title: A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors.
abstract: BACKGROUND
  MSC1992371A is an aurora kinase inhibitor with potential antitumor activity.
  
  
  METHODS
  This trial established the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral MSC1992371A given before or after gemcitabine (1,000 mg/m(2)) in a 21-day cycle in patients with advanced malignancies. In schedule 1 (n = 31), gemcitabine was administered on days 1 and 8 followed by escalating doses of MSC1992371A on days 2 and 9. In schedule 2 (n = 35), MSC1992371A was given on days 1 and 8 followed by gemcitabine on days 2 and 9. Patients had a range of solid tumors, the most frequent of which was colorectal (n = 19).
  
  
  RESULTS
  In both schedules, the 37 mg/m(2) dose level was defined as the MTD. The main DLT was grade 4 neutropenia. Adverse events consisted of neutropenia, thrombocytopenia, asthenia, fatigue, nausea, vomiting, anorexia, and diarrhea. Administration of MSC1992371A prior to gemcitabine had no effect on the metabolism or elimination of gemcitabine. Time to reach maximum plasma concentration and area under the plasma concentration-time curve for MSC1992371A increased proportionally with dose. Exploration of drug-target-related and tumor biomarkers did not identify predictors of biologic activity or response. Two patients (1 with lung carcinoma and 1 with hepatocellular carcinoma) had durable partial responses in schedule 2, and 5 patients had stable disease (SD) lasting 6 - 14 months.
  
  
  CONCLUSIONS
  Oral MSC1992371A can be administered at a MTD of 37 mg/m(2) in combination with the standard 1,000 mg/m(2) dose of gemcitabine, but hematologic toxicity requires careful monitoring. Preliminary signs of efficacy were indicated by durable responses and SD.
authors.affiliation: Service Inter-Hospitalier de Cancérologie Beaujon-Bichat, Hôpital Beaujon, Clichy, France, eric.raymond@bjn.aphp.fr.
authors.forename: E
authors.initials: E
authors.lastname: Raymond
authors.forename: J
authors.initials: J
authors.lastname: Alexandre
authors.forename: S
authors.initials: S
authors.lastname: Faivre
authors.forename: F
authors.initials: F
authors.lastname: Goldwasser
authors.forename: T
authors.initials: T
authors.lastname: Besse-Hammer
authors.forename: A
authors.initials: A
authors.lastname: Gianella-Borradori
authors.forename: V
authors.initials: V
authors.lastname: Jego
authors.forename: L
authors.initials: L
authors.lastname: Trandafir
authors.forename: N
authors.initials: N
authors.lastname: Rejeb
authors.forename: A
authors.initials: A
authors.lastname: Awada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003710:Demography; D003841:Deoxycytidine / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D009636:Norbornanes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C000592140:MSC1992371A; D009636:Norbornanes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003841:Deoxycytidine; D000093542:Gemcitabine
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