Abstract CT172: Phase 2 clinical trial of dianhydrogalactitol (VAL-083) in patients with newly diagnosed MGMT-unmethylated GBM
Bibliographic record
Abstract
Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. The majority of glioblastoma multiforme (GBM) patients have an unmethylated MGMT promoter status, leading to limited response to TMZ and decreased survival. Current standard-of-care includes surgery followed by chemoradiation and TMZ. An unmethylated promoter for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is strongly correlated with poor outcomes. VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated drug-resistance and has demonstrated cytotoxicity in MGMT-unmethylated GBM cell lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. A Phase 2, open-label, biomarker-driven, study is being conducted to evaluate the tolerability and efficacy of VAL-083 in combination with radiation therapy (RT) in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 given IV at 20, 30, or 40 mg/m2/day x 3 days every 21 days and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study has 2 stages: Stage 1, dose-escalation, has identified a recommended dose of 30 mg/m2/day of VAL-083 in combination with RT as generally safe and well-tolerated. Stage 2, an expansion stage, has enrolled 20 additional patients at 30 mg/m2/day IV infusion on days 1, 2, and 3 of 21-day cycles. As of January 11, 2021, all 29 subjects in the study have been enrolled and completed the treatment stage of the study. Tumor response are assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. The trial is continuing as planned and an update on primary results on safety and efficacy, and pharmacokinetics will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736. Citation Format: Zhong-ping Chen, Cheng-cheng Guo, Qun-ying Yang, Jia-wei Li, Shao-xiong Wu, John Langlands, Gregory Johnson, Claire Kwan, Sarath Kanekal, Richard Schwartz, Jeffrey Bacha, Anne Steino, Dennis Brown. Phase 2 clinical trial of dianhydrogalactitol (VAL-083) in patients with newly diagnosed MGMT-unmethylated GBM [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 CT172.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".