title: A phase I study of two dosing schedules of oral BI 847325 in patients with advanced solid tumors.
abstract: OBJECTIVE
  This study determined the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of BI 847325, an oral dual MEK and Aurora kinase inhibitor, in patients with refractory solid tumors.
  
  
  METHODS
  This trial recruited patients with an advanced non-resectable and/or metastatic solid tumor following failure of conventional treatment (NCT01324830; 1287.1). BI 847325 was administered orally, once daily (starting at 6 mg in the first cohort) using two dosing schedules: Schedule A (2 weeks on, 1 week off) and Schedule B (three periods of 5 days on, 2 days off). The primary objective was to identify the MTD of BI 847325 for both dosing schedules.
  
  
  RESULTS
  Sixty-nine patients (Schedule A, n = 47; Schedule B, n = 22) were treated. The MTD was 120 mg per day for Schedule A (cumulative dose of 1680 mg per 3-week cycle) and 150 mg per day for Schedule B (cumulative dose of 2250 mg per 3-week cycle). Reversible hematologic and gastrointestinal toxicities were the most common dose-limiting toxicities. One patient with esophageal cancer (receiving 160 mg BI 847325, Schedule A) experienced a partial response for 67 days, and 21 patients (n = 11 [23.4%], Schedule A; n = 10 [45.5%], Schedule B) had stable disease. Pharmacokinetic analyses showed at least bi-exponential disposition, with high inter-subject variability. There was no obvious relationship between markers of MEK or Aurora kinase inhibition and exposure to BI 847325 (exploratory analysis).
  
  
  CONCLUSIONS
  This first-in-human trial suggests that BI 847325 has an acceptable safety profile. However, due to insufficient drug exposure at the MTD to achieve relevant MEK inhibition, a decision was taken to halt the development of BI 847325.
authors.affiliation: Department of General Medical Oncology and Laboratory of Experimental Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Louvain, Belgium. patrick.schoffski@uzleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.affiliation: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Aftimos
authors.affiliation: Department of General Medical Oncology and Laboratory of Experimental Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Louvain, Belgium.
authors.forename: Herlinde
authors.initials: H
authors.lastname: Dumez
authors.affiliation: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Amélie
authors.initials: A
authors.lastname: Deleporte
authors.affiliation: Department of General Medical Oncology and Laboratory of Experimental Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Louvain, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: De Block
authors.affiliation: Department of General Medical Oncology and Laboratory of Experimental Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000, Louvain, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Costermans
authors.affiliation: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Maureen
authors.initials: M
authors.lastname: Billiet
authors.affiliation: Boehringer Ingelheim Belgium, Brussels, Belgium.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Meeus
authors.affiliation: Boehringer Ingelheim, Bracknell, Berkshire, UK.
authors.forename: Chooi
authors.initials: C
authors.lastname: Lee
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Schnell
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Rainer-Georg
authors.initials: RG
authors.lastname: Goeldner
authors.affiliation: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D064127:Aurora Kinases / Q000037:antagonists & inhibitors; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000606531:BI-847325; D007211:Indoles; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Aurora kinase inhibitor; BI 847325; Dose escalation; MEK inhibitor; Phase I; Solid tumors