Abstract CT115: Phase II study of dianhydrogalactitol (VAL-083) in patients with MGMT-unmethylated, bevacizumab-naïve recurrent glioblastoma
Bibliographic record
Abstract
Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and maintenance TMZ. Almost all GBM patients experience recurrent/progressive disease, and median survival after recurrence is 3-9 months. Effective therapies for recurrent GBM (rGBM) are lacking, representing a significant unmet medical need. The unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor prognoses. Second-line treatment with the anti-angiogenic agent bevacizumab (BEV) has not improved survival, and 5-year survival is less than 3%. VAL-083 is a bi-functional DNA-targeting agent that rapidly induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083’s cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM in vitro and in vivo models. We previously completed a 3+3 dose-escalation trial of VAL-083 in TMZ- and BEV-refractory rGBM. 40mg/m2/day given on days 1-3 of a 21-day cycle was generally well-tolerated, and this dose was selected for further clinical evaluation in Phase II trials. The trial described here is an ongoing single-arm, biomarker-driven Phase II trial in MGMT-unmethylated BEV-naïve adult rGBM. In this trial, patients are receiving VAL-083 at 30 or 40mg/m2/day on days 1-3 of a 21-day cycle. Tumor response is assessed by MRI approximately every 42 days, per RANO criteria. The primary objective of this study is to determine if VAL-083 improves median overall survival (mOS) for MGMT-unmethylated rGBM patients compared to a historical mOS of 7.1 months for such patients treated with lomustine (EORTC26101). Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life (QOL) evaluation using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. Thirty-five (35) subjects have received 40 mg/m2/day VAL-083 as the starting dose. Consistent with prior studies, myelosuppression (thrombocytopenia and neutropenia) is the most common adverse event in this study, and we observed that a higher potential for myelosuppression appears to be inversely correlated with the number of cycles of prior TMZ maintenance therapy, (>5 cycles vs. ≤5 cycles, p<0.05). Therefore, to minimize the potential for hematological toxicity in patients who have had significant prior TMZ maintenance therapy, subsequent patients in this study have initiated treatment with a starting VAL-083 dose of 30 mg/m2/d x 3 every 21 days. Earlier initiation of maintenance treatment with VAL-083 in the therapeutic management plan, in lieu of maintenance TMZ in MGMT-unmethylated GBM patients is currently under consideration. Enrollment, safety data and protocol updates will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962. Citation Format: Barbara O'Brien, John De Groot, Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Jeffrey Bacha, Dennis Brown, Anne Steino, John Langlands, Richard Schwartz, Sarath Kanekal, Lorena Lopez, Marta Penas-Prado. Phase II study of dianhydrogalactitol (VAL-083) in patients with MGMT-unmethylated, bevacizumab-naïve recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT115.
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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) | 0.002 | 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 | 0.002 |
| 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".