Background: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. Methods: A total of 22 patients received paclitaxel (135-175 mg m 2) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90-240 mg) daily. Results: One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180 mg combined with paclitaxel 175 mg m 2. A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting 3 months. Conclusion: The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions. © 2010 Cancer Research UK.

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doi.org/10.1038/sj.bjc.6605917, hdl.handle.net/1765/21643
British Journal of Cancer
Erasmus MC: University Medical Center Rotterdam

Herpen, C., Eskens, F., de Jonge, M., Desar, I., Hooftman, L., Bone, E., … Verweij, J. (2010). A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours. British Journal of Cancer, 103(9), 1362–1368. doi:10.1038/sj.bjc.6605917