CS1-CAR T Therapy Following Chemotherapy in Treating Patients With Relapsed or Refractory CS1 Positive Multiple Myeloma

  • STATUS
    Recruiting
  • End date
    Dec 10, 2023
  • participants needed
    30
  • sponsor
    City of Hope Medical Center
Updated on 4 February 2022
platelet count
fludarabine
cyclophosphamide
ejection fraction
serum pregnancy test
measurable disease
growth factor
cell transplantation
gilbert's syndrome
neutrophil count
autograft
line of therapy
proteasome inhibitor
plasmacytoma
bone marrow plasma cells

Summary

This phase I trial studies the side effects and best dose of CS1-chimeric antigen receptor (CAR) T therapy after chemotherapy in treating patients who have CS1 positive multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Immune cells can be engineered to kill multiple myeloma cells by inserting a piece of deoxyribonucleic acid (DNA) into the immune cells using a lentiviral vector such as CS1, that allows them to recognize multiple myeloma cells. These engineered immune cells, CS1-CAR T cells, may kill multiple myeloma cells.

Description

PRIMARY OBJECTIVE:

I. To evaluate the safety and tolerability of intravenous (i.v.) delivered autologous CS1-CAR T cells for research participants with CS1+ recurrent/refractory multiple myeloma (MM).

SECONDARY OBJECTIVES:

I. Evaluate the response rates at days 28, 100, and 180 post CAR T cell infusion.

II. Measure the persistence of CS1-CAR T cells in blood and marrow. III. Measure phenotype and anti-tumor functionality of CS1-CAR T cells in marrow and blood.

IV. Measure the levels of cytokines in blood and marrow, and soluble CS-1 in blood post infusion as a surrogate indicator of CAR T cell activity.

V. Evaluate CS-1 expression on MM cancer cells before, during and at progressive disease (PD) to determine antigenic loss.

EXPLORATORY OBJECTIVE:

I. Describe the percentage of MM cells that express CS-1 surface marker before, during and at PD.

OUTLINE: This is a dose-escalation study of CS1-CAR T cells.

Patients undergo leukapheresis over 2-4 hours. Beginning 3-4 weeks, patients receive cyclophosphamide intravenously (IV) on days -4 and/or -3 or fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients then undergo CS1-CAR T therapy over 10-15 minutes on day 0.

After completion of study treatment, patients are followed up at 1 day, at least every 2 days for up to a minimum of 14 days, weekly for 1 month, monthly for 1 year, then periodically for up to 15 years.

Details
Condition Recurrent Plasma Cell Myeloma, Refractory Plasma Cell Myeloma
Treatment cyclophosphamide, leukapheresis, Fludarabine, CS1-CAR T Therapy
Clinical Study IdentifierNCT03710421
SponsorCity of Hope Medical Center
Last Modified on4 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Documented informed consent of the participant and/or legally authorized representative
Assent, when appropriate, will be obtained per institutional guidelines
Karnofsky Performance Status (KPS) of >= 70%
Life expectancy >= 16 weeks
Participant must have a confirmed diagnosis of active MM as defined by the International Myeloma Working Group (IMWG) criteria
Participant must have a confirmed CS1+ MM as evaluated by City of Hope (COH) Pathology Core
Participant must have measurable disease defined as meeting at least one of the criteria below
Serum M-protein >= 0.5 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%
Participant must have relapsed or refractory disease after all 3 prior treatment regimens with the following requirements
Participant must have received prior treatment with an immunomodulatory agent
Participant must have received prior treatment with a proteasome inhibitor
Participant must have received prior treatment with an anti-CD38 antibody
Participants must be refractory to last line of therapy prior to study enrollment (refractory myeloma is defined as disease that is nonresponsive, progression on treatment, or shows progression within 60 days after the last prior line of therapy)
Participants who were not candidates to receive one or more of the above treatments are eligible; however, the reason must be clearly documented in the case report form
Note: induction chemotherapy, autologous stem-cell transplantation (ASCT), and maintenance therapy should be considered as 1 "regimen
Additionally, if a participation underwent autologous transplant he/she be >= 90 days from transplant at the time of enrollment
Total serum bilirubin =< 2.0 mg/dL
Participants with Gilbert syndrome may be included if their total bilirubin is =< 3.0
Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN)
Alanine aminotransferase (ALT) < 2.5 x ULN
Serum creatinine =< 2.5 x ULN or estimated creatinine clearance of >= 40 mL/min per the Cockcroft-Gault formula, and the participant is not on hemodialysis
Absolute neutrophil count >= 1000/uL. Transfusions and growth factors must not be used to meet these requirements at initial screening
Hemoglobin (Hb) >= 8 g/dl. Transfusions and growth factors must not be used to meet these requirements at initial screening
Platelet count >= 50,000/uL (>= 30,000/uL if bone marrow plasma cells are >= 50% of cellularity). Transfusions and growth factors must not be used to meet these requirements at initial screening
Left ventricular ejection fraction >= 45% within 8 weeks before enrollment
Oxygen (O2) saturation >= 92%
Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy
Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria

Prior allogeneic stem cell transplantation
Autologous transplantation =< 90 days of enrollment
Growth factors within 14 days of enrollment
Platelet transfusions within 7 days of enrollment
Epstein-Barr virus (EBV) positivity by polymerase chain reaction (PCR) at the time of enrollment
Participants receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
Participants with known additional malignancy that is progressing or required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
Participants with toxicities from prior therapies, with the exception of peripheral neuropathy attributable to bortezomib, that have not recovered to grade =< 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria or to the subject's prior baseline
Participants with known active hepatitis B or C infection; research participants who are human immunodeficiency virus (HIV) positive based on testing performed within 4 weeks of enrollment; research participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections
Participants with active auto-immune disease, including connective tissue disease, sarcoidosis, multiple sclerosis, inflammatory bowel disease or have a history of severe (as judged by the principal investigator) autoimmune disease that will require prolonged immunosuppressive therapy
Have New York Heart Association (NYHA) Class III or IV heart failure, unstable angina, or a history of recent (within 6 months) myocardial infarction
Participants with a history or presence of clinically relevant central nervous system (CNS) pathology such as uncontrolled seizure disorder, stroke, severe brain injuries, dementia, cerebellar disease or psychosis
Participants with known active central nervous system (CNS) involvement by malignancy. Subjects with prior CNS disease that has been effectively treated will be eligible if treatment was completed at least 3 months prior to enrollment with no evidence of symptomatic disease and stable abnormalities on repeat imaging
Participants with plasma cell leukemia (PCL) or symptomatic amyloidosis. However, participants with a prior history of PCL are not excluded
Participants with any known contraindications to leukapheresis, cyclophosphamide, fludarabine, cetuximab or tocilizumab
Dependence on corticosteroids
Defined as doses of corticosteroids of greater than or equal to 10 mg/day of prednisone or equivalent doses of other corticosteroids
Note: Topical and inhaled corticosteroids in standard doses and physiologic replacement for subjects with adrenal insufficiency are allowed
Participants with inadequate venous access for leukapheresis, and who are either unable to or unwilling to have a supportive line (temporary or other) placed for the procedure
Females only: Pregnant or breastfeeding
Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures
Prospective subjects who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
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