Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients (pts) with recurrent ovarian carcinoma.

Abstract

5000 Background: AMG 386 is an investigational peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction between the Tie2 receptor and angiopoietin 1 and 2. We evaluated the safety and efficacy of AMG 386 combined with paclitaxel in recurrent ovarian cancer. Methods: Pts with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer were randomized 1:1:1 to receive paclitaxel at 80 mg/m2 IV QW (3 on/1 off) plus AMG 386 at 10 mg/kg (Arm A), 3 mg/kg (Arm B) or placebo (Arm C) IV QW, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response per RECIST (ORR), CA-125 response (per GCIG), safety and pharmacokinetics. Results: 161 pts were randomized (Arms A/B/C, n=53/53/55). Efficacy results are shown in the table. Notable adverse events included peripheral edema (Arm A/B/C, 71/51/29%; grade ≥3, 4/6/4%), hypokalemia (21/15/5%; grade ≥3, 12/11/4%), thromboembolic events (arterial, 2/2/0%, all grade ≥3; venous, 8/8/11%; grade ≥3, 6/6/9%) and hypertension (8/8/5%, no grade 3). There were no bowel perforations in AMG 386 treated patients; no deaths on study were considered treatment-related. 3 of 92 treated pts had non-neutralizing anti-AMG 386 antibodies. AMG 386 Cmax and Cmin values were dose-proportional and similar to those observed in prior monotherapy studies. Conclusions: In this study, AMG 386 combined with weekly paclitaxel was tolerable with a manageable safety profile distinct from VEGF inhibitors and showed promising evidence of antitumor activity with a dose-response effect. Further studies are warranted. Arm A* (n = 53) AMG 386 10 mg/kg Arm B* (n = 53) AMG 386 3 mg/kg Arm C* (n = 55) placebo Primary endpoint Median PFS (80% CI), mos 7.2 (5.7, 7.5) 5.7 (5.2, 7.8) 4.6 (2.0, 5.5) Cox model,** HR (80% CI) vs. Arm C 0.76 (0.57, 1.02) p=0.23 0.75 (0.56, 1.00) p=0.21 0.76 (0.59, 0.98), p=0.17 Dose response, ordered log-rank test,** p value 0.074 Secondary endpoint ORR (CR + PR), % 37 19 27 CA-125 response, % 71 58 28 * All arms received weekly paclitaxel. ** Stratified by prior anti-VEGF therapy, progression on or within 6 mos of last chemotherapy regimen. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Amgen, Schering-Plough Amgen