This phase Ib trial tests the safety, side effects, and best dose of autologous anti-prostate stem cell antigen (PSCA)-chimeric antigen receptor (CAR)-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes (PSCA-CAR T cells), plus or minus radiation, in treating patients with castration-resistant prostate cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Castration-resistant prostate cancer continues to grow and spread despite the surgical removal of the testes or medical intervention to block androgen production. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving PSCA-targeting CAR T-cells, with or without radiation, may kill more tumor cells in men with castration-resistant prostate cancer.
PRIMARY OBJECTIVE: I. Assess the feasibility, safety, and activity of lymphodepleting chemotherapy followed by up to 3 cycles of 50M PSCA-CAR T cell immunotherapy per course either alone (treatment plan 1 \[TP1\]) or in combination with metastasis-directed radiation therapy (MDRT) (treatment plan 2 \[TP2\]) in adult patients with metastatic castration-resistant prostate cancer (mCRPC). SECONDARY OBJECTIVES: I. Describe persistence and expansion of CAR T cells in peripheral blood (PB). II. Describe cytokine levels over the study period. III. Estimate disease response rates. IV. Estimate 6-month progression-free survival (PFS) rate. V. Estimate 1-year overall survival (OS) rate. EXPLORATORY OBJECTIVES: I. Describe the immune landscape changes in PB and tumors. II. Describe phenotype of CAR T cells in PB. III. Describe tumor evolution in PB (circulating tumor cells \[CTCs\], circulating cell-free deoxyribonucleic acid \[DNA\] \[cfDNA\]) and tumors. IV. Determine whether urine cytokines and cellularity is predictive of cystitis occurrence/severity. V. Analyze microbial changes in stool associated with CAR T cell therapy. OUTLINE: Patients are assigned to 1 of 2 treatment plans. TREATMENT PLAN I: Patients undergo leukapheresis and lymphodepletion and receive PSCA-CAR T cells intravenously (IV) up to 3 times on study. TREATMENT PLAN II: Patients undergo leukapheresis, radiation in 2 doses, and lymphodepletion, and receive PSCA-CAR T cells IV up to 3 times on study. Patients in both arms undergo bone scan, computed tomography (CT) scan, tumor biopsy, and collection of blood, stool and urine samples throughout the trial.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
21
Given IV
Undergo tumor biopsy
Undergo blood, stool, and urine sample collection
Undergo bone scan
Undergo CT scan
Undergo radiation
Undergo leukapheresis
Undergo lymphodepletion
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence of adverse events
Dose limiting toxicities (DLTs), cystitis, grade 3 toxicities and the full toxicity profile as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 and cytokine release syndrome (CRS) and neurotoxicity as assessed by modified CRS grading. The recommended phase 2 dose (RP2D) will be based on the treatment plan 2 toxicity, activity and correlative data. Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for DLTs within the DLT period. Tables will be created to summarize all toxicities and side effects by attribution to treatment arm, dose, organ and severity.
Time frame: Post chimeric antigen receptor (CAR) T cell infusion up to 15 years
50% prostate specific antigen (PSA) level reduction
Statistical and graphical methods will be used to describe cytokine levels (peripheral blood) and PSA levels over the study period.
Time frame: From baseline measurement up to 1 year post study treatment
Persistence of CAR T cells
Maximum persistence (in days) will be described by treatment plan, recognizing the number of CAR T cycles the participant received.
Time frame: Up to 28 days post last study treatment
Expansion of CAR T cells
Peak expansion (log10 copies/ug of genomic deoxyribonucleic acid \[DNA\]) will be described by treatment plan, recognizing the number of CAR T cycles the participant received.
Time frame: Up to 28 days post last study treatment
PSCA tumor expression
PSCA expression on tumor cells by IHC and/or flow cytometry.
Time frame: From baseline to end of cycle 1 (Cycle length is 56 days)
Serum cytokine profile
Statistical and graphical methods will be used.
Time frame: Before CAR T cell infusion through completion of cycle 2, up to 4 months (Cycle length is 56 days)
Overall survival
Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated.
Time frame: From time of lymphodepletion to date of death, assessed at 1 year
Progression-free survival
Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated.
Time frame: Survival without radiographic evidence of disease progression from time of lymphodepletion to the date of progression or death, assessed at 6 months
Disease response by PSA
Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated.
Time frame: From baseline up to 1 year post study treatment
Disease response by immune-modified Response Evaluation Criteria in Solid Tumors criteria
Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated.
Time frame: At baseline, and months 3, 6, 9 and 12
Disease response by Prostate Cancer Working Group criteria
Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated.
Time frame: At baseline, and months 3, 6, 9 and 12
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