Clinical Trial Protocol for LuCAB: A Phase I-II Trial Evaluating Cabazitaxel in Combination with [Lu]Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer.

[Lu]Lu-prostate-specific membrane antigen (PSMA)-617 is a standard treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and an androgen receptor pathway inhibitor. However, for many, responses are short and progression is inevitable. Contributing factors to treatment resistance include molecular heterogeneity with variable PSMA expression, micrometastases that may not absorb sufficient radiation from Lu to result in cell death, and inherent or acquired radioresistance because of genomic alterations or the tumor microenvironment. Cabazitaxel is a radiosensitizer and may treat PSMA-negative disease that would otherwise evade targeting by [Lu]Lu-PSMA-617. We hypothesize that the combination of [Lu]Lu-PSMA-617 and cabazitaxel will be synergistic with an acceptable safety profile. This investigator-initiated phase I-II trial aims to evaluate the safety, tolerability, and preliminary efficacy of cabazitaxel and [Lu]Lu-PSMA-617 in combination. Up to 38 patients with mCRPC will receive up to 6 doses of [Lu]Lu-PSMA-617 administered intravenously every 6 wk at a fixed dose of 7.4 GBq. Cabazitaxel will be administered concurrently (dose range, 12.5-20 mg/m) on day 2 and day 23 of each 6-wk cycle, with dose escalation determined using a traditional 3 + 3 design to establish the maximum tolerated or administered dose. Key eligibility criteria include a diagnosis of progressive mCRPC with PSMA-positive disease on PSMA PET/CT (SUV ≥ 15) and no sites of discordance on [F]F-FDG PET/CT. Patients must have received prior docetaxel and an androgen receptor pathway inhibitor, have adequate bone marrow and organ function, and have an Eastern Cooperative Oncology Group performance status of 0 or 1. The primary objective is to assess for dose-limiting toxicities and determine the recommended phase II dose of cabazitaxel and [Lu]Lu-PSMA-617 in combination. Secondary objectives include further safety evaluation through the measurement of the frequency and severity of adverse events, assessment of efficacy, and evaluation of changes in pain and health-related quality of life over the first 12 mo from treatment commencement. Plasma will be collected at baseline, during treatment, and at disease progression for circulating tumor DNA analysis, which will be correlated with clinical outcomes to identify potential biomarkers of treatment response or resistance. Enrollment commenced in August 2022, with anticipated completion in 2025.