Phase I study of bosutinib, a Src/Abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors

Adil I. Daud, Smitha S. Krishnamurthi, Mansoor N. Saleh, Barbara J. Gitlitz, Mitesh J. Borad, Philip J. Gold, Elena G. Chiorean, Gregory M. Springett, Richat Abbas, Shefali Agarwal, Nathalie Bardy-Bouxin, Poe Hirr Hsyu, Eric Leip, Kathleen Turnbull, Charles Zacharchuk, Wells A. Messersmith

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74 Citations (Scopus)


Purpose: 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. Patients and 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.

Original languageEnglish
Pages (from-to)1092-1100
Number of pages9
JournalClinical Cancer Research
Issue number4
Publication statusPublished - 15 Feb 2012
Externally publishedYes


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