ACTR-18. PHASE II TRIAL OF TEMOZOLOMIDE AND TRC 102, BASE EXCISION REPAIR INHIBITOR, IN BEVACIZUMAB NAÏVE GLIOBLASTOMA AT FIRST RECURRENCE

Abstract

BACKGROUND: Temozolomide forms O6-methylguanine (O6mG), 7-methylguanine (N7mG), and 3- methyladenine (N3mA) DNA adducts. The O6mG DNA adduct is repaired by MGMT. N7mG and N3mA DNA adducts are removed by the base excision repair (BER) pathway. TRC-102 is a BER inhibitor that binds to the apurinic site created through the action of the glycosylase. METHODS: A phase II study of adult patients with bevacizumab- naive first recurrence of glioblastoma after radiation and temozolomide was performed in the Adult Brain Tumor Consortium. Temozolomide was administered at 150 mg/ m2 and oral TRC-102 at 150 mg daily, days 1-5 every 4 weeks. Primary objective was efficacy measured by objective radiographic response rate (RR= CR+PR). Secondary objectives included safety and PFS-6. Exploratory objectives were to assess treatment efficacy with tumor expression of N-methylpurine DNA glycosylase (MPG), a BER protein, and MGMT status with RR, PFS, and OS. The study was designed to test the hypothesis that combination therapy would achieve a RR of 30%. RESULTS: Nineteen patients were enrolled in the first stage. Median age was 60 years (range: 48-76), 53% females, median KPS was 80 (range: 70-90). Median cycles of treatment was 2 (range: 1-12). No responses were observed. Median OS was 11.0 months (95% CI: 8-18 months), median PFS was 2.0 months (95%CI: 1.8-3.6 months). PFS-6 rate was 10.5 % (2/19). The combination was safe; two grade 3-4 toxicities included lymphopenia, thrombocytopenia. MGMT promoter was unmethylated in all patients. MPG staining was negative in six, 1+ in five and 2+ in three patients. PFS of 11 + months in two patients was associated with MPG expression. CONCLUSIONS: TRC 102 and temozolomide has acceptable safety but did not meet the primary endpoint of response. Tissue correlates will be presented. The study was terminated early and the combination will not be tested in bevacizumab refractory patients.