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BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03502577
Recruitment Status : Suspended (Waiting on confirmation of additional funding)
First Posted : April 18, 2018
Last Update Posted : February 4, 2022
Sponsor:
Collaborators:
Juno Therapeutics, Inc.
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Fred Hutchinson Cancer Center

Tracking Information
First Submitted Date  ICMJE April 11, 2018
First Posted Date  ICMJE April 18, 2018
Last Update Posted Date February 4, 2022
Actual Study Start Date  ICMJE May 23, 2018
Estimated Primary Completion Date April 14, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • Maximum tolerated dose (MTD) of chimeric antigen receptor (CAR) T cells [ Time Frame: Up to 28 days following CAR T-cell infusion ]
    This is defined as the dose associated with a true dose-limiting toxicity (DLT) rate of 25% in each of the cohorts. DLTs are events that occur within the first 28 days following CAR T-cell infusion.
  • Incidence of general toxicities [ Time Frame: Up to 1 year ]
    This will be measured according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 30, 2021)
  • Objective response rate of complete remission and partial remission [ Time Frame: Up to 1 year ]
  • Progression-free survival [ Time Frame: Up to 1 year ]
  • Overall survival [ Time Frame: Up to 1 year ]
  • Duration of persistence of adoptively transferred B-cell maturation antigen (BCMA) CAR T cells [ Time Frame: Up to 1 year ]
  • Evaluation of the migration of adoptively transferred BCMA CAR T cells [ Time Frame: Up to 1 year ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • Incidence of general toxicities [ Time Frame: Up to 15 years ]
    This will be measured according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
  • Objective response rate of complete remission and partial remission [ Time Frame: Up to 15 years ]
  • Progression-free survival [ Time Frame: Up to 15 years ]
  • Overall survival [ Time Frame: Up to 15 years ]
  • Duration of persistence of adoptively transferred B-cell maturation antigen (BCMA) CAR T cells [ Time Frame: Baseline up to 15 years ]
  • Evaluation of the migration of adoptively transferred BCMA CAR T cells [ Time Frame: Baseline up to 15 years ]
Current Other Pre-specified Outcome Measures
 (submitted: April 11, 2018)
Plasma cell BCMA expression and soluble (s)BCMA levels with LY3039478 administration [ Time Frame: Up to 1 year ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma
Official Title  ICMJE A Phase I Study of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells in Combination With JSMD194, a Small Molecule Inhibitor of Gamma Secretase, in Patients With Relapsed or Persistent Multiple Myeloma
Brief Summary This phase I trial determines the side effects and best dose of B-cell maturation antigen (BCMA)-chimeric antigen receptor (CAR) T-cells when combined with gamma-secretase inhibitor LY3039478 (JSMD194), cyclophosphamide, and fludarabine in treating participants with multiple myeloma that that has come back or remains despite treatment. Placing genes added in the laboratory into immune T-cells may make the T-cells recognize BCMA, a protein on the surface of cancer cells. JSMD194 may enhance the killing of cancer cells by increasing the BCMA expression on multiple myeloma cells, making the targeted BCMA CAR-T treatment more effective. JSMD194 also decreases the amount of BCMA found in the circulation (called soluble BCMA) that is not bound to the myeloma cells. JSMD194 can therefore reduce the potential for soluble BCMA to act as a decoy. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving BCMA CAR T therapy with JSMD194, cyclophosphamide, and fludarabine may work better in treating participants with relapsed or persistent multiple myeloma.
Detailed Description

OUTLINE: This is a dose escalation study of BCMA-specific CAR T-cells.

Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells intravenously (IV) over 20-30 minutes on day 0 and gamma-secretase inhibitor LY3039478 orally (PO) on days 2, 4, 7, 9, 11, 14, 16, and 18. Patients will also receive JSMD194 orally before the fludarabine and cyclophosphamide to evaluate the effect of this drug alone on multiple myeloma cell BCMA levels.

After completion of study treatment, participants are followed up every 6 months for years 1-5 and annually for years 6-15.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma
Intervention  ICMJE
  • Biological: BCMA-specific CAR-expressing T Lymphocytes
    Receive CAR T infusion
    Other Names:
    • Anti-BCMA CAR T Cells
    • Anti-BCMA-CAR-transduced T Cells
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Drug: Fludarabine
    Given IV
    Other Name: Fluradosa
  • Drug: Gamma-Secretase Inhibitor LY3039478
    Given PO
    Other Names:
    • LY 3039478
    • LY-3039478
    • LY3039478
    • JSMD194
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacokinetic Study
    Correlative studies
    Other Names:
    • PHARMACOKINETIC
    • PK Study
Study Arms  ICMJE Experimental: Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Participants receive fludarabine and cyclophosphamide on days -4 to -2. Participants then receive BCMA-specific CAR T-cells IV over 20-30 minutes on day 0 and LY3039478 PO on days 2, 4, 7, 9, 11, 14, 16, and 18.
Interventions:
  • Biological: BCMA-specific CAR-expressing T Lymphocytes
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
  • Drug: Gamma-Secretase Inhibitor LY3039478
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacokinetic Study
Publications * Pont MJ, Hill T, Cole GO, Abbott JJ, Kelliher J, Salter AI, Hudecek M, Comstock ML, Rajan A, Patel BKR, Voutsinas JM, Wu Q, Liu L, Cowan AJ, Wood BL, Green DJ, Riddell SR. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019 Nov 7;134(19):1585-1597. doi: 10.1182/blood.2019000050.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: April 11, 2018)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 14, 2022
Estimated Primary Completion Date April 14, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status score =< 2
  • Have measurable disease by International Myeloma Working Group (IMWG) criteria based on one or more of the following findings:

