This report presents results from the expansion cohort of the first-in-human, phase I trial of the novel anti-activin receptor-like kinase-1 monoclonal antibody PF-03446962. Treatment with PF-03446962 showed favorable safety, clinical activity, and modulation of selected biomarkers in patients with advanced hepatocellular carcinoma and disease progression following prior antiangiogenic therapy.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 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. 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 a parts per thousand yen12 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 a parts per thousand yen12 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. 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.

Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma / M. Simonelli, P. Zucali, A. Santoro, M.B. Thomas, F.G. de Braud, H. Borghaei, J. Berlin, C.S. Denlinger, C. Noberasco, L. Rimassa, T. Kim, P.A. English, A. Abbattista, C. Gallo Stampino, M. Carpentieri, J.A. Williams. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - 27:9(2016 Sep), pp. 1782-1787. [10.1093/annonc/mdw240]

Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma

M. Simonelli
Primo
;
F.G. de Braud;
2016

Abstract

This report presents results from the expansion cohort of the first-in-human, phase I trial of the novel anti-activin receptor-like kinase-1 monoclonal antibody PF-03446962. Treatment with PF-03446962 showed favorable safety, clinical activity, and modulation of selected biomarkers in patients with advanced hepatocellular carcinoma and disease progression following prior antiangiogenic therapy.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 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. 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 a parts per thousand yen12 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 a parts per thousand yen12 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. 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.
ALK-1; PF-03446962; TGF-β receptor; activin-receptor-like kinase-1; angiogenesis; hepatocellular carcinoma
Settore MED/06 - Oncologia Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/442291
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