Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours
Mené sur 116 patients avec tumeurs solides de stade avancé, cet essai de phase I évalue le saracatinib, un inhibiteur sélectif de la kinase Src, en combinaison avec du carboplatine ou du paclitaxel
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 mg m−2 q3w, paclitaxel 80 mg m−2 every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m−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 300 mg (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 greater than or equal to3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; greater than or equal to225 mg, 33%), and grade greater than or equal to3 neutropenia occurred more commonly at doses greater than or equal to225 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.