PMID- 27329247 OWN - NLM STAT- MEDLINE DCOM- 20180102 LR - 20200206 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 27 IP - 9 DP - 2016 Sep TI - Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma. PG - 1782-7 LID - 10.1093/annonc/mdw240 [doi] AB - BACKGROUND: This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study. RESULTS: Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3-4 AEs were reported in eight patients (33.3%). Treatment-related grade 3-4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted >/=12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal-epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for >/=12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-beta and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression. CONCLUSIONS: The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents. TRIAL REGISTRATION NUMBER: NCT00557856. CI - (c) The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Simonelli, M AU - Simonelli M AD - Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy matteo.simonelli@cancercenter.humanitas.it. FAU - Zucali, P AU - Zucali P AD - Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy. FAU - Santoro, A AU - Santoro A AD - Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy. FAU - Thomas, M B AU - Thomas MB AD - Division of Hematology/Oncology, Medical University of South Carolina, Charleston, USA. FAU - de Braud, F G AU - de Braud FG AD - Department of Medical Oncology, European Institute of Oncology, Milan, Italy. FAU - Borghaei, H AU - Borghaei H AD - Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia. FAU - Berlin, J AU - Berlin J AD - Department of Gastrointestinal Oncology, Vanderbilt University, Nashville, USA. FAU - Denlinger, C S AU - Denlinger CS AD - Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia. FAU - Noberasco, C AU - Noberasco C AD - Department of Medical Oncology, European Institute of Oncology, Milan, Italy. FAU - Rimassa, L AU - Rimassa L AD - Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy. FAU - Kim, T-Y AU - Kim TY AD - Department of Medical Oncology/Hematology, Seoul National Hospital, Seoul, Republic of Korea. FAU - English, P A AU - English PA AD - Pfizer Oncology, La Jolla, USA. FAU - Abbattista, A AU - Abbattista A AD - Pfizer Oncology, Milan, Italy. FAU - Gallo Stampino, C AU - Gallo Stampino C AD - Pfizer Oncology, Milan, Italy. FAU - Carpentieri, M AU - Carpentieri M AD - Pfizer Oncology, Milan, Italy. FAU - Williams, J A AU - Williams JA AD - Pfizer Oncology, La Jolla, USA. LA - eng SI - ClinicalTrials.gov/NCT00557856 PT - Clinical Trial, Phase I PT - Journal Article DEP - 20160620 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Biomarkers, Tumor) RN - 0 (Protein Kinase Inhibitors) RN - 716FQ5REVO (ascrinvacumab) RN - EC 2.7.11.30 (ACVRL1 protein, human) RN - EC 2.7.11.30 (Activin Receptors, Type II) SB - IM MH - Activin Receptors, Type II/antagonists & inhibitors/*immunology MH - Adult MH - Aged MH - Aged, 80 and over MH - Angiogenesis Inhibitors/administration & dosage/adverse effects MH - Antibodies, Monoclonal/*administration & dosage/adverse effects/pharmacokinetics MH - Antibodies, Monoclonal, Humanized MH - Biomarkers, Tumor/antagonists & inhibitors/immunology MH - Carcinoma, Hepatocellular/*drug therapy/immunology/pathology MH - Drug Administration Schedule MH - Drug-Related Side Effects and Adverse Reactions/pathology MH - Female MH - Humans MH - Liver Neoplasms/*drug therapy/immunology/pathology MH - Male MH - Middle Aged MH - Protein Kinase Inhibitors/administration & dosage/adverse effects OTO - NOTNLM OT - ALK-1 OT - PF-03446962 OT - TGF-beta receptor OT - activin-receptor-like kinase-1 OT - angiogenesis OT - hepatocellular carcinoma EDAT- 2016/06/23 06:00 MHDA- 2018/01/03 06:00 CRDT- 2016/06/23 06:00 PHST- 2016/01/25 00:00 [received] PHST- 2016/06/09 00:00 [accepted] PHST- 2016/06/23 06:00 [entrez] PHST- 2016/06/23 06:00 [pubmed] PHST- 2018/01/03 06:00 [medline] AID - S0923-7534(19)35872-7 [pii] AID - 10.1093/annonc/mdw240 [doi] PST - ppublish SO - Ann Oncol. 2016 Sep;27(9):1782-7. doi: 10.1093/annonc/mdw240. Epub 2016 Jun 20.