A phase I study of the human anti-activin receptor-like kinase 1 antibody PF-03446962 in Asian patients with advanced solid tumors.

Abstract

Preclinical studies suggest that ALK-1 signaling mediates a complementary angiogenesis pathway activated upon development of resistance to vascular endothelial growth factor (VEGF)-targeted therapies. Inhibition of ALK-1 signaling may lead to disruption of tumor angiogenesis and growth. We report findings from a multicenter, open-label, phase I study of the fully human anti-ALK-1 mAb PF-03446962 conducted in Japan and South Korea, in Asian patients with advanced solid tumors. The dose escalation Part 1 of the study was based on a standard 3 + 3 design (n = 16). In Part 2, patients were treated with PF-03446962 at 7 and 10 mg/kg (10/cohort), including patients with disease progression following prior VEGF receptor (R)-targeted therapy. Primary objectives were determination of the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity of PF-03446962. No dose-limiting toxicity (DLT) was noted in the 12 DLT-evaluable patients. Treatment was well tolerated. The MTD for biweekly intravenous administration was estimated to be 10 mg/kg and the RP2D 7 mg/kg. Treatment-related grades 1-3 thrombocytopenia was experienced by 27.8% patients. The most frequent nonhematologic treatment-related AEs were grades 1-2 pyrexia and epistaxis. Four patients (3/4 with hepatocellular carcinoma) developed telangiectasia suggesting vascular targeting and in vivo ALK-1 inhibition by PF-03446962. Stable disease for 12 weeks or more was observed in 25.7% of patients and in 44.4% of those with hepatocellular carcinoma. ALK-1 inhibition by PF-03446962 may represent a novel antiangiogenic strategy for patients with advanced solid malignancies complementary to current treatment with VEGF(R)-targeted inhibitors or chemotherapy.

• Authors: Toshihiko Doi, Kyung-Hun Lee, Tae-Min Kim, Atsushi Ohtsu, Tae Yong Kim, Masafumi Ikeda, Kiyotaka Yoh, Corrado Gallo Stampino, Tomoko Hirohashi, Akiyuki Suzuki, Yosuke Fujii, James Andrew Williams, Yung-Jue Bang
• Journal: Cancer medicine (Cancer Med) Vol. 5 Issue 7 Pg. 1454-63 (07 2016) ISSN: 2045-7634 [Electronic] United States
• PMID: 27075560 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Protein Kinase Inhibitors
• ascrinvacumab
• ACVRL1 protein, human
• Activin Receptors, Type II

Topics

• Activin Receptors, Type II (antagonists & inhibitors)
• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Asian People
• Combined Modality Therapy
• Female
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (diagnostic imaging, drug therapy, metabolism, pathology)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Retreatment
• Treatment Outcome