Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1-5 every 28 days). Almost all GBM patients experience recurrent/progressive disease, with a median survival of 3-9 months after recurrence. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter status for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor prognosis. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. VAL-083's cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. The trial described here is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring adjuvant therapy after chemoradiation with TMZ (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/day on days 1, 2, and 3 of a 21-day cycle. For Group 1 the primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients compared to historical control. For Group 2, the primary objective of this study is to determine the effect of VAL-083 on progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemoradiation with TMZ, compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS) (Group 1), overall response rate (ORR), duration of response (DOR), and quality-of-life (QoL). Tumor response will be assessed by MRI approximately every 42 days, as per RANO criteria. The initial starting dose in this study was 40 mg/m2/day, which was subsequently reduced to 30 mg/m2/day to improve tolerance due to myelosuppression. As of January 11, 2021, 35 evaluable subjects have enrolled at a starting dose of 40 mg/m2/day, and 46 evaluable subjects have enrolled at a starting dose of 30 mg/m2/day in Group 1. In Group 2, 31 evaluable subjects had enrolled at a starting dose of 30 mg/m2/day. As anticipated from prior studies with VAL-083, myelosuppression (thrombocytopenia and neutropenia) has been the most common adverse event observed. The trial is continuing as planned, and an enrollment, efficacy and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962

Citation Format: Barabara J. O'Brien, Carlos Kamiya-Matusoka, Shaio-Pei Weathers, WK Alfred Yung, WK Alfred Yung, Monica Loghin, Rebecca Harrison, Nazanin Majd, Stephanie Knight, Ying Yuan, Jeffrey Bacha, Dennis Brown, Anne Steino, Gregory Johnson, Sarath Kanekal, John Langlands, Lorena Lopez, Richard Schwartz, Marta Penas-Prado, John de Groot. Phase 2 study of dianhydrogalactitol (VAL-083) inpatients with MGMT-unmethylated, bevacizumab-naivepatients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent and adjuvant setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT238.