Abstract 3280: Phase 1 study of AMG 386, an anti-angiogenic Fc fusion protein targeting angiopoietin-1 and -2, in Japanese patients with advanced solid tumors
Authors: Doi Toshihiko , Ohtsu Atsushi , Fuse Nozomu , Yoshino Takayuki , Tahara Makoto , Suzuki Noriko , Shibayama Kazuhiro , Takahara Eiji , Nakai Katsuhiko , Weinreich David M. 
Published: June 2012

Abstract
Background: AMG 386, a first-in-class investigational peptide-Fc fusion protein (peptibody), blocks angiogenesis via inhibiting the interaction between angiopoietin-1 and -2 and the Tie2 receptor. This first-in Japanese study evaluated the safety, tolerability, and pharmacokinetics (PK) of AMG 386 in patients with advanced solid tumors.
Method: This is the dose escalation, non-randomized, open-label, Phase 1 study of AMG 386 (JapicCTI-101161(en)) in Japanese patients with advanced solid tumors. Six patients were enrolled in each cohort (3, 10 or 30 mg/kg), and received AMG 386 intravenously once weekly to evaluate safety and PK profile as monotherapy. Dose-limiting toxicity (DLT) and PK profile were assessed for 28 days after initial dosing of AMG 386. DLT was defined as any related, grade ≥ 4 hematologic, grade ≥ 3 non-hematologic toxicity, or &gt; 10 times upper limits of normal (ULN) AST or ALT elevation. Tumor response was evaluated per RECIST 1.0. The patients continued to receive AMG 386 until DLT or disease progression.
Results: Eighteen Japanese patients (median age, 57.5 years old; male/female=10/8; mean body weight, 55.7 kg) with ECOG 0-1 received at least 1 dose of AMG 386. The median number of doses was 5.5, 6 and 6 in 3, 10 and 30 mg/kg cohort, respectively. Tumor types included gastric (6 including GIST), rectal (4 including rectal cartinoid), pancreatic (3), colon (2), breast (1), endometrial (1) and bladder (1). No DLTs were observed in this study. Adverse events (AEs) were reported in all patients. The most common grade ≥ 3 AEs were Gamma-glutamyltransferase increased, which were not considered related to AMG 386. Four serious adverse events were reported; only cholecystitis in a patient with colon cancer was considered to be related to AMG 386. No neutralizing anti-AMG 386 antibodies were detected. PK in the dose range of 3 to 30 mg/kg of AMG 386 was dose-linear and terminal-phase elimination half-life values (t1/2,Z) ranged from 91.6 to 110 hours. Total serum clearance appeared to be similar across the dose range. After the 4th administration, Cmin appeared to reach an approximately constant value in 3 cohorts. The accumulation ratio was approximately 1.2 to 1.3. Two patients had a partial response (PR) as a best response. Stable disease as best response was reported in 2 patients, and progressive disease was reported in 14 patients. Patients with colon cancer in 3 mg/kg cohort and bladder cancer in 30 mg/kg cohort are still continuing the study treatment with PR for 56 weeks and 24 weeks, respectively. Conclusions: Weekly administration of AMG 386 (3, 10 or 30 mg/kg) was well tolerated in Japanese patients with advanced solid tumors. The safety and PK profiles in Japanese were similar to those previously observed in non-Japanese patients. AMG 386 monotherapy has shown some monotherapy activity with 2 confirmed PRs in this heavily pre-treated patient population.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3280. doi:10.1158/1538-7445.AM2011-3280