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

NCT03502577 | Terminated Phase 1 DMC FDA Drug

• 3 other identifiers: 9952NCI-2018-00514RG9218033
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

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.

Conditions

Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (MTD) of chimeric antigen receptor (CAR) T cells

  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.

  Up to 28 days following CAR T-cell infusion

• Incidence of general toxicities

  This will be measured according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

  Up to 1 year

Secondary Outcomes (5)

• Objective response rate of complete remission and partial remission

  Up to 1 year

• Progression-free survival

  Up to 1 year

• Overall survival

  Up to 1 year

• Duration of persistence of adoptively transferred B-cell maturation antigen (BCMA) CAR T cells

  Up to 1 year

• Evaluation of the migration of adoptively transferred BCMA CAR T cells

  Up to 1 year

Other Outcomes (1)

• Plasma cell BCMA expression and soluble (s)BCMA levels with LY3039478 administration

  Up to 1 year

Study Arms (1)

Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)

EXPERIMENTAL

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; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Gamma-Secretase Inhibitor LY3039478; Other: Laboratory Biomarker Analysis; Other: Pharmacokinetic Study

Interventions

BCMA-specific CAR-expressing T Lymphocytes BIOLOGICAL

Receive CAR T infusion

Also known as: Anti-BCMA CAR T Cells, Anti-BCMA-CAR-transduced T Cells

Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-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

Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)

Fludarabine DRUG

Given IV

Also known as: Fluradosa

Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)

Gamma-Secretase Inhibitor LY3039478 DRUG

Given PO

Also known as: LY 3039478, LY-3039478, LY3039478, JSMD194

Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)

Pharmacokinetic Study OTHER

Correlative studies

Also known as: PHARMACOKINETIC, PK Study

Treatment (Chemotherapy, BCMA-specific CAR T-cells, LY3039478)

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• Juno Therapeutics, Inc., a Bristol-Myers Squibb Company: collaborator
• The Leukemia and Lymphoma Society: collaborator

Study Sites (1)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Related Publications (2)

• Cowan AJ, Pont MJ, Sather BD, Turtle CJ, Till BG, Libby EN 3rd, Coffey DG, Tuazon SA, Wood B, Gooley T, Wu VQ, Voutsinas J, Song X, Shadman M, Gauthier J, Chapuis AG, Milano F, Maloney DG, Riddell SR, Green DJ. gamma-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial. Lancet Oncol. 2023 Jul;24(7):811-822. doi: 10.1016/S1470-2045(23)00246-2.

  PMID: 37414012 DERIVED

• 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.

  PMID: 31558469 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Cyclophosphamide; fludarabine; crenigacestat; Pharmacogenomic Variants

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Polymorphism, Genetic; Genetic Variation; Genetic Phenomena

Study Officials

• Andrew Cowan

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2018
• First Posted: April 18, 2018
• Study Start: May 23, 2018
• Primary Completion: April 20, 2022
• Study Completion: April 20, 2022
• Last Updated: January 8, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)