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Published on: October 27, 2014
VAL-083 is effective in patients with newly-diagnosed MGMT-unmethylated glioblastoma: report of phase II study
Chengcheng Guo1, Qunying Yang1, Meiling Deng2
1Department of Neurosurgery/Neuro-Oncology, Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China.
Purpose:
Unmethylated MGMT is a validated biomarker for temozolomide (TMZ) resistance and poor prognosis in glioblastoma. VAL-083 (dianhydrogalactitol; DAG) is a DNA-targeting agent that forms interstrand crosslinks at O6/N7-guanine, inducing double-strand breaks and cell death independently of MGMT-mediated DNA repair. This study aimed to evaluate whether first-line VAL-083 combined with radiotherapy improves efficacy compared to standard-of-care TMZ plus radiotherapy in newly diagnosed MGMT-unmethylated GBM patients.
Methods:
VAL-083 was administered intravenously on days 1-3 of a 21-day cycle, starting on day 1 of radiotherapy, with a second 3-day cycle on days 22-24 of radiotherapy. After completing the 6-week radiotherapy regimen, patients began adjuvant maintenance therapy with VAL-083 alone, administered IV at the same dose and regimen (Cycles 3-10), for up to 8 maintenance cycles.
Results:
At the censor date, the median overall survival (OS) across all patients from the start of VAL-083 treatment was 19.2 months across all dose levels. Survival probabilities from VAL-083 were 93.0%, 68.7%, 51.2%, and 28.4% at 6, 12, 18, and 24 months, respectively. For patients receiving 30 mg/m2/day VAL-083, 15/25 (60%) had died by the censor date, with a median survival of 18.0 months. Pharmacokinetics exhibited dose-linearity. CSF levels at 2 h post-infusion were comparable to or exceeded plasma levels. Common adverse events included thrombocytopenia and neutropenia.
Conclusions:
VAL-083 (30 mg/m2/day) combined with radiation therapy was generally safe and well tolerated. Adverse events aligned with previous studies. This regimen, compared to standard-of-care TMZ, showed potential benefits in terms of disease progression and overall survival. Trial registration ClinicalTrials.gov ID NCT03050736, dated: February 13, 2017.
