Randomized phase II study with window-design to evaluate anti-tumor activity of the survivin antisense oligonucleotide (ASO) ly2181308 in combination with docetaxel for first-line treatment of castrate-resistant prostate cancer (CRPC).

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5019 Background: In prostate cancer, expression of survivin, a protein that inhibits apoptosis, is associated with resistance to taxanes and poor outcome. LY2181308 reduces survivin expression and consequently is expected to improve activity of taxanes, such as docetaxel. A randomized phase II study was conducted to assess the activity of the combination. Methods: Adult patients (pts) with CRPC, ECOG performance status <2, and no bone or CNSmetastases were randomized 1:2 to standard docetaxel/prednisone every 21 days (Arm A) or standard therapy combined with LY2181308 given as a 3-hr IV infusion (Arm B). Analysis was planned and performed after 130 pts progressed or died. This assessment provided a 70% chance of detecting a difference in progression-free survival (PFS) at the 10% significance level. Initially, LY2181308 was given as a loading dose (3 consecutive days) and then as a weekly 3-hr IV maintenance dose. Arm B also included a window treatment with LY2181308 monotherapy equivalent to a 21-day cycle of docetaxel before starting combined treatment. The primary endpoint was PFS. Results: This study enrolled 154 pts. The median PFS for Arm B was 8.64 (90% CI, 7.39–10.45) months vs. 9.00 (90% CI, 7.00–10.09) months in Arm A, showing no statistical difference (log rank p=0.755). The median overall survival (OS) for Arm B was 27.04 (90% CI, 19.94–33.41) months vs. 29.04 (90% CI, 20.11–39.26) months for Arm A (log-rank p= 0.838). The PSA responses (>50% reduction in PSA) were similar: 56.9% for Arm A and 56.1% in Arm B (p=0.856). Most pts had no pain or mild pain at baseline and during the active period. Pts treated in Arm B had a higher frequency of serious and nonserious adverse events (AEs) than those in Arm A. The observed AE and pharmacokinetic (PK) profiles were consistent with the known safety and PK profiles of LY2181308 and docetaxel. Conclusions: The addition of LY2181308 to a standard docetaxel/prednisone regimen showed no improvement in PFS, PSA response, and OS in first line CRPC pts. The safety profile of docetaxel and LY2181308 is predictable and consistent with the known safety profiles. Clinical trial information: NCT00642018.

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