title: A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors.
abstract: Aurora kinase inhibitors (AKIs) are a class of antimitotic, small-molecule anticancer agents. MSC1992371A is an AKI being evaluated for the treatment of patients with solid tumors. This phase I, open-label, dose-escalation study determined the maximum tolerated dose (MTD) of MSC1992371A in different dosing schedules in patients with locally advanced or metastatic solid tumors. MSC1992371A was administered on days 1 and 8 (schedule 1) or on days 1, 2, and 3 (schedule 2) of a 21-day cycle. The study was expanded with a third schedule (study drug on days 1-3 and 8-10). Adverse events were monitored throughout the study. Antitumor efficacy, drug pharmacokinetics, and pharmacodynamics were evaluated. Ninety-two patients were enrolled. MSC1992371A was dosed over eight levels in schedules 1 and 2, and the MTD was determined as 74 mg/m(2) per cycle for both schedules and as 60 mg/m(2) in schedule 3, albeit only in three patients due to discontinuation of the study. Overall, the most common grade 3 or 4 treatment-emergent adverse events were neutropenia, febrile neutropenia, thrombocytopenia, anemia, and fatigue. The most frequent dose-limiting toxicity over all schedules was neutropenia. MSC1992371A plasma concentrations tended to increase with increasing dose levels. Although no complete or partial responses were seen, stable disease ≥3 months was observed in 11 patients. Analysis for markers of target modulation and pharmacodynamics effects was unsuccessful. MSC1992371A was generally well tolerated in patients, with mainly transient hematologic toxicities apparent at an MTD of 60-74 mg/m(2)/21-day cycle, independent of dosing frequency.
authors.affiliation: Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, TX, USA, Monica.Mita@cshs.org.
authors.forename: M
authors.initials: M
authors.lastname: Mita
authors.forename: M
authors.initials: M
authors.lastname: Gordon
authors.forename: N
authors.initials: N
authors.lastname: Rejeb
authors.forename: A
authors.initials: A
authors.lastname: Gianella-Borradori
authors.forename: V
authors.initials: V
authors.lastname: Jego
authors.forename: A
authors.initials: A
authors.lastname: Mita
authors.forename: J
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: K
authors.initials: K
authors.lastname: Sankhala
authors.forename: D
authors.initials: D
authors.lastname: Mendelson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009636:Norbornanes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000592140:MSC1992371A; D009636:Norbornanes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064096:Aurora Kinase A