Discover oncology · 2025
VAL-083 is effective in patients with newly-diagnosed MGMT-unmethylated glioblastoma: report of phase II study.
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Guo Chengcheng, Yang Qunying, Deng Meiling, Qiu Xiaoling, Wu Shaoxiong, Du Xiaojing, Sai Ke, Dai Ziyu, Chen Zhenghe, Zhang Ji, Lin Fuhua, Ke Chao, Xi Shaoyan, Hu Wanming, Zhou Zhihuan, Li Jiawei, Cao Xi, Liao Yixiang, Lv Yanchun, Brown Dennis, Langlands John, Johnson Gregory, Bacha Jeffrey, Kwan Claire, Kanekal Sarath, Schwartz Richard, Chen Zhongping
Аннотация
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.
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.