ATNT-26PHASE I/II STUDY OF DIANHYDROGALACTITOL IN PATIENTS WITH RECURRENT MALIGNANT GLIOMA
Bibliographic record
Abstract
Glioblastoma multiforme (GBM) is the most common brain cancer. Front-line systemic therapy with temozolomide is often ineffective due to O6-methylguanine-DNA-methyltransferase (MGMT)-mediated resistance. Dianhydrogalactitol (VAL-083) is a bi-functional DNA N7 cross-linking agent that crosses the blood-brain barrier and demonstrated cytotoxic activity independent of MGMT in vitro. The main goal of this clinical trial was to determine an appropriate dose for Phase II/III trials in refractory GBM. METHODS: Open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed GBM, previously treated with radiation and must have failed both temozolomide and bevacizumab, unless contraindicated. The study utilized 3 + 3 dose-escalation design. Patients received VAL-083 on days 1, 2, 3 of a 21-day cycle. RESULTS: 30 GBM patients were enrolled across 8 dose cohorts ranging from 1.5 to 50mg/m2/d. No drug-related severe adverse events were reported, and myelosuppression was mild at doses ≤40mg/m2/d. Dose limiting toxicities (DLT) consisting of thrombocytopenia were observed at 50mg/m2/d. Platelet nadir occurred around day 20, and DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment. Pharmacokinetic analyses show dose-dependent linear systemic exposure with a short 1-2h plasma terminal half-life; Cmax ranged 739-1130ng/mL (5.1-7.7 µM) at 40mg/m2/d resulting in calculated CNS concentrations within the IC50 range observed for multiple GBM cell-lines in vitro. Preliminary analysis shows increasing dose-dependent median survival with median OS = 9.0 months at doses ≥30mg/m2/d vs. 4.4 months at doses <10mg/m2/d. An expansion cohort of up to 14 patients has been initiated at 40mg/m2/d. A small cohort (n = 3) at an interim 45mg/m2/d dose will also be studied, and the expansion cohort may be continued at this higher dose if safety data warrant. CONCLUSIONS: VAL-083 dosing appears limited by myelosuppression; however, 40mg/m2/d dose exhibited favorable safety profile, with a trend toward improved survival vs. lower doses. Updated safety and efficacy data from the expansion cohort will be presented. ClinicalTrials.gov Identifier NCT01478178.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".