Amgen (Nasdaq: AMGN) today announced that AMG 386, combined with paclitaxel, demonstrated antitumor activity in a randomized Phase 2 trial involving 161 patients with recurrent ovarian cancer. The results are being presented for the first time in an oral presentation at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting. (Abstract Number: 5000)
AMG 386 is a first-in-class investigational peptibody that is designed to block angiogenesis by inhibiting angiopoietin-1 and -2 (Ang1 and Ang2). Angiopoietins interact with the Tie2 receptor, which mediates vascular remodeling. Ang1 and Ang2 are thought to play opposing roles, and the maturation of blood vessels appears to be controlled by their precise balance.
"The reality of ovarian cancer is that 80 percent of women diagnosed in later stages will experience recurrence, often multiple times, and eventually die from the disease," said 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. "In this study, AMG 386 showed promising antitumor activity and extended progression-free survival."
Patients were randomized to receive paclitaxel via IV weekly, three weeks on and one week off, plus AMG 386 at 10 mg/kg (Arm A,>
Median progression-free survival (PFS), the study's primary endpoint, in the 10 mg/kg arm was 7.2 months versus 5.7 months in the 3 mg/kg arm and 4.6 months in the placebo group (80 percent CI, 0.59 - 0.98;>
Grade 3 or higher adverse events (AEs), where the difference in incidence was more than five percent in the AMG 386 arm than the placebo arm, included: hypokalemia (Arm A/B/C percentages 12/11/4), peripheral neuropathy (10/2/4), anorexia (2/6/0), neutropenia (8/9/4), and dyspnea (2/9/4).
Other grade 3 or higher AEs 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 Number: 5042)
Two Analyses Suggest Placental Growth Factor May be a Biomarker of Therapeutic Response to Motesanib
Results of two analyses evaluating biomarkers as predictors of response to treatment with motesanib were also presented at the meeting. Motesanib is an investigational, orally-administered, small molecule antagonist of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3, platelet-derived growth factor receptor, and stem cell factor receptor. It is being investigated for its potential to inhibit the activity of all three VEGF receptors, which are key drivers of angiogenesis and lymphangiogenesis.
In the first study, a panel of five biomarkers was evaluated in patients with locally recurrent or advanced HER2-negative metastatic breast cancer who were treated with motesanib, bevacizumab, or placebo in combination with paclitaxel. Results showed that increases in circulating placental growth factor (PlGF) were associated with subsequent tumor response to treatment with motesanib plus paclitaxel. (Abstract Number: 1048)
In a separate study, a variety of biomarkers were evaluated in patients with progressive, advanced thyroid cancer, advanced non-squamous, non-small cell lung cancer, and locally recurrent or advanced metastatic breast cancer. Data from this analysis also suggested that PlGF elevation predicts clinical outcome across tumor types in patients treated with motesanib. (Abstract Number: 3037)
Motesanib is being developed in collaboration with Takeda and Millenium, the Takeda Oncology Company.
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