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.
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.
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)
