title: Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors.
abstract: OBJECTIVE
  Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies.
  
  
  METHODS
  This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non-small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non-small cell lung) and median overall survival (pancreas).
  
  
  RESULTS
  In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met.
  
  
  CONCLUSIONS
  Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. adaud@medicine.ucsf.edu
authors.forename: Adil I
authors.initials: AI
authors.lastname: Daud
authors.forename: Smitha S
authors.initials: SS
authors.lastname: Krishnamurthi
authors.forename: Mansoor N
authors.initials: MN
authors.lastname: Saleh
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Gitlitz
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Gold
authors.forename: Elena G
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Springett
authors.forename: Richat
authors.initials: R
authors.lastname: Abbas
authors.forename: Shefali
authors.initials: S
authors.lastname: Agarwal
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bardy-Bouxin
authors.forename: Poe-Hirr
authors.initials: PH
authors.lastname: Hsyu
authors.forename: Eric
authors.initials: E
authors.lastname: Leip
authors.forename: Kathleen
authors.initials: K
authors.lastname: Turnbull
authors.forename: Charles
authors.initials: C
authors.lastname: Zacharchuk
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib