Phase I evaluation of OXi4503, a vascular disrupting agent, in patients with advanced solid tumours

Abstract

14146 Background: OXi4500, the active product of OXi4503, is a vascular disrupting agent acting at the colchicine binding site on the β subunit of tubulin. OXi4503 has greater anti-tumour activity in human cancer cell lines, causes a greater reduction in tumour blood flow than combretastatin A4P and has single agent activity in human tumour xenograft models. A phase I trial has commenced to examine the safety, tolerability and pharmacokinetics of OXi4503, with the primary objective being determination of MTD. FDG-PET scans were performed prior to and 28 days after the first infusion of OXi4503. Several other pharmacodynamic endpoints are also being assessed including DCE & BOLD MRI, circulating endothelial progenitor cells and cytokeratin 18. Methods: OXi4503 is administered by 3 weekly iv infusions to a maximum of 6 cycles. Starting dose was 0.06mg/m2. 100% dose escalation in single patient cohorts proceeded to 3.84mg/m2, when cohorts were expanded to three patients and 30% escalation due to emergence of grade 2 drug-related toxicity (thrombocytopaenia). Results: 11 patients have so far received OXi4503 (5F 6M, median age 54, range 33–68); median cycles received was 2 (range 1–4). Common AE’s include hypertension, pyrexia and anaemia. PK profiles show a dose-dependent linear increase in peak plasma concentrations and AUC of both OXi4503 and OXi4500. OXi4500 concentrations at current dosing (5 mg/m2) are close to that seen at the MTD in rats and dogs. DCE-MRI showed significant reduction in Ktrans in one patient (0.24mg/m2). In the 2 patients studied to date, PET images showed a decrease in the standardised uptake value (SUV) in 3 out of 4 metastases for one subject (1.92mg/m2) and in 5 out of 7 metastases for the other subject (3.84mg/m2) demonstrating a reduction in FDG uptake following drug treatment. Of 10 patients assessed, 2 have stable disease and 8 disease progression. Conclusions: OXi4503 has been tolerated at doses up to 5mg/m2 with no DLT observed, but changes in functional activity have been seen in 3 patients. MTD has not been reached and recruitment is ongoing. [Table: see text]