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2031 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.

2026 Background: There is a critical need for more specific and less invasive diagnostic and pharmacodynamic biomarkers in glioblastoma (GBM) patients (pts). Previously, we detected TERT promoter hotspot mutations (C228T and C250T) in the ctDNA of IDH wildtype ( IDHwt) TERT promoter mutant GBM pts with 100% specificity using mutation-specific droplet digital PCR (ddPCR) assays. Here, we explored the dynamics and clinical associations of mutant TERT ctDNA levels in GBM pts undergoing therapy. Methods: We examined 14 pts with suspected IDHwt GBM based on preoperative MRI. Plasma was isolated and frozen from ~15 mL whole blood samples collected pre- and post-op, at end of radiation (RT), and 1, 3, and 6 m after end of RT. TERT promoter mutations were identified in FFPE tumor samples using ddPCR assays for C228T/C250T. Plasma samples were analyzed using ddPCR assays specific for the corresponding tumor mutation. The validated thresholds for positive detection were 1.5 (C228T) and 1.7 copies/mL (C250T). Results: 13/14 (92.9%) IDHwt tumors had TERT mutations (7 C228T and 6 C250T). Six of these 13 (46%) pts had positive plasma TERT ctDNA preop (4 C228T, 2 C250T). The mean cross sectional area of enhancing disease at presentation for positive or negative preop mutant ctDNA was similar. All 4 pts with multiple contrast enhancing lesions had positive preop mutant ctDNA. 2 pts who were negative initially developed detectable mutant ctDNA preceding progression. 3/4 pts with equivocal radiographic pseudoprogression had ctDNA dynamics that correlated with eventual clinical outcome. One patient with unresectable GBM had declining mutant ctDNA in later collections during clinical stability. Conclusions: We detected plasma TERT ctDNA in 46% of TERT mutant GBM pts before surgery, and in 100% of pts with multiple contrast enhancing lesions. TERT mutant ctDNA levels correlated with pseudoprogression or true disease progression and predicted progression before MRI. These data suggest that larger studies to test circulating cell-free TERT mutation as a diagnostic and pharmacodynamic biomarker in GBM are warranted.