Abstract B216: Exposure-response (E-R) relationship of ABT-263-induced thrombocytopenia in cancer patients in phase 1 studies

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Abstract Background: ABT-263 is a novel small molecule Bcl-2 family protein inhibitor that binds with high affinity to multiple antiapoptotic Bcl-2 family proteins. The pharmacokinetics, safety and preliminary efficacy of ABT-263 in patients with relapsed or refractory lymphoid malignancies, CLL/SLL, SCLC and other non-hematological malignancies are being studied in three Phase 1/2a studies. Both a 14/21-day dosing schedule and a continuous dosing preceded with a 7-day lead-in period are being evaluated in these studies. Grade 4 thrombocytopenia has been the most prominent, mechanism-related, dose-limiting toxicity in patients in these studies. E-R relationship in this drug-induced thrombocytopenia may inform the selection of the dose and dosing schedule for a Phase 3 study in CLL patients. Methods: ABT-263 plasma concentrations and platelet data from more than 100 patients in the three ongoing Phase 1/2a studies were included in the analysis. ABT-263 plasma concentration data were described using a two-compartment model with first-order absorption and elimination. The relationship between the circulating platelet count and ABT-263 plasma concentration was described with a semi-physiological model that had been developed using data in dogs. Simulations were preformed to compare the 14/21-day dosing schedule and the continuous dosing schedule with a low-dose lead-in period and project the incidence rates of Grades 3 and 4 thrombocytopenia in the dose range of 200 and 350 mg. Results: The E-R relationship was generally well described by the semi-physiology model. Simulations indicated that, compared to the 14/21-day dosing schedule, continuous dosing preceded with a 7-day lead-in period minimizes platelet variability across cycles. The lead-in treatment appeared to blunt the initial sharp drop in platelet count according to the simulations with 250 mg dose. Although there seemed to be little difference in the incidence rate of Grade 4 thrombocytopenia, continuous dosing showed a trend of lower rate of Grade 3 thrombocytopenia than the 14/21-day dosing schedule. In terms of the rates of Grade 3 and 4 thrombocytopenia, the dose-response curve between 200 and 350 mg was quite shallow. Conclusions: A continuous dosing preceded with a 7-day lead-in period is superior to the 14/21-day dosing schedule because it minimizes platelet variability across cycles and blunts the initial sharp drop in platelet count. Drug-induced thrombocytopenia is not sensitive to the change in dose does not provide significant differentiation in the dose range of 200 mg and to 350 mg. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B216.