Safety, pharmacokinetics, and efficacy of TAK-700 in metastatic castration-resistant prostrate cancer: A phase I/II, open-label study.

Abstract

3084 Background: TAK-700 is a selective 17,20 lyase inhibitor that substantially reduced in vivo adrenal androgen levels in preclinical studies. Methods: This phase I/II open-label, dose-escalation study assesses the safety and tolerability of oral twice-daily (BID) TAK-700 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Secondary objectives include assessment of efficacy, as shown by prostate-specific antigen (PSA) response, and TAK-700 pharmacokinetics (PK). Here we report the phase I portion of the study. Results: 26 pts (median age 70 y, 11 had received prior ketoconazole) received TAK-700 at 5 dose levels: 100 (3 pts), 200 (3), 300 (3), 400 (6) or 600 (5) mg BID; a further 6 pts received TAK-700 400 mg BID plus prednisone 5 mg BID. At data cut-off (29 Dec 2009), 11 pts remain on study; 15 patients discontinued, including 6 due to adverse events (AEs), 4 due to radiologic disease progression, 2 due to PSA progression, 2 due to patient request and 1 for other reasons. All pts experienced ≥1 treatment-emergent AE (TEAE); 92% were drug-related and 54% were grade ≥3. The most common TEAE was fatigue (17 pts, 3 grade ≥3 with 600 mg BID), followed by non-dose-related GI events such as nausea (11 pts, 1 grade 3), constipation (10), anorexia (9) and vomiting (7, 2 grade ≥3). Preliminary PK analysis indicates approximate dose- proportional increases in single- and multiple-dose Cmax and AUC0–8hr over the 100–600 mg BID dose range. Multiple-dose PK are consistent with the single-dose PK. At 4 wks, median testosterone and DHEA-S levels had decreased from 5.5 to 0.6 ng/dL and 50.0 μ g/dL to below quantifiable levels, respectively, in all patients treated with TAK-700. All patients treated with ≥300 mg had a PSA decrease; of 15 pts who received TAK-700 ≥300 mg for ≥3 cycles and had a 3-month PSA determination, 12 (80%) had PSA reductions ≥50% and 4 (27%) had reductions ≥90%. Conclusions: TAK-700 ≥300 mg BID appears active and well tolerated in pts with mCRPC. The phase II portion of the study is ongoing (31 pts enrolled by data cut-off) and will further assess the safety and efficacy of TAK-700 and the need for concomitant prednisone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium AstraZeneca, Endo Pharmaceuticals, MethylGene, Millennium, Ortho Biotech, Transgene sanofi-aventis Millennium