A phase I study of volasertib combined with afatinib, in advanced solid tumors.
OBJECTIVE
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.
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.
Jean-Pascal
JP
Machiels
Department of Oncology, Antwerp University Hospital, Wijlrijkstraat 10, 2650, Edegem, Belgium.
Marc
M
Peeters
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.
Catherine
C
Herremans
Department of Respiratory Medicine/Thoracic Oncology, Ghent Hospital University, Pintelaan 185, 9000, Ghent, Belgium.
Veerle
V
Surmont
Department of Oncology, Antwerp University Hospital, Wijlrijkstraat 10, 2650, Edegem, Belgium.
Pol
P
Specenier
Clinical Operations, SCS Boehringer Ingelheim Comm.V, Avenue Ariane 16, 1200, Brussels, Belgium.
Marina
M
De Smet
Global Clinical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.|ClinDevConsult GmbH, Egginger Str. 22/1, 89155, Erbach, Germany.
Korinna
K
Pilz
Global Biometry and Clinical Applications, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.
Natalja
N
Strelkowa
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.
Dan
D
Liu
Department of Medical Oncology Ghent University Hospital, Heymans Institute of Pharmacology, Ghent University, Pintelaan 185, 9000, Ghent, Belgium.
Sylvie
S
Rottey
D000284:Administration, Oral; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011621:Pteridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000139:chemically induced / Q000503:physiopathology
C541363:BI 6727; D047428:Protein Kinase Inhibitors; D011621:Pteridines; D011799:Quinazolines; D000077716:Afatinib
Advanced cancer; Afatinib; EGFR; PLK; Phase I trial; Volasertib