Abstract 748: Phase I trial of fractionated-dose 177Lutetium radiolabeled anti-prostate-specific membrane antigen monoclonal antibody J591 (177Lu-J591) in patients with metastatic castration-resistant prostate cancer (metCRPC) (2012)

Abstract Background: J591 is a monoclonal antibody against the external domain of PSMA; 177Lu is a short-range ≤ and ≤ emitter. A phase II trial of single-dose 177Lu-J591 radioimmunotherapy (RIT) in patients (pts) with metCRPC demonstrated efficacy with acceptable toxicity and an apparent dose-response relationship. Dose fractionation of RIT may decrease toxicity while maintaining or increasing efficacy. Methods: In this phase I study, cohorts of 3-6 pts with progressive metCRPC received 2 fractionated doses of 177Lu -J591 2 weeks apart: Cohort 1 (20 mCi/m2 x2), dose escalation 5 mCi/m2 per dose per cohort up to 45 mCi/m2 x2. The primary endpoint was to determine dose limiting toxicity and the cumulative maximum tolerated dose (MTD) of fractionated 177Lu -J591 RIT and secondary endpoints of efficacy, with expansion cohorts enrolling. 177Lu-J591 imaging with semi-quantitative scoring was performed. Results: 28 pts were treated in the dose-escalation phase, receiving up to 45 mCi/m2 x2 (highest anticipated dose), 6 additional pts have been enrolled to date in expansion cohorts at the 2 highest dose levels. Median age is 73 (range 55-86), median baseline PSA 44.7 (2 - 766.5). 88% had bone mets and 38.2% extra-osseous visceral mets (lung, liver). Median Halabi nomogram score 147 (range 108-192, predicted median survival 15 mo). All pts had progressed after 1-4 hormonal therapies and 47.1% progressed on 1-4 lines of chemotherapy including docetaxel. Despite cumulative doses exceeding the single-dose MTD (70 mCi/m2, a dose at which 41% require platelet transfusions), during the dose-escalation phase only 6 pts receiving up to 90 mCi/m2 experienced Gr 4 thrombocytopenia (2 requiring a transfusion). 3 pts experienced Gr 4 neutropenia without fever or growth factors. Gr &amp;gt;1 non-heme toxicity was rare. The MTD for the regimen without growth factor is 40 mCi/m2 x2 (no transfusions needed at this dose). By planar imaging, accurate targeting of known sites of PC mets was seen in 82.4%. Including expansion cohorts, 50% overall experienced PSA declines, with 10 of 18 experiencing PSA decline at the recommended phase 2 doses. 12 of 13 pts with baseline and follow up circulating tumor cell counts (CellSearch methodology) became or remained favorable at follow up. Median survival is 25.3 mo [95% CI 15.3, 35.3] Conclusions: Fractionated dose 177Lu-J591 is well tolerated, with reversible myelosuppression. With dose-fractionation, pts are able to tolerate higher cumulative doses than with single-dose 177Lu-J591 (confirming our hypothesis) and preliminary efficacy has been demonstrated. Building upon these data, a phase I fractionated-dose 177Lu-J591 plus docetaxel study has begun enrollment, utilizing improved tolerability of fractionated dose RIT plus the radiosensitizing and debulking properties of docetaxel. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 748. doi:1538-7445.AM2012-748