Phase 1 study of LY317615 (enzastaurin) and temozolomide in patients with gliomas - EORTC trial 26054.

e13005 Background: Enzastaurin (Enz) is a small selective inhibitor of protein kinase C (PKC). Synergy with temozolomide (TMZ) has been demonstrated in vitro. This phase I trial investigated optimal dosing and toxicity when Enz was combined with a standard TMZ regimen. METHODS Patients (pts) with recurrent high-grade glioma or newly diagnosed disease not amenable to radiotherapy (RT) and WHO PS 0-1 were eligible. Pts on EIAEDs were excluded. Two dose levels (DL) of Enz were explored. DL1: Loading dose 500 mg followed by 250 mg daily. DL2: Loading dose 1,125 mg followed by 500 mg daily. TMZ was given at 150 mg/m2 d1-d5 every 28 days in cycle 1, escalating to 200 mg/m2 in subsequent cycles. Dose-limiting toxicity (DLT) was defined by CTCAE 3.0 criteria in the first two cycles as (1) any non haematological toxicity grade 3/4 (2) ANC < 500/mm3 (3) thrombocytopenia grade 3/4 (4) any toxicity reducing drug dose intensity to <80%. RESULTS 15 pts were included, three at DL1, 12 at DL2. 13 pts had received prior RT, seven prior chemotherapy, and two were newly diagnosed. Median number of cycles was four (range 2-8).Treatment is ongoing in five pts. TMZ dose was escalated in all pts with no DLT. Modest and reversible thrombocytopenia was the most frequent toxicity, occurring in seven pts (3 @ Gd 1, 3 @ Gd2, 1 @ Gd 3) and led to TMZ dose reduction in two pts and treatment delays in four pts (multiple in 2). One pt discontinued after three cycles due to persistent thrombocytopenia. Five pts developed neutropenia not requiring dose modification. Two pts developed hyperbilirubinemia. Six SAE's (3 at each DL) were recorded, and one death (DL2). None was considered treatment related. Two pts showed a partial response, six pts stable disease. CONCLUSIONS Enz can be safely combined with standard TMZ regimen. Results of the just completed phase I part with Enz 250 mg twice daily dosing will also be presented at the meeting. [Table: see text].