ACTR-69. PHASE I TRIAL OF TG02 PLUS DOSE-DENSE OR METRONOMIC TEMOZOLOMIDE FOR ADULTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA AND GLIOBLASTOMA

BACKGROUND: Most therapies for recurrent high grade gliomas have not been successful, largely due to the complexity of the disease. Our preclinical studies have demonstrated the anti-glioma effects of TG02 and the synergy with temozolomide (TMZ) through modulation of transcription and metabolism. We hypothesize that given the multiple mechanisms of TG02 and established efficacy of TMZ, combined treatment may be effective for malignant gliomas. We launched a phase I/II trial and herein report the phase I results. METHODS: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, no more than 2 prior relapses, and no prior bevacizumab were enrolled. A Bayesian Optimal Interval design was employed to determine the maximum tolerated dose (MTD) and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD 125mg/m2/d, 7on/7off) or metronomic (MN; 50mg/m2/d) dosing schedule on a 28-day cycle. RESULTS: A total of 15 patients have been enrolled; 80% are male, median age 50.6. Nine patients were enrolled in DD TMZ arm 1/6 receiving TG02 at 200mg had grade 4 diarrhea, a dose-limiting toxicity (DLT); 1/3 patients receiving TG02 at 250mg in the DD arm had grade 4 neutropenia, a DLT. In MN TMZ arm, 0/3 patients receiving TG02 at 200mg had a DLT. 1/3 patients receiving TG02 at 250mg had a DLT of grade 4 lymphopenia. To date, although not a primary endpoint, 2 partial objective responses have been observed in ongoing patients receiving 200mg TG02 in combination with TMZ. CONCLUSION: The combination of TG02 at 200mg and DD/MN TMZ is well tolerated. Dose escalation continues in both DD/MN arms (currently at TG02 250mg) with determination of MTD anticipated soon. Additionally, objective responses have been observed suggesting activity for this regimen.