LuCAB: A phase I/II trial evaluating cabazitaxel in combination with [177Lu]Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Abstract

TPS278 Background: [177Lu]Lu-PSMA-617 was recently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Despite conferring a survival benefit, for many the treatment response is short, and progression is inevitable. One of the likely mechanisms limiting the durability of responses to [177Lu]Lu-PSMA-617 is heterogeneity in tumor PSMA expression. This can be screened for visually using PSMA and FDG PET/CT scans and inspecting for discordant disease, however, micrometastatic disease is unable to be evaluated in this way. In addition, [177Lu]Lu-PSMA-617 may not effectively target micrometastatic disease due to the longer path length of beta emitters. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of [177Lu]Lu-PSMA-617, whilst also treating any PSMA-negative disease. We hypothesize that the combination of [177Lu]Lu-PSMA-617 and cabazitaxel will be well tolerated and lead to more durable responses. Methods: This single-centre, single-arm phase I/II trial will enrol 32-38 pts with mCRPC to evaluate the safety and preliminary efficacy of cabazitaxel and [177Lu]Lu-PSMA-617 in combination. Up to 6 doses of [177Lu]Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m2 - 20mg/m2), on Day 2 and Day 23 of each 6-week cycle. The dose of cabazitaxel will be escalated using a traditional 3+3 design. Key eligibility criteria include a diagnosis of mCRPC with PSMA-positive disease on PSMA PET/CT (SUVmax ≥15), with no evidence of diffuse marrow disease or sites of discordance on FDG PET/CT. Pts must have progressed after prior docetaxel and a second-generation antiandrogen, have adequate bone marrow and organ function and an ECOG performance status of 0-1. The primary objective is to establish the maximum tolerated dose of cabazitaxel and [177Lu]Lu-PSMA-617. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life over the first 12 months. Bloods will be taken at baseline, during treatment and at progression for ctDNA analysis, the results of which will be correlated with baseline pt and disease characteristics, and response outcomes, to determine biomarkers of treatment response and resistance. Pt recruitment commenced in August 2022 and will continue for 18 months. Clinical trial information: NCT05340374 .