Abstract A91: A phase I dose-escalation study of bosutinib plus capecitabine in selected advanced solid tumors.
Authors: Isakoff Steven , Wang Ding , Campone Mario , Calles Antonio , Bardy-Bouxin Nathalie , Duvillie Ladan , Calvo Emiliano 
Published: June 2012

Abstract
Background: Bosutinib is an orally active, dual Src and Abl tyrosine kinase inhibitor that has demonstrated efficacy and acceptable safety in patients (pts) with metastatic breast cancer and chronic myelogenous leukemia. Capecitabine is a standard of care for metastatic breast cancer. Preclinical evidence suggests that the combination of a Src inhibitor and capecitabine may have improved activity.
Methods: This phase 1, open-label study determined the maximum tolerated dose (MTD) of bosutinib plus capecitabine in pts with advanced colon, breast, pancreatic, cholangiocarcinoma, and glioblastoma tumors, and evaluated the safety and efficacy of this combination. Part 1 of this study incorporated an “up-and-down” dose escalation scheme to determine the MTD. The initial dose cohorts were 1) bosutinib 200 mg/day + capecitabine 750 mg/m2 BID on Days 1 to 14 of a 21-day cycle and 2) bosutinib 300 mg/day + capecitabine 625 mg/m2 BID on Days 1 to 14. Additional cohorts could be enrolled at higher or lower dose levels based on the number of dose-limiting toxicities (DLTs) during the first 21 days in the current cohort of 2 pts, the cumulative toxicity rate at that dose combination, and the current dose of bosutinib and capecitabine. The design allowed up to 9 dose combinations, of which 8 were evaluated.
Results: A total of 32 pts were enrolled: median age was 62 years (range, 42–82 years) and 44% were male. Three pts experienced DLTs: 1 pt receiving bosutinib 400 mg/day + capecitabine 750 mg/m2 BID (grade 3 neurological pain), 1 pt receiving bosutinib 400 mg/day + 1,000 mg/m2 BID (grade 3 increased alanine aminotransferase [ALT] and rash), and 1 pt receiving bosutinib 200 mg/day + capecitabine 1,000 mg/m2 BID (grade 4 fatigue). Based on the observed toxicity, the MTD was determined to be bosutinib 300 mg/day + capecitabine 1,000 mg/m2 BID (n = 9 treated at the MTD). The most common treatment-related adverse events across all dose cohorts were diarrhea (66%), nausea (41%), palmar-plantar erythrodysesthesia syndrome (PPE; 31%), fatigue (28%), vomiting (25%), and decreased appetite (16%). Although diarrhea was common, 91% of events were grade 1/2, all pts had their diarrhea resolve (median cumulative duration of 10 days), and no pt discontinued treatment due to diarrhea. The most common grade 3/4 treatment-related events were increased ALT, increased aspartate aminotransferase (AST), and PPE (9% each). All grade 3/4 ALT and AST elevations resolved, with no pt discontinuing treatment due to ALT or AST elevation. Six (19%) deaths occurred during the study, including 5 deaths within 28 days of the last study dose (all due to cancer-related causes and/or disease progression); no drug-related deaths were reported. Best overall response included 2 (6%) pts with partial responses and 14 (44%) pts with stable disease, including 4 (13%) pts with stable disease for &gt;24 weeks.
Conclusions: The combination of bosutinib and capecitabine was well tolerated with a safety profile characterized by low-grade gastrointestinal events, similar to that previously observed for bosutinib monotherapy. Bosutinib plus capecitabine also demonstrated promising preliminary efficacy. The “up-and-down” dose-escalation design allowed estimation of a MTD contour, with more pts evaluated at near-MTD doses compared with standard 3+3 designs. A phase 2 evaluation in breast cancer pts was planned.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A91.