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

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ClinicalTrials.gov Identifier: NCT03502577
Recruitment Status : Recruiting
First Posted : April 18, 2018
Last Update Posted : April 4, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

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.

Condition or disease Intervention/treatment Phase
Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma Biological: BCMA-specific CAR-expressing T Lymphocytes Drug: Cyclophosphamide Drug: Fludarabine Drug: Gamma-Secretase Inhibitor LY3039478 Other: Laboratory Biomarker Analysis Other: Pharmacokinetic Study Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 23, 2018
Estimated Primary Completion Date : July 30, 2021
Estimated Study Completion Date : July 30, 2034

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. Objective response rate of complete remission and partial remission [ Time Frame: Up to 15 years ]
  3. Progression-free survival [ Time Frame: Up to 15 years ]
  4. Overall survival [ Time Frame: Up to 15 years ]
  5. Duration of persistence of adoptively transferred B-cell maturation antigen (BCMA) CAR T cells [ Time Frame: Baseline up to 15 years ]
  6. Evaluation of the migration of adoptively transferred BCMA CAR T cells [ Time Frame: Baseline up to 15 years ]

Other Outcome Measures:
  1. Plasma cell BCMA expression and soluble (s)BCMA levels with LY3039478 administration [ Time Frame: Up to 1 year ]


Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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,
      • Demonstrate disease that persists after > 4 cycles of induction therapy and that is double refractory (persistence/progression) after therapy with both a proteasome inhibitor 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 or presence 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 one week of enrollment) and have no evidence of new sites of CNS activity
  • Pregnant or breastfeeding females
  • Allogeneic 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
    • Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) within 90 days of leukapheresis
    • 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)

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): NCT03502577


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Immunotherapy Trials Intake, SCCA    206-606-4668    immunotherapy@seattlecca.org   
Principal Investigator: Andrew J. Cowan         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Andrew Cowan Fred Hutch/University of Washington Cancer Consortium

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT03502577     History of Changes
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 )
P30CA015704 ( U.S. NIH Grant/Contract )
RG9218033 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: April 18, 2018    Key Record Dates
Last Update Posted: April 4, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites