Jean-Pascal Machiels1, Marc Peeters2, Catherine Herremans3, Veerle Surmont4, Pol Specenier2, Marina De Smet5, Korinna Pilz6,7, Natalja Strelkowa8, Dan Liu9, Sylvie Rottey10. 1. Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium. Jean-Pascal.Machiels@uclouvain.be. 2. Department of Oncology, Antwerp University Hospital, Wijlrijkstraat 10, 2650, Edegem, Belgium. 3. Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium. 4. Department of Respiratory Medicine/Thoracic Oncology, Ghent Hospital University, Pintelaan 185, 9000, Ghent, Belgium. 5. Clinical Operations, SCS Boehringer Ingelheim Comm.V, Avenue Ariane 16, 1200, Brussels, Belgium. 6. Global Clinical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. 7. ClinDevConsult GmbH, Egginger Str. 22/1, 89155, Erbach, Germany. 8. Global Biometry and Clinical Applications, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. 9. Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. 10. Department of Medical Oncology Ghent University Hospital, Heymans Institute of Pharmacology, Ghent University, Pintelaan 185, 9000, Ghent, Belgium.
Abstract
PURPOSE: To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, combined with afatinib, an oral irreversible ErbB family blocker, in patients with advanced solid tumors (NCT01206816; Study 1230.20). METHODS: Patients with advanced non-resectable and/or metastatic disease following failure of conventional treatment received intravenous volasertib 150-300 mg on day 1 every 21 days, combined with oral afatinib 30-40 mg on days 2-21 of a 3-week cycle (Schedule A), or 50-90 mg on days 2-6 of a 3-week cycle (Schedule B). The primary objective was to determine the MTD of volasertib in combination with afatinib. RESULTS: Fifty-seven patients (Schedule A, N = 29; Schedule B, N = 28) were treated. The MTDs were volasertib 300 mg plus afatinib 30 mg days 2-21 and 70 mg days 2-6 of a 3-week cycle for Schedules A and B, respectively. The most common Grade 3/4 adverse events were neutropenia (31.0 %), diarrhea (13.8 %), and thrombocytopenia (10.3 %) in Schedule A; neutropenia (39.3 %), thrombocytopenia (35.7 %), hypokalemia (14.3 %), febrile neutropenia, and nausea (each 10.7 %) in Schedule B. The best overall response was two partial responses (6.9 %; both in Schedule A); eight patients in each schedule achieved stable disease. Volasertib showed multi-exponential pharmacokinetic (PK) behavior; co-administration of volasertib and afatinib had no significant effects on the PK profile of either drug. CONCLUSIONS: Volasertib combined with afatinib had manageable adverse effects and limited antitumor activity in this heavily pretreated population.
PURPOSE: To determine the maximum tolerated dose (MTD) of volasertib, a Polo-like kinase inhibitor, combined with afatinib, an oral irreversible ErbB family blocker, in patients with advanced solid tumors (NCT01206816; Study 1230.20). METHODS:Patients with advanced non-resectable and/or metastatic disease following failure of conventional treatment received intravenous volasertib 150-300 mg on day 1 every 21 days, combined with oral afatinib 30-40 mg on days 2-21 of a 3-week cycle (Schedule A), or 50-90 mg on days 2-6 of a 3-week cycle (Schedule B). The primary objective was to determine the MTD of volasertib in combination with afatinib. RESULTS: Fifty-seven patients (Schedule A, N = 29; Schedule B, N = 28) were treated. The MTDs were volasertib 300 mg plus afatinib 30 mg days 2-21 and 70 mg days 2-6 of a 3-week cycle for Schedules A and B, respectively. The most common Grade 3/4 adverse events were neutropenia (31.0 %), diarrhea (13.8 %), and thrombocytopenia (10.3 %) in Schedule A; neutropenia (39.3 %), thrombocytopenia (35.7 %), hypokalemia (14.3 %), febrile neutropenia, and nausea (each 10.7 %) in Schedule B. The best overall response was two partial responses (6.9 %; both in Schedule A); eight patients in each schedule achieved stable disease. Volasertib showed multi-exponential pharmacokinetic (PK) behavior; co-administration of volasertib and afatinib had no significant effects on the PK profile of either drug. CONCLUSIONS:Volasertib combined with afatinib had manageable adverse effects and limited antitumor activity in this heavily pretreated population.
Entities:
Keywords:
Advanced cancer; Afatinib; EGFR; PLK; Phase I trial; Volasertib
Authors: Antonio Giordano; Yueying Liu; Kent Armeson; Yeonhee Park; Maya Ridinger; Mark Erlander; James Reuben; Carolyn Britten; Christiana Kappler; Elizabeth Yeh; Stephen Ethier Journal: PLoS One Date: 2019-11-21 Impact factor: 3.240