Format

Send to

Choose Destination
Cancer Med. 2016 Jul;5(7):1454-63. doi: 10.1002/cam4.724. Epub 2016 Apr 14.

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

Author information

1
National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, Japan.
2
Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.
3
Pfizer Global Oncology Research and Development, Via Anna Maria Mozzoni, 12, Milan, 20152, Italy.
4
Pfizer Japan, 3-22-7 Yoyogi, Shibuya-ku, Tokyo, 151-8589, Japan.
5
Pfizer Oncology, 10555 Science Center Drive, San Diego, 92121, California.

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.

KEYWORDS:

Activin receptor-like kinase 1; PF-03446962; bone morphogenetic protein; hepatocellular carcinoma; solid tumors

PMID:
27075560
PMCID:
PMC4944871
DOI:
10.1002/cam4.724
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center