Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with advanced cancer.

Abstract

PURPOSE:

The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor-like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors.

EXPERIMENTAL DESIGN:

Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1-4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression.

RESULTS:

In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose-limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (≥12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients.

CONCLUSION:

Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway.

• Authors: Johanna C Bendell, Michael S Gordon, Herbert I Hurwitz, Suzanne F Jones, David S Mendelson, Gerard C Blobe, Neeraj Agarwal, Carolyn H Condon, Dawn Wilson, Amelia E Pearsall, Yijun Yang, Ty McClure, Kenneth M Attie, Matthew L Sherman, Sunil Sharma
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 2 Pg. 480-9 (Jan 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24173543 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Immunoglobulin Fc Fragments
• Ligands
• Recombinant Fusion Proteins
• Fluorodeoxyglucose F18
• ACVRL1 protein, human
• Activin Receptors, Type II
• ALK1-Fc fusion protein, human

Topics

• Activin Receptors, Type II (metabolism, pharmacology, therapeutic use)
• Adult
• Aged
• Aged, 80 and over
• Angiogenesis Inhibitors (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Female
• Fluorodeoxyglucose F18
• Humans
• Immunoglobulin Fc Fragments (pharmacology, therapeutic use)
• Ligands
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Positron-Emission Tomography
• Recombinant Fusion Proteins (pharmacology, therapeutic use)
• Telangiectasis (chemically induced)
• Treatment Outcome