The DART Study: Results from the dose-escalation and expansion cohorts evaluating the combination of dalantercept plus axitinib in advanced renal cell carcinoma.

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The DART Study: Results from the dose-escalation and expansion cohorts evaluating the combination of dalantercept plus axitinib in advanced renal cell carcinoma.

Clin Cancer Res. 2016 Dec 28;:

Authors: Voss MH, Bhatt RS, Plimack ER, Rini BI, Alter RS, Beck JT, Wilson D, Zhang X, Mutyaba M, Glasser C, Attie KM, Sherman ML, Pandya SS, Atkins M

Abstract
PURPOSE: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and vascular endothelial growth factor (VEGF) signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1 receptor-fusion protein that acts as a ligand trap for bone morphogenetic proteins (BMP) 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing.
EXPERIMENTAL DESIGN: Patients received dalantercept 0.6, 0.9, or 1.2 mg/kg subcutaneously every 3 weeks plus axitinib 5 mg by mouth twice daily until disease progression or intolerance.
RESULTS: Twenty-nine patients were enrolled in the dose-escalation (n=15) and expansion (n=14) cohorts. There were no dose-limiting toxicities or grade 4/5 treatment-related adverse events. In addition to common VEGFR tyrosine kinase inhibitor effects such as fatigue and diarrhea, commonly seen treatment-related adverse events were peripheral edema, epistaxis, pericardial effusion, and telangiectasia. The objective response rate (ORR) by RECIST v1.1 was 25% with responses seen at all dose levels. The overall median progression-free survival was 8.3 months.
CONCLUSIONS: The combination of dalantercept plus axitinib is well tolerated and associated with clinical activity. Based on safety and efficacy results, the 0.9-mg/kg dose level was chosen for further study in a randomized phase 2 trial of dalantercept plus axitinib vs. placebo plus axitinib.

PMID: 28031424 [PubMed - as supplied by publisher]

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