AMG 386 is a 1st-in-class investigational peptibody that has been created to block angiogenesis (process of developing new blood vessels) by inhibiting angiopoietin-1 and -2 (Ang1 and Ang2). Angiopoietins work together with the Tie2 receptor, which mediates vascular remodeling. Ang1 and Ang2 are believed to play opposing roles, and the maturation of blood vessels is thought to be controlled by their precise balance.
Beth Karlan, M.D., director of the Women's Cancer Research Institute at Cedars-Sinai's Samuel Oschin Comprehensive Cancer Institute and director of Cedars-Sinai Medical Center's Division of Gynecologic Oncology, said:
The reality of ovarian cancer is that 80% of women diagnosed in later stages will experience recurrence, often multiple times, and eventually die from the disease. In this study, AMG 386 showed promising antitumor activity and extended progression-free survival.
Patients were randomized (selected by chance alone) to receive paclitaxel via IV (intravenously) weekly, three weeks on and one week off, plus AMG 386 at 10 mg/kg (Arm A, n=53), AMG 386 at 3 mg/kg (Arm B, n=53), or placebo (Arm C, n=55).
Median progression-free survival (PFS), the study's primary endpoint was:
7.2 months in the 10 mg/kg arm
5.7 months in the 3 mg/kg arm
4.6 months in the placebo group (80% CI, 0.59 - 0.98; p=0.17)
The objective response rate, per RECIST, was:
37% in the 10 mg/kg arm
19% in the 3 mg/kg arm
27% in the placebo group
Response rate measured by serum CA-125 levels, per the guidance from the Gynecologic Cancer Intergroup (GCIG), was:
71% in the 10 mg/kg arm
58% in the 3 mg/kg arm
28% in the placebo group
Grade 3 or higher adverse events, where the difference in incidence was more than 5% in the AMG 386 arm than the placebo arm, included:
Hypokalemia - Low blood potassium (Arm A/B/C percentages 12/11/4)
Peripheral neuropathy - nerves outside the spinal cord not working properly (10/2/4)
Anorexia - markedly reduced appetite (2/6/0)
Neutropenia - not enough neutrophils, types of white blood cells (8/9/4)
Dyspnea - shortness of breath, difficult or labored breathing (2/9/4)
Other grade 3 or higher adverse events of interest included thromboembolic events (arterial 2/2/0; venous 6/6/9). No grade 3 or higher hypertension was observed and there were no bowel perforations in patients treated with AMG 386. No treatment-related deaths occurred in the study.
The results of a population pharmacokinetic/pharmacodynamic analysis were presented separately in a poster at the Annual Meeting. This analysis suggests that investigation using higher doses of AMG 386 for patients with ovarian cancer is warranted.
Abstract 5000 (at ASCO Annual Meeting 2010)
"Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients (pts) with recurrent ovarian carcinoma."
B. Y. Karlan, A. M. Oza, V. L. Hansen, G. E. Richardson, D. M. Provencher, P. Ghatage, M. Tassoudji, D. E. Stepan, D. M. Weinreich, I. B. Vergote; Cedars-Sinai Medical Center, Los Angeles, CA; Princess Margaret Hospital, Toronto, ON, Canada; Northern Utah Associates, Ogden, UT; Cabrini Hospital, Malvern, Australia; CHUM-Hôpital Notre-Dame, Montreal, QC, Canada; Tom Baker Cancer Centre, Calgary, AB, Canada; Amgen, South San Francisco, CA; Amgen, Thousand Oaks, CA; University Hospital Leuven, Leuven, Belgium
Source: Amgen Inc., ASCO
