AMG 386 in Combination With Sorafenib in Patients With Metastatic Clear Cell Carcinoma of the Kidney A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study

作者：Rini Brian^*; Szczylik Cezary; Tannir Nizar M; Koralewski Piotr; Tomczak Piotr; Deptala Andrzej; Dirix Luc Y; Fishman Mayer; Ramlau Rodryg; Ravaud Alain; Rogowski Wojciech; Kracht Karolyn; Sun Yu Nien; Bass Michael B; Puhlmann Markus; Escudier Bernard

来源：Cancer, 2012, 118(24): 6152-6161.

DOI：10.1002/cncr.27632

• sorafenib
• AMG 386
• clear cell renal cell carcinoma
• randomized controlled trial
• phase 2 clinical trial

BACKGROUND: This study evaluated the tolerability and antitumor activity of AMG 386, a peptibody (a peptide Fc fusion) that neutralizes the interaction of angiopoietin-1 and angiopoietin-2 with Tie2 (tyrosine kinase with immunoglobulin-like and EGF-like domains 2), plus sorafenib in patients with clear cell metastatic renal cell carcinoma (mRCC) in a randomized controlled study. METHODS: Previously untreated patients with mRCC were randomized 1: 1: 1 to receive sorafenib 400 mg orally twice daily plus intravenous AMG 386 at 10 mg/kg (arm A) or 3 mg/kg (arm B) or placebo (arm C) once weekly (qw). Patients in arm C could receive open-label AMG 386 at 10 mg/kg qw plus sorafenib following disease progression. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 152 patients were randomized. Median PFS was 9.0, 8.5, and 9.0 months in arms A, B, and C, respectively (hazard ratio for arms A and B vs arm C, 0.88; 95% confidence interval [CI], 0.60-1.30; P = .523). The objective response rate (95% CI) for arms A, B, and C, respectively, was 38% (25%-53%), 37% (24%-52%), and 25% (14%-40%). Among 30 patients in arm C who had disease progression and subsequently received open-label AMG 386 at 10 mg/kg qw, the objective response rate was 3% (95% CI, 0%-17%). Frequently occurring adverse events (AEs) included diarrhea (arms A/B/C, 70%/67%/56%), palmar-plantar erythrodysesthesia syndrome (52%/47%/54%), alopecia (50%/45%/50%), and hypertension (42%/49%/46%). Fifteen patients had grade 4 AEs (arms A/B/C, n = 3/7/5); 4 had fatal AEs (n = 2/1/1), with 1 (abdominal pain, arm B) considered possibly related to AMG 386. CONCLUSIONS: In patients with mRCC, AMG 386 plus sorafenib was tolerable but did not significantly improve PFS compared with placebo plus sorafenib. Cancer 2012;118:6152-61.

• 出版日期2012-12-15
• 单位河北医科大学