Phase I and pharmacological studies of the cryptophycin analogue LY355703 administered on a single intermittent or...

LY355703 is a synthetic derivative of the marine cryptophycins, cytotoxic agents which induce mitotic arrest by binding at the microtubule vinca binding domain. Promising preclinical features of LY355703 were the 40-400 greater potency than paclitaxel or vinca alkaloids, the broad spectrum of antitumor activity in xenografts and the antitumour activity in multidrug resistant (MDR)-expressing murine tumours. Aims of this study were to define the maximum tolerated dose (MTD) and the dose recommended for Phase II, the pattern of toxicity, the pharmacokinetic profile and to document hints of antitumour activity of LY355703 given as 2-h infusion on day 1 every 3 weeks (Study 1) or, later on, on days 1, 8 and 15 every 4 weeks (Study 2). The latter weekly regimen was selected because of the acute dose-related toxicity reported in Study 1. The dose was escalated using a modified Continual Reassessment Method. Pharmacokinetic studies were performed on day 1 of cycle 1 in both studies; LY355703 plasma concentrations were assessed by liquid chromatography with tandem mass spectrometry. A total of 35 adult patients with solid tumours entered Study 1; the dose was escalated from 0.1 to 1.92 mg/m(2); at this dose 2 of 5 patients presented grade 3 neuropathy and myalgias; 1.48 mg/m(2) was then recommended for Phase II study. A total of 8 patients were treated in Study 2 at 1 mg/m(2); cumulative long-lasting neuroconstipation and neurosensory toxicity precluded the completion of the cycle in 9 out of 15 cycles; the clinical development of the weekly regimen was then discontinued. Other toxicities included cardiac dysrhythmia and mild alopecia. Pharmacokinetics of LY355703 appeared to be linear over the dose range studied. The administration of LY355703 on a 3-week schedule is associated with an acute dose-dependent peripheral neuropathy and myalgia of high interpatient variability for which possible risk factors and pharmacokinetic correlates could not be identified.