Phase I results of ABT-751, a novel microtubulin inhibitor, administered daily × 7 every 3 weeks

Abstract

2079 Background: ABT-751 is an oral anti-mitotic agent that binds to the colchicine site of β-tubulin. ABT-751 has antitumor activity in various human xenograft models and additive effects in combination with cytotoxic chemotherapy. Methods: This Phase I study is evaluating the pharmacology and safety of ABT-751 given daily × 7 every 3 weeks. Two dosing schedules, daily (QD) and twice daily (BID), are being tested. Overall, 37 subjects (N=15, QD; N=22, BID) have been studied. Results: The maximum tolerated dose (MTD) for the QD regimen was determined to be 250 mg. Dose-limiting toxicities (DLTs) were abdominal pain and constipation at 300 mg QD. Two of 9 patients experienced DLT (fatigue, ileus, constipation, and abdominal pain) at the 150 mg BID dose level. In the 175 mg BID dosing regimen in which patients with underlying constipation or performance score (PS) of 2 were excluded and patients were instructed to take stool softeners or laxatives on a regular basis, there were no Cycle 1 DLTs, but a 2-grade increase in fatigue was observed in 3 of 6 patients during the first 2 cycles of therapy. All toxicities have been reversible. Overall, the average duration of therapy was 2.5 cycles (range 0.5–8). ABT-751 was rapidly absorbed (Tmax ∼ 1.6 h) and eliminated (t1/2 ∼ 4.7 h). ABT-751 was excreted into urine primarily as sulfate and glucuronide metabolites (≥ 70% of dose). There was a linear relationship between dose and AUC. In the BID dosing schedule, the AUC and t1/2 of ABT-751 were similar for morning and evening doses. To date, 4 patients have exhibited stable disease for at least 6 cycles of ABT-751, including 1 patient with recurrent anaplastic astrocytoma. Conclusions: The MTD of ABT-751 is 250 mg QD x 7. Dose-limiting toxicities include abdominal pain and constipation. The MTD of ABT-751 is at least 175 mg BID x 7 when administered to good PS patients in conjunction with supportive measures. Several patients have received > 6 cycles of study drug. This study was supported by the GCRC (NIH RR00095) and a grant from Abbott Laboratories. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Pharmaceuticals