The DASH Study: A phase 1b study of dalantercept plus sorafenib in advanced hepatocellular carcinoma.

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TPS495 Background: The activin receptor-like kinase (ALK1) pathway is a novel target in angiogenesis that promotes blood vessel maturation and stabilization. ALK1 binds to the ligand bone morphogenetic protein 9 (BMP9) which is overexpressed in hepatocellular carcinoma (HCC) compared to normal hepatocytes. Dalantercept is an ALK1 receptor fusion protein that binds BMP9 and acts as a ligand trap. Sorafenib, a multi-kinase and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI), is the standard therapy for advanced HCC. In a preclinical model of HCC, simultaneous blockade of ALK1 and VEGF signaling with dalantercept and sorafenib resulted in additive tumor growth inhibition. In a completed Phase 1 study in thirty-seven subjects with solid tumors, dalantercept monotherapy demonstrated preliminary anti-tumor activity and a safety profile that was generally non-overlapping with VEGFR TKIs. Methods: An open label, multi-center, dose escalating, phase 1b study to evaluate dalantercept plus sorafenib in subjects with advanced HCC is ongoing. The primary endpoint includes the evaluation of the safety and tolerability of dalantercept plus sorafenib and determination of the recommended phase 2 dose levels of the combination. Secondary endpoints include assessments of the pharmacokinetic profile of the combination, preliminary activity including response rate using RECIST 1.1 and time to progression, and pharmacodynamic biomarkers in the serum and tissue including ALK1 and BMP9 expression. In the first two cohorts of 3-6 subjects each, the dalantercept dose levels will be 0.6 and 0.9 mg/kg, respectively, administered subcutaneously (SC) every 3 weeks in combination with sorafenib 400 mg PO once daily. In cohort three, 3-6 subjects will receive dalantercept dose level 0.9 mg/kg SC every 3 weeks with sorafenib 400 mg PO twice daily. Patient safety data through day 22 will be evaluated prior to escalation to the next cohort. An expansion cohort will enroll 10-20 subjects at or below the maximum tolerated dose level. Key eligibility criteria: histologically confirmed advanced HCC, Child-Pugh A liver disease, ECOG performance status of 0-1, and no prior systemic therapy in the advanced setting. Clinical trial information: NCT02024087.