    • Serum monoclonal immunoglobulin (M-protein) >= 1 g/dL
    • Urine M-protein >= 200 mg/24 hour
    • Involved serum free light chain (sFLC) level >= 10 mg/dL with abnormal kappa/lambda ratio
    • Measurable biopsy-proven plasmacytomas (>= 1 lesion that has a single diameter >= 2 cm)
    • Bone marrow plasma cells >= 30%
  • Have a diagnosis of multiple myeloma (MM); the MM diagnosis must be confirmed by internal pathology review of a fresh biopsy specimen at the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance (FHCRC/SCCA)
  • Have relapsed or treatment refractory disease with >= 10% CD138+ malignant plasma cells immunohistochemistry (IHC) on BM core biopsy, either:

    • Following autologous stem-cell transplantation (ASCT)
    • Or, if a patient has not yet undergone ASCT, the individual must:

      • Be transplant ineligible, due to age, comorbidity, patient choice, insurance reasons, concerns of rapidly progressive disease, and/or discretion of attending physician and principal investigator and,
      • Demonstrate disease that persists after > 4 cycles of induction therapy and that is double refractory (persistence/progression) after therapy with both a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) administered either in tandem, or in sequence, or demonstrate intolerance to both classes of agents (IMiD and PI); > 4 cycles of therapy are not required for patients with a diagnosis of plasma cell leukemia
  • Male and female patients of reproductive potential must be willing to use an effect contraceptive method before, during, and for at least 4 months after the BCMA CAR T cell infusion

Exclusion Criteria:

  • History of another primary malignancy that requires intervention beyond surveillance or that has not been in remission for at least 1 year (the following are exempt from the 1-year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, curatively treated superficial bladder cancer and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear)
  • Active hepatitis B, hepatitis C at the time of screening
  • Patients who are human immunodeficiency virus (HIV) seropositive
  • Subjects with uncontrolled active infection
  • > 1 hospital admission for infection in prior 6 months
  • Presence of acute or chronic graft-versus-host disease (GVHD) unless limited to skin involvement and managed with topical steroid therapy alone
  • History of any one of the following cardiovascular conditions within the past 6 months: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease as determined by the principal investigator (PI) or designee
  • History of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis, active central nervous system MM involvement and/or carcinomatous meningitis; subjects with previously treated central nervous systems involvement may participate, provided they are free of disease in the CNS (documented by flow cytometry performed on the cerebrospinal fluid [CSF] within 14 days of enrollment) and have no evidence of new sites of CNS activity
  • Pregnant or breastfeeding females
  • Allogeneic hematopoietic stem cell transplantation (HSCT) or donor lymphocyte infusion within 90 days of leukapheresis
  • Use of any of the following:

    • Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis; physiologic replacement, topical, and inhaled steroids are permitted
    • Cytotoxic chemotherapeutic agents within 1 week of leukapheresis; oral chemotherapeutic agents are allowed if at least 3 half-lives have elapsed prior to leukapheresis
    • Lymphotoxic chemotherapeutic agents within 2 weeks of leukapheresis
    • Experimental agents within 4 weeks of leukapheresis unless progression is documented on therapy and at least 3 half-lives have elapsed prior to leukapheresis
    • Daratumumab (or other anti-CD38 therapy) within 30 days of leukapheresis
  • Absolute neutrophil count (ANC) < 1000/mm^3, per PI discretion if cytopenia thought to be related to underlying myeloma
  • Hemoglobin (Hgb) < 8 mg/dl, per PI discretion if cytopenia thought to be related to underlying myeloma
  • Platelet count < 50,000/mm^3, per PI discretion if cytopenia thought to be related to underlying myeloma
  • Active autoimmune disease requiring immunosuppressive therapy
  • Creatinine clearance < 20 ml/min
  • Significant hepatic dysfunction (serum glutamic-oxaloacetic transaminase [SGOT] > 5 x upper limit of normal; bilirubin > 3.0 mg/dL)
  • Forced expiratory volume in one second (FEV1) of < 50% predicted or carbon monoxide diffusing capacity (DLCO) (corrected) < 40% (patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing)
  • Anticipated survival of < 3 months
  • Contraindication to cyclophosphamide or fludarabine chemotherapy
  • Patients with known amyloidosis (AL) subtype amyloidosis
  • Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as judged by the investigator; or unwillingness or inability to follow the procedures required in the protocol
  • Documented malabsorptive syndromes including enteropathies, gastroenteritis (acute or chronic) or diarrhea (acute or chronic)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 21 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03502577
Other Study ID Numbers  ICMJE 9952
NCI-2018-00514 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9952 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
RG9218033 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fred Hutchinson Cancer Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Center
Collaborators  ICMJE
  • Juno Therapeutics, Inc.
  • The Leukemia and Lymphoma Society
Investigators  ICMJE
Principal Investigator: Andrew Cowan Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Center
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP