Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours

BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel.METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mgm(-2) q3w, paclitaxel 80mgm(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175mgm(-2) q3w. The primary endpoint was safety/tolerability.RESULTS: A total of 116 patients received saracatinib 125 (N - 20), 175 (N - 44), 225 (N - 40), 250 (N - 9), or 300mg (N - 3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade >= 3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; >= 225 mg, 33%), and grade >= 3 neutropenia occurred more commonly at doses >= 225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w.CONCLUSION: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials.British Journal of Cancer (2012) 106, 1728-1734. doi:10.1038/bjc.2012.158 www.bjcancer.com Published online 24 April 2012 (C) 2012 Cancer Research UK