Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

• Published in: Clinical cancer research 2012-02, Vol.18 (4), p.1092-1100
• Main Authors: DAUD, Adil I, KRISHNAMURTHI, Smitha S, BARDY-BOUXIN, Nathalie, HSYU, Poe-Hirr, LEIP, Eric, TURNBULL, Kathleen, ZACHARCHUK, Charles, MESSERSMITH, Wells A, SALEH, Mansoor N, GITLITZ, Barbara J, BORAD, Mitesh J, GOLD, Philip J, CHIOREAN, Elena G, SPRINGETT, Gregory M, ABBAS, Richat, AGARWAL, Shefali
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Aniline Compounds - administration & dosage; Aniline Compounds - adverse effects; Aniline Compounds - therapeutic use; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Female; Humans; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Neoplasms - drug therapy; Neoplasms - mortality; Neoplasms - pathology; Nitriles - administration & dosage; Nitriles - adverse effects; Nitriles - therapeutic use; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - therapeutic use; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - therapeutic use; Survival Analysis; Treatment Outcome; Tumors; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-2378

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. 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). 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. 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.