A randomized phase II trial of 177lu radiolabeled monoclonal antibody J591 (177Lu-J591) and ketoconazole in patients (pts) with high-risk castrate biochemically relapsed prostate cancer (PC) after local therapy.

Abstract

TPS248 Background: Biochemical recurrence without evidence of PC on standard CT/MRI and bone scans after local therapy is common. Salvage radiotherapy affords a cure to a proportion of pts with biochemical relapse, but most suffer disease progression because of micrometastatic PC outside of the radiation field. J591 is a monoclonal antibody that targets the extracellular domain of prostate specific membrane antigen (PSMA). A phase II trial of single-dose 177Lu-J591 radioimmunotherapy (RIT) in pts with progressive, metastatic castration-resistant prostate cancer (CRPC) demonstrated excellent targeting of metastatic sites, efficacy, and acceptable toxicity (Tagawa et al, ASCO 2008). In general, RIT appears to have its greatest impact in the setting of minimal disease (Kaminski NEJM 2005; Leonard JCO2005; Press JCO 2006) and the beta emission of 177Lu is best suited for lesions 1-3 mm in diameter (O'Donoghue J Nuc Med 1995) (i.e. micrometastatic disease). Methods: Men with high-risk CRPC (PSA doubling time < 8 months and/or PSA > 20 [Smith JCO 2005]) and no evidence of disease on CT/MRI and bone scans are randomized in a 2:1 fashion to receive double-blinded 177Lu-J951 vs 111In-J591 (control) and will undergo planar gamma camera imaging with SPECT following infusion. All pts receive ketoconazole plus hydrocortisone. The primary endpoint of the study is 18-month metastasis-free survival. 140 pts will be treated to allow 80% power with a 2-sided alpha of 5% to detect a 25% absolute difference (50% vs. 75% metastasis free) in radiographically apparent metastasis at 18 months (with interim analysis after 50% of pts have at least 12 months follow- up). Secondary/exploratory endpoints include evaluation of radiolabeled J591 imaging to detect sites of metastases not apparent on standard CT/MRI and bone scan, validation of adrenal androgen levels as biomarkers for ketoconazole (Ryan Clin Cancer Res 2007), analysis of circulating tumor cells for PSMA expression and to predict the appearance of radiographic metastases, and exploration of plasma markers of hemostasis, fibrinolysis, and angiogenesis as biomarkers. No significant financial relationships to disclose.