title: 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.affiliation: National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.
authors.forename: Tae Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yoh
authors.affiliation: Pfizer Global Oncology Research and Development, Via Anna Maria Mozzoni, 12, Milan, 20152, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Gallo Stampino
authors.affiliation: Pfizer Japan, 3-22-7 Yoyogi, Shibuya-ku, Tokyo, 151-8589, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hirohashi
authors.affiliation: Pfizer Japan, 3-22-7 Yoyogi, Shibuya-ku, Tokyo, 151-8589, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Pfizer Japan, 3-22-7 Yoyogi, Shibuya-ku, Tokyo, 151-8589, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Pfizer Oncology, 10555 Science Center Drive, San Diego, 92121, California.
authors.forename: James
authors.initials: J
authors.lastname: Andrew Williams
authors.affiliation: Seoul National University College of Medicine and Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C575087:ascrinvacumab; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II
keywords: Activin receptor-like kinase 1; PF-03446962; bone morphogenetic protein; hepatocellular carcinoma; solid tumors