2065 Background: ABTC conducted a dose finding trial of ABT-888, an orally administered Poly(ADP-ribose) polymerase [PARP] inhibitor, during daily TMZ with post-operative RT for GBM. PARP is important in repair pathways for RT induced DNA injury and TMZ induced alkylation at N7-methylguanine and N3-methyldenine. Methods: An initial safety group (no concurrent RT), received ABT-888 10 mg BID po during 42 days of daily TMZ 75 mg/m2. After this, the planned dosing steps included ABT-888 BID concurrent with standard RT and TMZ, with planned ABT-888 dose escalation or de-escalation based on observed toxicity. Dose limiting toxicity (DLT) is ≥ grade 3 non-hematologic or neurologic not responding to steroids, and hematologic ANC<500/mm3 and platelets (PLT) < 25K/mm3. The pharmacokinetics (PK) of ABT-888 were characterized for dose 1 and at steady-state. Results: Without concurrent RT, DLT (thrombocytopenia) occurred in 1/6 patients. With concurrent RT/TMZ and ABT-888 10 mg BID, 4/12 patients had DLT (thrombocytopenia). As per the planned dose de-escalation, ABT-888 10 mg BID was then given every other week during TMZ/RT. This resulted in 3/6 patients with DLT (2 thrombocytopenia, 1 neutropenia). The hematologic toxicity with this regimen was judged high enough that accrual was discontinued. In the setting of continuous dosing for 6 weeks, the total body clearance of ABT-888 for the first dose (27.5±9.5 L/h, n = 15) and at steady-state after BID dosing (23.5±10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56±33%. Steady-state peak and trough concentrations of the drug in plasma were 66±29 ng/mL and 18±10 ng/mL, respectively. Additional PK data will be presented. Conclusions: Administering ABT-888 BID po in combination with standard RT/TMZ was not tolerable in GBM patients as a result of hematologic toxicity. ABT-888 PK in GBM patients were very similar to findings reported for solid tumor patients. There is strong scientific rationale for continued development of an appropriate dosing regimen for this agent in the initial therapy of GBM. Clinical trial information: NCT00770471.