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

• ClinicalTrials.gov Identifier: NCT03502577
• Recruitment Status: Terminated
• First Posted: April 18, 2018
• Last Update Posted: January 8, 2024
• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Juno Therapeutics, Inc., a Bristol-Myers Squibb Company; The Leukemia and Lymphoma Society
• Information provided by (Responsible Party): Fred Hutchinson Cancer Center

Tracking Information

• First Submitted Date: April 11, 2018
• First Posted Date: April 18, 2018
• Last Update Posted Date: January 8, 2024
• Actual Study Start Date: May 23, 2018
• Actual Primary Completion Date: April 20, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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 (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: BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma
• Official Title: 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: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent Plasma Cell Myeloma
• Refractory Plasma Cell Myeloma

Intervention

• 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

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. gamma-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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 29, 2023): 19
• Original Estimated Enrollment (submitted: April 11, 2018): 18
• Actual Study Completion Date: April 20, 2022
• Actual Primary Completion Date: April 20, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 21 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03502577
• Other Study ID Numbers: 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

• Plan to Share IPD: No

• Current Responsible Party: Fred Hutchinson Cancer Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Fred Hutchinson Cancer Center
• Original Study Sponsor: Same as current

Collaborators

• Juno Therapeutics, Inc., a Bristol-Myers Squibb Company
• The Leukemia and Lymphoma Society

Investigators

• Principal Investigator: Andrew Cowan; Fred Hutch/University of Washington Cancer Consortium

• PRS Account: Fred Hutchinson Cancer Center
• Verification Date: December 2023