M Simonelli1, P Zucali2, A Santoro2, M B Thomas3, F G de Braud4, H Borghaei5, J Berlin6, C S Denlinger5, C Noberasco4, L Rimassa2, T-Y Kim7, P A English8, A Abbattista9, C Gallo Stampino9, M Carpentieri9, J A Williams8. 1. Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy matteo.simonelli@cancercenter.humanitas.it. 2. Humanitas Clinical and Research Center, Humanitas Cancer Center, Rozzano, Milano, Italy. 3. Division of Hematology/Oncology, Medical University of South Carolina, Charleston, USA. 4. Department of Medical Oncology, European Institute of Oncology, Milan, Italy. 5. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia. 6. Department of Gastrointestinal Oncology, Vanderbilt University, Nashville, USA. 7. Department of Medical Oncology/Hematology, Seoul National Hospital, Seoul, Republic of Korea. 8. Pfizer Oncology, La Jolla, USA. 9. Pfizer Oncology, Milan, Italy.
Abstract
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.
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.
Authors: Kevin J Morine; Xiaoying Qiao; Vikram Paruchuri; Mark J Aronovitz; Emily E Mackey; Lyanne Buiten; Jonathan Levine; Keshan Ughreja; Prerna Nepali; Robert M Blanton; S Paul Oh; Richard H Karas; Navin K Kapur Journal: Cardiovasc Pathol Date: 2017-07-18 Impact factor: 2.185
Authors: Jeffrey Melson Clarke; Gerard C Blobe; John H Strickler; Hope Elizabeth Uronis; S Yousuf Zafar; Michael Morse; Evan Dropkin; Leigh Howard; Margot O'Neill; Christel N Rushing; Donna Niedzwiecki; Hollie Watson; Emily Bolch; Christy Arrowood; Yingmiao Liu; Andrew B Nixon; Herbert I Hurwitz Journal: Cancer Chemother Pharmacol Date: 2019-08-23 Impact factor: 3.333