will be quantified at the specified timepoints by flow cytometry.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 71 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age greater than or equal to 18.00 years and less than 71.00 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/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.
  4. Patient must have additional stored stem cells greater than or equal to 2x106 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 within 6 months after the auto HCT and have received at least 6 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 achieved less than a VGPR (Section 3.1) in reference to time of initiation of initial systemic anti-myeloma therapy1 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/mm3 (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) or 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 therapy1
    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 [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.

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): NCT05032820


Contacts
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Contact: Megan Scott 240-599-5648 ext 15648 bmtctn1902@emmes.com
Contact: Adam Mendizabal, PhD amendizabal@emmes.com

Locations
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United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010
Contact: Myo Htut       mhtut@coh.org   
Contact: Ryotaro Nakamura       rnakamura@coh.org   
Stanford Hospital and Clinics
Palo Alto, California, United States, 94305
Contact: Surbhi Sidana       surbhi.sidana@stanford.edu   
Contact: Janet McDowell       janetm2@stanford.edu   
University of California, San Francisco
San Francisco, California, United States, 94143
Contact: Nina Shah       nina.shah@ucsf.edu   
Contact: Kate Rafanova       Kate.Rafanova@ucsf.edu   
United States, Florida
H. Lee Moffitt Cancer Center
Tampa, Florida, United States, 33612
Contact: Taiga Nishihori       taiga.nishihori@moffitt.org   
Contact: Joseph Pidala       joseph.pidala@moffitt.org   
United States, Illinois
Loyola University Medical Center
Maywood, Illinois, United States, 60153
Contact: Nasheed Hossain       pstiff@lumc.edu   
Contact: Rachel Ochoa       rochoa@luc.edu   
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Contact: David Avigan       davigan@bidmc.harvard.edu   
Contact: Emma Logan       eklogan@bidmc.harvard.edu   
United States, New York
Roswell Park Cancer Center
Buffalo, New York, United States, 14203
Contact: Philip McCarthy       Philip.McCarthy@RoswellPark.org   
Contact: Jessica Doersam       Jessica.Doersam@RoswellPark.org   
Mount Sinai Medical Center
New York, New York, United States, 10029
Contact: Shambavi Richard, MD       Shambavi.richard@mountsinai.org   
Contact: Schantel Williams       schantel.williams@mssm.edu   
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Contact: Sergio Giralt       giralts@mskcc.org   
Contact: Elizabeth Hoover       hoovere@mskcc.org   
United States, North Carolina
Levine Cancer Institute/ Carolinas HealthCare
Charlotte, North Carolina, United States, 28204
Contact: Saad Usmani       saad.usmani@atriumhealth.org   
Contact: Donna Acampora       donna.acampora@atriumhealth.org   
Duke University Medical Center
Durham, North Carolina, United States, 27705
Contact: Taewoong Choi       taewiing.choi@duke.edu   
Contact: Matthew Fister       matthew.fister@duke.edu   
United States, Pennsylvania
University of Pennsylvania Hospital Center
Philadelphia, Pennsylvania, United States, 19104
Contact: Alfred Garfall       Alfred.Garfall@pennmedicine.upenn.edu   
Contact: Harjeet Sembhi       Harjeet.Sembhi@pennmedicine.upenn.edu   
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
Contact: Tamila Kindwall-Keller       TLK5DE@hscmail.mcc.virginia.edu   
Contact: Giana Strand       GRS9ZJ@hscmail.mcc.virginia.edu   
United States, Wisconsin
University of Wisconsin Hospitals and Clinics
Madison, Wisconsin, United States, 53792
Contact: Natalie Callander       nsc@medicine.wisc.edu   
Contact: Carolyn Serpe       cserpe@wisc.edu   
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Contact: Binod Dhakal       bdhakal@mcw.edu   
Contact: Debra Pastorek       dpastore@mcw.edu   
Sponsors and Collaborators
Marcelo Pasquini, MD
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Celgene a wholly owned subsidiary of BMS
Investigators
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Study Director: Mary Horowitz, MD, MS Center for International Blood and Marrow Transplant Research
Additional Information:
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Responsible Party: Marcelo Pasquini, MD, Primary Investigator, Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT05032820    
Other Study ID Numbers: BMT CTN 1902
2U10HL069294-11 ( U.S. NIH Grant/Contract )
First Posted: September 2, 2021    Key Record Dates
Last Update Posted: October 21, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Results will be published in a manuscript and supporting information submitted to NIH BioLINCC (including data dictionaries, case report forms, data submission documentation, documentation for outcomes dataset, etc., where indicated).
Supporting Materials: Study Protocol
Time Frame: Within 6 months of official study closure at participating sites
Access Criteria: Available to public
URL: https://biolincc.nhlbi.nih.gov/home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Marcelo Pasquini, MD, Medical College of Wisconsin:
Multiple Myeloma
CAR T-cells
Anti-Myeloma Agents
lenalidomide
Maintenance Therapy
Hematologic Disorders
Infusion
Additional relevant MeSH terms:
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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
Lenalidomide
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents