Abstract 3276: A Phase 1 dose escalating study with ACE-041, a novel inhibitor of ALK1 mediated angiogenesis, in patients with advanced solid tumors

Background: Activin receptor-like kinase-1 (ALK1) is a type I receptor predominantly expressed on activated vascular endothelial cells that mediates signaling by members of the TGFs superfamily of proteins. ACE-041, a soluble receptor fusion protein consisting of the extracellular domain of ALK1 linked to the IgG1-Fc region, binds with high affinity to BMP9 and BMP10 but not TGFs1, 2, or 3, VEGF, or bFGF. ACE-041 is able to inhibit both VEGF- and bFGF-stimulated angiogenesis, indicating that ALK1 is downstream of VEGF and bFGF signaling. In a variety of murine tumors, ACE-041 has demonstrated the ability to decrease both tumor vascularity and growth. Methods: The primary objective of this ongoing phase 1 study is to evaluate the safety and tolerability of ACE-041. Secondary objectives include identifying MTD, PK, preliminary activity on PD markers, and antitumor activity by RECIST, PET-CT, and DCE-MRI. Cohorts of 3-6 patients were enrolled at escalating dose levels. Once the MTD has been determined, 12-24 additional patients may be enrolled at the MTD or lower dose levels. ACE-041 is administered SC every 3 weeks for a total of 4 doses or until disease progression. Patients with stable or responding disease may continue treatment for up to 12 months. Results: The dose escalation phase of the study has completed enrollment of 25 patients (13M/12F) at seven dose levels (0.1 to 4.8 mg/kg). An expansion cohort of 12 additional patients at1.6 mg/kg is currently being enrolled. The mean t½ was approximately 13 to 23 days and the mean Tmax was 4 to 7 days. ACE-041 was generally well-tolerated; preliminary data show that common treatment-related AEs included peripheral edema, fatigue, nausea, headache, anorexia, and anemia. Most AEs were Grade 1 or 2. Grade 3 congestive heart failure was reported in one patient as possibly related to drug. Based on preliminary results, stable disease lasting at least 6 cycles was observed in 4 patients having previously progressed on prior therapies. Several patients were noted to have had a positive 18-FDG-PET response with a decrease in metabolic activity approximately 2 weeks following the first dose. Conclusions: ACE-041 is a first-in-class angiogenesis inhibitor that targets the ALK1 pathway. Treatment by subcutaneous injection every 3 weeks has been generally well-tolerated to date and preliminary evidence of antitumor activity has been observed in this ongoing study. 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 3276. doi:10.1158/1538-7445.AM2011-3276