Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% 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, Arm 1) or metronomic (MN; 50mg/m²/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264