A phase 1b study of PSCA CAR T cells plus or minus radiation for the treatment of patients with PSCA+ metastatic castration-resistant prostate cancer.

TPS5112 Background: Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies but application of CAR T cell therapy in solid malignancies remains a high priority. We previously demonstrated initial safety of a PSCA CAR T cells in patients with mCRPC following a reduced lymphodepletion regimen (LD) in a phase 1 trial (NCT03873805). There was preliminary evidence of anti-tumor activity (Dorff 2023) but escalation was not pursued due to concerns of toxicity. Additional dose exploration is needed. Preclinical work suggests that radiation therapy directed to tumor sites modifies the tumor microenvironment providing rationale for combining metastasis directed radiation therapy (MDRT) with CAR T cell therapy. The phase 1b dose exploration study aims to test a multi-dose strategy and whether the addition of MDRT could further enhance response. Methods: This is a single-center, open-label, phase Ib trial for patients with PSCA+ mCRPC. Key inclusion criteria are a diagnosis of mCRPC with evaluable disease, at least one area of metastasis amenable for radiation (for the MDRT cohort), PSCA expression by immunohistochemistry on archival tissue, and prior progression on abiraterone or enzalutamide or both; prior taxane chemotherapy is allowed. The primary objective will be to assess the feasibility, safety, and activity of PSCA CAR T cell therapy. Primary endpoints will include evaluation of toxicity through DLT’s and activity through rate of PSA50 and objective responses. Secondary endpoints will include overall survival, progression-free survival (PCWG3 criteria), measurement of CAR T cell and cytokine kinetics, and T cell infiltration in pre- and post-treatment tumor biopsies. Exploratory endpoints will include phenotypes and frequencies of immune cell subsets in peripheral blood pre- and post-therapy, gene expression of CTCs, CAR immunogenicity by the presence of anti CAR antibodies or T cell mediated immune responses, urine analysis, cfDNA whole exome sequencing, and phenotype tumor infiltrating lymphocytes. This study includes 2 treatment plans (TP). The participants on TP 1 will receive 50 million PSCA CAR T cells every 2 weeks for up to 6 doses after LD chemotherapy. Based on these results, the number of cycles of CAR T will be determined for TP2. Participants on TP 2 will receive PSCA CAR T therapy after MDRT and LD. The first 3 participants on each TP will be staggered, all further participants will be treated in cohorts of 3. Toxicities will be monitored based on a Wald sequential probability ratio test. Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for DLTs within the DLT period, disease response based on PSA50/RECIST/PCWG3 criteria, PFS at 6 months, and OS at 1 year. The results will be used to identify the optimal strategy to move to phase 2. The study is currently open to enrollment. Clinical trial information: NCT05805371 .