Phase I study of CYT997, a novel cytotoxic and vascular disrupting agent, given as a 24-hour intravenous infusion to patients with advanced solid tumours

Abstract

14115 Background: CYT997 is a novel tubulin-binding small molecule which inhibits microtubule assembly and also demonstrates potent vascular-disrupting activity in preclinical tumour models. Methods: CYT997 was administered by continuous infusion over 24 hours every 3 weeks to patients with advanced cancer. Dose escalation proceeded by a standard phase I design (3 patients per dose level) for the first 18 patients; subsequently, an accelerated titration design (1 patient per dose level) was utilized. Intrapatient dose escalation was permitted. Pharmacokinetic (PK) analyses were performed in the first cycle. Tumour response was determined every second cycle using RECIST criteria. Pharmacodynamic effects on the tumour vasculature were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 22 patients (M/F: 11/11; median age 57.5, range 28–75) were enrolled with tumour types including melanoma (4), renal cell (4), colorectal (2), non-small cell lung (2) and adenoid cystic (2) carcinomas, mesothelioma (2) and others (6). A total of 66 cycles of CYT997 were administered (median 2/patient, range 1–6) over 10 dose levels (7, 14, 23, 35, 49, 65, 86, 114, 152 and 202 mg/m2). No dose-limiting toxicity was observed. Because of grade-2 injection site reactions in 2 patients (one each at dose levels 3 and 4), all subsequent patients received CYT997 via a central venous access device. Other toxicities included grade-2 renal toxicity at dose- level 8 in one patient with abnormal baseline renal function and grade-1 QTc prolongation in one patient at dose-level 10. No myelosuppression, gastrointestinal toxicity or clinically-significant cardiac toxicity were observed. PK data revealed dose-related increases in Cmax and AUC values. Six patients had stable disease after 4 cycles of CYT997. Conclusions: CYT997 was well tolerated at the doses studied and accrual to the 269 mg/m2 dose level will now proceed. No significant financial relationships to disclose.