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Purpose <p>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.</p> Methods <p>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.</p> Results <p>At the censor date, the median overall survival (OS) across all patients from the start of VAL-083 treatment was 19.2&#xa0;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&#xa0;months, respectively. For patients receiving 30&#xa0;mg/m<sup>2</sup>/day VAL-083, 15/25 (60%) had died by the censor date, with a median survival of 18.0&#xa0;months. Pharmacokinetics exhibited dose-linearity. CSF levels at 2&#xa0;h post-infusion were comparable to or exceeded plasma levels. Common adverse events included thrombocytopenia and neutropenia.</p> Conclusions <p>VAL-083 (30&#xa0;mg/m<sup>2</sup>/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.</p> <p><i>Trial registration</i> ClinicalTrials.gov ID NCT03050736, dated: February 13, 2017.</p>

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VAL-083 is effective in patients with newly-diagnosed MGMT-unmethylated glioblastoma: report of phase II study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Chengcheng Guo,
  • Qunying Yang,
  • Meiling Deng,
  • Xiaoling Qiu,
  • Shaoxiong Wu,
  • Xiaojing Du,
  • Ke Sai,
  • Ziyu Dai,
  • Zhenghe Chen,
  • Ji Zhang,
  • Fuhua Lin,
  • Chao Ke,
  • Shaoyan Xi,
  • Wanming Hu,
  • Zhihuan Zhou,
  • Jiawei Li,
  • Xi Cao,
  • Yixiang Liao,
  • Yanchun Lv,
  • Dennis Brown,
  • John Langlands,
  • Gregory Johnson,
  • Jeffrey Bacha,
  • Claire Kwan,
  • Sarath Kanekal,
  • Richard Schwartz,
  • Zhongping Chen

摘要

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.