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

  • STATUS
    Recruiting
  • End date
    Jul 30, 2034
  • participants needed
    18
  • sponsor
    Fred Hutchinson Cancer Research Center
Updated on 27 January 2021
cancer
fludarabine
cyclophosphamide
monoclonal antibodies
measurable disease
cell transplantation
leukemia
induction therapy
progressive disease
monoclonal antibody therapy
monoclonal protein
immunoglobulin
plasma cell leukemia
proteasome inhibitor
plasmacytoma
immunomodulatory imide drug
bone marrow plasma cells
gamma-secretase inhibitor ly3039478

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.

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.

Details
Condition Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma, Refractory Multiple Myeloma
Treatment cyclophosphamide, laboratory biomarker analysis, Fludarabine, Pharmacokinetic Study, BCMA-specific CAR-expressing T Lymphocytes, Gamma-Secretase Inhibitor LY3039478
Clinical Study IdentifierNCT03502577
SponsorFred Hutchinson Cancer Research Center
Last Modified on27 January 2021

Eligibility

Yes No Not Sure

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)
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