Abstract #5567: Phase I dose-escalation, safety, and pharmacokinetic study of weekly oral AEZS-112, a small molecule anti-cancer agent in patients with advanced cancer and lymphoma

Background: AEZS-112 is a novel orally available low molecular weight tubulin inhibitor which also inhibits topoisomerase II, arrests cancer cells in G2/M phase at nanomolar concentrations and induces apoptosis. It showed activity in cell lines that were resistant to cisplatin, vincristine and doxorubicin. This Phase I study was designed to evaluate the safety, tolerability and pharmacokinetics of ascending doses of AEZS-112 in patients with advanced solid tumors or lymphoma. Methods: AEZS-112 was administered once weekly for 3 consecutive weeks followed by 1 week without treatment. Capsules of 13 mg and 40 mg were administered with light food. Starting dose was 13 mg/week; at least 3 patients were to be treated per dose group. Due to the large number of capsules needed to be taken at a time and evidence of decreasing bioavailability at higher single doses in part I of the study, part II evaluates a modified split-dose scheme in which the weekly dose is divided into 3 administrations 8 hours apart. The starting dose of part II was 120 (= 40 x3) mg/week. Blood samples for pharmacokinetics (PK) of AEZS-112 and metabolites were collected to characterize peak plasma concentration and accumulation of trough levels through subsequent cycles. Results: In part I, 22 patients (12M/10F) were studied on 7 dose levels ranging from 13 to 800 mg/week. In all, 62 treatment cycles were administered (mean: 2.8 / patient); 2 patients were treated for 7 cycles (prostate CA, melanoma), 3 patients for 5 cycles (adenocarcinoma, colon CA 2x). In part II, 4 additional dose levels ranging from 120 to 480 (=160 x3) mg/week have been studied in a total of 13 patients (8M/5F). Similar to part I, prolonged courses of stable disease were noted, with lead patients ongoing after 5 (pancreas CA) and 6 (tracheal CA) treatment cycles. No clinically relevant drug-related adverse events or changes in laboratory parameters were observed. AEZS-112 was shown to be metabolically stable in human plasma. As predicted by PK modelling based on data from part I of the study (t max \#8773; 4-6 hrs; t 1/2 \#8773; 3-4 days), the split-dose scheme leads to a higher C max and trough values after administration of comparable doses. Conclusions: At all doses tested, AEZS-112 was well tolerated over repeated treatment courses. Dose escalation is ongoing in the absence of dose-limiting drug-related adverse events. Prolonged courses of stable disease in both parts of the study are an encouraging observation in this ongoing Phase I study. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5567.