A Phase Ib, Open-Label Study of Dalantercept, an Activin Receptor-Like Kinase 1 Ligand Trap, plus Sorafenib in Advanced Hepatocellular Carcinoma

Lessons learned: Patients with hepatocellular carcinoma (HCC) often have limited therapeutic responses to the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor sorafenib, which is standard of care in advanced HCC. Targeting the activin receptor-like kinase 1 (ALK1) and VEGF pathways simultaneously by combining the ALK1 ligand trap dalantercept with sorafenib may result in more effective angiogenic blockade and delay tumor progression in patients with advanced HCC.Although the combination was generally well tolerated, there was no additive antitumor activity with the combination of dalantercept plus sorafenib in patients with advanced HCC. No complete or partial responses were observed, and overall survival ranged from 1.9 to 23.3 months.These results suggest that, in this patient population, further development of the possible limited benefits of combination therapy with dalantercept plus sorafenib is not warranted.

Background: Targeting the activin receptor-like kinase 1 (ALK1) and vascular endothelial growth factor (VEGF) pathways may result in more effective angiogenic blockade in patients with hepatocellular carcinoma (HCC).

Methods: In this phase Ib study, patients with advanced HCC were enrolled to dose-escalation cohorts, starting at 0.6 mg/kg dalantercept subcutaneously every 3 weeks plus 400 mg sorafenib orally once daily, or to a dose expansion cohort. The primary objective was to determine the safety and tolerability and the dalantercept maximum tolerated dose (MTD) level. Secondary objectives were to assess the preliminary activity and the association of pharmacodynamic biomarkers with tumor response.

Results: A total of 21 patients were enrolled in the study. Five patients received 0.6 mg/kg dalantercept in the first dose escalation cohort. Based on the initial safety results, the dose level was de-escalated to 0.4 mg/kg in the second cohort (n = 6). The MTD was identified as 0.4 mg/kg and used for the dose expansion cohort (n = 10). At this dose level, the combination was generally well tolerated. Overall survival ranged from 1.9 to 23.3 months, and the best overall response was stable disease.

Conclusion: The addition of dalantercept to sorafenib did not improve antitumor activity in patients with HCC. The dalantercept program in this population was discontinued.