An open label phase II trial of BI 2536, a novel Plk1 inhibitor, in patients with metastatic hormone refractory prostate cancer (HRPC)

Abstract

14547 Background: BI 2536 is a novel, highly selective, potent inhibitor of Polo-like kinase 1 (Plk1), a key regulator of mitotic progression. BI 2536 has demonstrated favorable tolerability and antitumor activity in Phase I trials. We investigated the activity, safety and pharmacokinetics of BI 2536 in patients (pts) with metastatic HRPC. Methods: This open label, single arm Phase II study used a modified Gehan two-stage design. The primary objective was to determine the PSA response rate at 12 weeks according to Prostate Specific Antigen Working Group (PSAWG) criteria. HRPC pts with castrate testosterone levels, PSA progression and a PSA of >10 ng/ml were entered. 15 pts had to complete ≥4 courses to be evaluable for Stage 1 analysis. In case of at least two PSA responders, 35 additional pts were planned for Stage 2. Pts were treated with 200 mg BI 2536 given as a 1h i.v. infusion on Day 1 every 3 weeks. The dose was escalated to 250 mg from cycle 2 onwards in pts with <Grade 2 drug related non-hematologic and <Grade 3 hematologic toxicity. Results: 20 men with a median age of 70 years (range: 56–76) and a median Gleason score of 9 were treated. The median PSA at study entry was 47 ng/ml. Of the 15 evaluable pts entered into Stage 1, 3 were docetaxel pretreated and 11 were chemonaive. There were no PSAWG criteria PSA responders; 9 pts progressed, 6 pts had stable disease with 1 pt achieving a 25% PSA reduction. RECIST evaluation showed stable disease in 5 pts after 4 courses. Overall, BI 2536 was very well tolerated. Neutropenia was the main toxicity observed. At 200 mg dosing, Grade 3/4 neutropenia was observed in 20%, and after escalation to 250 mg, in 73% of pts. There were 2 cases of neutropenic infection requiring hospitalization in the Stage 1 population. Due to the lack of PSA responders the accrual did not continue beyond Stage 1 analysis. Conclusions: BI 2536 was very well tolerated in metastatic HRPC pts, with some indications of antitumor activity by PSA reduction and radiologically stable disease. As the Stage 1 study objectives were not reached, BI 2536 will not be assessed further as a single agent. Ongoing preclinical work is assessing the potential for synergy of BI 2536 in combination therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim