TY - JOUR
T1 - Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma
AU - Simonelli, Matteo
AU - Zucali, P.
AU - Santoro, A.
AU - Thomas, M. B.
AU - de Braud, F. G.
AU - Borghaei, H.
AU - Berlin, J.
AU - Denlinger, C. S.
AU - Noberasco, C.
AU - Rimassa, L.
AU - Kim, T. Y.
AU - English, P. A.
AU - Abbattista, A.
AU - Gallo Stampino, C.
AU - Carpentieri, M.
AU - Williams, J. A.
N1 - © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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-β 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.
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-β 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.
KW - Activin Receptors, Type II/antagonists & inhibitors
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Angiogenesis Inhibitors/administration & dosage
KW - Antibodies, Monoclonal, Humanized
KW - Antibodies, Monoclonal/administration & dosage
KW - Biomarkers, Tumor/antagonists & inhibitors
KW - Carcinoma, Hepatocellular/drug therapy
KW - Drug Administration Schedule
KW - Drug-Related Side Effects and Adverse Reactions/pathology
KW - Female
KW - Humans
KW - Liver Neoplasms/drug therapy
KW - Male
KW - Middle Aged
KW - Protein Kinase Inhibitors/administration & dosage
UR - http://www.scopus.com/inward/record.url?scp=84995543441&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000383599300020&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1093/annonc/mdw240
DO - 10.1093/annonc/mdw240
M3 - Article
C2 - 27329247
SN - 0923-7534
VL - 27
SP - 1782
EP - 1787
JO - Annals of Oncology
JF - Annals of Oncology
IS - 9
ER -