Abstract CT054: Phase II study of dianhydrogalactitol in patients with <i>MGMT</i>-unmethylated bevacizumab-naive recurrent glioblastoma
Bibliographic record
Abstract
Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine and inducing interstrand cross-links, DNA double-strand breaks and cell-death in GBM cell-lines and GBM cancer stem cells. VAL-083’s cytotoxicity is independent of MGMT status and VAL-083 overcomes TMZ-resistance in vitro. Our recent phase I/II clinical trial in recurrent GBM patients failing both TMZ and bevacizumab, suggested VAL-083 offers clinically meaningful survival benefits for patients with recurrent GBM and pinpointing a new dosing regimen (40 mg/m2/d on days 1,2,3 of a 21-day cycle). A pivotal Phase 3 study in recurrent GBM after failing both TMZ and bevacizumab is being planned. If successful, this study will serve as the basis for a New Drug Application (NDA) submission for VAL-083. In addition, a single-arm Phase 2 study to confirm the tolerability of the new dosing regimen in combination with radiotherapy and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels is proceeding. In the present Phase 2 clinical trial, the main goal is to assess the overall survival (OS) in MGMT-unmethylated, recurrent, bevacizumab-naïve GBM. RATIONALE: The vast majority of GBM patients experience recurrent/progressive disease within a year from initial diagnosis and median survival after recurrence is 3-9 months. Chemotherapy regimens for these patients are lacking and there is a significant unmet medical need. Given VAL-083’s novel alkylating mechanism, promising clinical benefit, and favorable safety profile, a trial studying VAL-083 in MGMT-unmethylated recurrent GBM is warranted. METHOD: Open label, single-arm, biomarker-driven Phase 2 clinical trial in MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab. 48 patients will be enrolled to determine if treatment with VAL-083 will improve OS at 9-months compared to historical control with lomustine. The patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. Patients will be followed until death or for at least 9 months from enrollment, whichever occurs earlier. Survival will be compared to recently published EORTC26101 for recurrent MGMT-unmethylated GBM patients treated with lomustine. Secondary outcome measures include progression-free survival and overall response rate. Clinicaltrials.gov identifier: NCT02717962. Citation Format: Barbara J. O'Brien, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Richard Schwartz, Sarath Kanekal, Lorena Lopez, Marta Penas-Prado. Phase II study of dianhydrogalactitol in patients with MGMT-unmethylated bevacizumab-naive recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT054. doi:10.1158/1538-7445.AM2017-CT054
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.002 | 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) | 0.003 | 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".