AMG 386 in combination with sorafenib in patients (pts) with metastatic renal cell cancer (mRCC): A randomized, double-blind, placebo-controlled, phase II study.

Abstract

309 Background: AMG 386 inhibits angiogenesis by sequestering angiopoietin-1 and -2, thus preventing their interaction with the Tie2 receptor on endothelial cells. Combination with VEGF receptor inhibition has demonstrated additive effects in vivo. The efficacy and tolerability of sorafenib plus AMG 386, an investigational peptide-Fc fusion protein, were evaluated in mRCC pts. Methods: Treatment-naive pts with clear cell mRCC were randomized 1:1:1 to sorafenib 400 mgPO BID plus AMG 386 10 mg/kg (Arm A) or 3 mg/kg (Arm B) QW; or placebo (Arm C) IV QW. Endpoints were progression-free survival (PFS; primary); and (secondary) objective response rate (ORR), change in tumor burden, adverse events (AEs) and pharmacokinetics. Tumor assessment was performed at baseline and every 8 weeks thereafter. Results: 152 pts were randomized: Arms A/B/C, n=50/51/51. 60/61/61% of pts had intermediate and 40/39/37% had low MSKCC risk at baseline. PFS was similar in all 3 arms, whereas ORR was higher in the AMG 386 arms ( Table ). In Arms A/B/C the incidence of grade ≥ 3 AEs was 66/73/86% and serious AEs 36/49/28%. The most common AEs included diarrhea (70/67/56%; grade ≥3 8/10/8%), hand- foot syndrome (52/47/54%; grade ≥3 12/16/28%), alopecia (50/45/50%; grade ≥3 0/0/2%), and hypertension (42/49/46%; grade ≥3 18/20/14%). Median steady-state Cmax and Cmin for AMG 386 were similar to those reported previously. Sorafenib coadministration did not markedly affect AMG 386 exposure. Conclusions: Sorafenib plus AMG 386 was tolerable but did not improve PFS compared with sorafenib plus placebo. Increased ORR and the observed reduction in tumor burden are suggestive of an antitumor effect of AMG 386 in mRCC. [Table: see text] [Table: see text]