Cilengitide in asymptomatic metastatic androgen independent prostate cancer (AIPC) patients (pts): A randomized phase II trial

Abstract

5144 Background: Integrins αvβ3 and αvβ5 are involved in PC metastasis by regulating cell adhesion, migration, invasion, motility and angiogenesis. αvβ3 integrin is important in bone metabolism and may play a role in PC growth in bone. Cilengitide is a selective, competitive inhibitor of αvβ3 and αvβ5 integrins. Methods: Chemo-naïve pts with asymptomatic progressive metastatic AIPCa were randomized to cilengitide 500 mg or 2,000 mg IV 2X/week (wk) in 6-wk cycles using Simon 2-stage optimal design. Disease was assessed q 12 wks. The primary end point was 6 month (m) objective progression rate (PgR) (excluding PSA). Historically a 75% PgR is expected. We hypothesized cilengitide would lower the 6 m PgR to 55%. > 6 pts/arm with no Pg were needed to move to 2nd stage. Pts with asymptomatic Pg at 1st assessment were permitted to receive 1 more cycle followed by reassessment. Secondary end points include safety, response rate, changes in circulating tumor cells (CTCs) and bone markers. Results: 44 pts were accrued to 1st stage. Arms were balanced at baseline except for younger age (median 68yrs vs 74yrs) and lower PSA (median 66ng/ml vs 141ng/ml) in the 2,000mg arm. Median number of cycles was 3/arm (500mg arm: 1–8; 2,000 mg arm: 1- 15). At 6 m, 3 pts (14%) on the 500mg arm and 6 pts (27%) on the 2,000mg arm had not progressed. Best objective response was stable disease (SD); 27% on the 500 mg arm, 36% on 2000mg arm. 50% of the 24 pts who had Pg at 1st assessment stayed on study for an additional cycle. There were 3 grade (G) 3 and no G4 toxicities. At 12 weeks, analysis of bone markers did not reveal significant biologic trends. At Pg, bone specific alkaline phosphatase and N-telopeptide increased in all pts, less so in pts on the 2000mg arm and in pts who obtained SD at 6m. CTCs increased over time in both arms. Conclusions: Cilengitide was well tolerated. The 2,000 mg arm had a modest but not clinically significant effect so 2nd stage was not pursued. Neither dose level decreased the 6 m PgR. Decreased level of bone markers correlated with a trend towards decreased PgR. The unique study design using a non-Pg endpoint, not acting on PSA changes, and confirming Pg after 1st assessment was feasible. Supported by CTEP, Prostate SPORE Grant P50 CA069568–09, PC051375, Merck KGaA, PC051382, Immunicon. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Johnson & Johnson Merck KGaA