Clinical Trials /

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

NCT03502577

Description:

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.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 9952
  • SECONDARY ID: NCI-2018-00514
  • SECONDARY ID: 9952
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG9218033
  • NCT ID: NCT03502577

Conditions

  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
BCMA-specific CAR-expressing T LymphocytesAnti-BCMA CAR T Cells, Anti-BCMA-CAR-transduced T CellsTreatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Cyclophosphamide(-)-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- 138719Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
FludarabineFluradosaTreatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)
Gamma-Secretase Inhibitor LY3039478LY 3039478, LY-3039478, LY3039478, JSMD194Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)

Purpose

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

      PRIMARY OBJECTIVES:

      I. To evaluate the safety of BCMA-targeting CAR T-cells in combination with JSMD194 for
      patients with relapsed or treatment refractory multiple myeloma.

      II. To identify the recommended phase 2 dose (R2PD) of BCMA CAR T cells administered in
      combination with JSMD194 in patients with measurable tumor burden prior to T cell transfer.

      SECONDARY OBJECTIVES:

      I. To determine the peak concentration, in vivo persistence and the phenotype of transferred
      CAR T cells when administered in combination with JSMD194.

      II. To estimate the antitumor activity of adoptively transferred BCMA CAR T cells when
      administered with JSMD194.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)ExperimentalParticipants 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.
  • BCMA-specific CAR-expressing T Lymphocytes
  • Cyclophosphamide
  • Fludarabine
  • Gamma-Secretase Inhibitor LY3039478

Eligibility Criteria

        Inclusion Criteria:

          -  Have the capacity to give informed consent

          -  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 any other anti-CD38 monoclonal antibody 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] > 5x
             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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:21 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of chimeric antigen receptor (CAR) T cells
Time Frame:Up to 28 days following CAR T-cell infusion
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of general toxicities
Time Frame:Up to 15 years
Safety Issue:
Description:This will be measured according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Measure:Objective response rate of complete remission and partial remission
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure:Duration of persistence of adoptively transferred B-cell maturation antigen (BCMA) CAR T cells
Time Frame:Baseline up to 15 years
Safety Issue:
Description:
Measure:Evaluation of the migration of adoptively transferred BCMA CAR T cells
Time Frame:Baseline up to 15 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated

December 30, 2019