Phase I dose-escalation study of docetaxel/predisone and fractionated 177Lu-J591 for metastatic castrate-resistant prostate cancer (metCRPC).

Abstract

TPS247 Background: Nearly all prostate cancers express prostate specific membrane antigen (PSMA), with limited expression in other organs, making it an ideal therapeutic target. Monoclonal antibody J591 binds the extracellular domain of cells expressing PSMA with optimal affinity and is effectively internalized, with excellent targeting of metastatic sites when radiolabeled (Liu Clin Cancer Res 1997 & 1998, Milowsky JCO 2004, Bander JCO 2005). 177Lu is a radionuclide with gamma and short-range beta emission. A phase II trial of single-dose 177Lu-J591 radioimmunotherapy (RIT) in pts with metCRPC demonstrated efficacy with acceptable toxicity and an apparent dose-response relationship (Tagawa et al, ASCO 2008). It appears that dose-fractionation of 177Lu-J591 allows higher cumulative doses with less myelosuppression (Tagawa et al, submitted ASCO 2010). Docetaxel, which is standard chemotherapy for metCRPC, is a known radiosensitizer. We hypothesize that this combination will have superior clinical efficacy compared to either agent alone. The objective is to determine toxicity profile and maximal tolerated dose (MTD) of 177Lu-J591 plus docetaxel prior to the initiation of a phase II clinical trial. Methods: This is a multi-institutional phase I trial for men with progressive metCRPC that are docetaxel naive or have demonstrated prior docetaxel sensitivity. Docetaxel 75 mg/m2 is given every 3 weeks with prednisone 10 mg daily. Cohorts of 3-6 men receive escalated doses of fractionated 177Lu-J591 (20 mCi/m2 × 2, escalated in 5 mCi/m2 increments, to maximum of 45 mCi/m2 × 2). The initial dose of 177Lu-J591 is administered 2-3 days prior to cycle 3 of docetaxel to take advantage of initial chemotherapy debulking and to optimize radiosensitization (DeNardo Cancer 1997). Cycle 4 of docetaxel is administered upon adequate hematologic recovery. The primary endpoints are determination of MTD and toxicity profile. Secondary endpoints include response rate and survival. Exploratory objectives include the analysis of PSMA expression in circulating tumor cells and PSMA-based nuclear scans as biomarkers of response and/or toxicity with anti-PSMA-based RIT. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis