MULTICENTER PHASE-II PHARMACOLOGICAL EVALUATION OF RHIZOXIN

Rhizoxin is a macrocyclic lactone compound that binds to tubulin and i nhibits microtubule assembly. Rhizoxin demonstrated preclinical anti-t umour activity against a variety of human tumour cell lines and xenogr aft models. Phase I evaluation found a maximum tolerated rhizoxin dose of 2.6 mg m(-2), with reversible, but dose-limiting, mucositis, leuco penia and diarrhoea. Clinical trials were then initiated by the EORTC ECSG in melanoma, breast, head and neck, and non-small-cell lung cance rs with the recommended phase II rhizoxin dose of 2 mg m(-2). Pharmaco logical studies were instituted with the phase II trials to complement the limited pharmacokinetic data available from the phase I trial. Bl ood samples were obtained from 69 to 103 eligible patients enrolled in phase II rhizoxin studies, and these were evaluable for pharmacokinet ic analysis in 36 patients. Plasma rhizoxin concentrations were determ ined by high-performance liquid chromatography (HPLC), and post-distri bution pharmacokinetic parameters were estimated by a one-compartment model. Rhizoxin was rapidly eliminated from plasma, with a median syst emic clearance of 8.41 min(-1) m(-2) and elimination half-life of 10.4 min. Rhizoxin area under the concentration-time curve (AUC) was highe r in patients obtaining a partial response or stable disease than in t hose with progressive disease (median 314 vs 222 nl ml(-1) min; P=0.03 ). A predicted from previous studies, haematological and gastrointesti nal toxicity was observed, but could not be shown to be related to rhi zoxin AUC. This study demonstrated the rapid and variable elimination or rhizoxin from the systemic circulation. The presence of pharmacodyn amic relationships and the low level of systemic toxicity suggest that future trials of rhizoxin with alternative dosage or treatment schedu les are warranted.