Abstract CT217: Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioblastoma multiforme
Notice bibliographique
Résumé
Abstract Glioblastoma multiforme (GBM) is the most common and deadly form of human brain cancer. Median survival for patients with recurrent GBM is <6 months. Front-line systemic therapy is temozolomide, but resistance due to O6-methylguanine-DNA-methyltransferase (MGMT) activity is implicated in poor prognoses. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional DNA alkylating agent that crosses the blood-brain barrier and accumulates in brain tumor tissue. In recent in vitro studies, VAL-083 overcame resistance to MGMT and demonstrated cytotoxic activity against GBM cell lines, as well as GBM cancer stem cells, and was shown to act as a radiosensitizer. Previous clinical trials suggest that VAL-083 has activity against a range of tumors, including GBM. In light of extensive safety data and promising efficacy in CNS tumors, we initiated a new phase I/II clinical study to establish the maximum tolerated dose (MTD) using an optimized dosing scheme. The goal of the current clinical trial is to determine an appropriate dose for advancement into registration trials as a potential new therapy for the treatment of refractory GBM. Historical NCI-sponsored studies in GBM achieved promising results with limited toxicity using a dosing regimen of 25mg/m2/day for five days every five weeks. The present dosing regimen utilizes a daily dose for three days every three weeks. Seven cohorts have completed the current trial with no drug-related serious adverse events: MTD was not yet reached at 40mg/m2/day; 50mg/m2/day is being studied and higher doses may be explored. Compared to historical trials, the present regimen delivers substantively more drug as measured by Cmax and dose density. A dose density of 25 mg/m2/week in combination with radiation was previously shown superior to radiation alone against GBM; a dose density of 50 mg/m2/week is being enrolled in the current trial. Pharmacokinetic analyses show dose-dependent linear systemic exposure with a short plasma 1-2h terminal half-life; Cmax at 40mg/m2 in the current trial ranged from 1130-739ng/mL (7.7-5.1μM). Calculated CNS tissue concentrations, based on the plasma concentrations, exceed concentrations known to be effective against glioma cell lines in vitro. Methods: Open-label, single-arm phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of primary WHO Grade IV malignant glioma (glioblastoma). Patients enrolled have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab and temozolomide, unless contraindicated. The study utilizes a 3+3 dose-escalation design. Patients receive VAL-083 IV on days 1, 2, and 3 of a 21-day cycle. Tumor response is assessed according to RANO criteria prior to every other 21-day treatment cycle, and patients exhibiting stable disease or tumor regression are allowed to remain on study drug. ClinicalTrials.gov Identifier NCT01478178. Citation Format: Kent C. Shih, Manish R. Patel, Nicholas Butowski, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Richard Schwartz, Sarath Kanekal, Lorena M. Lopez, Howard A. Burris. Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT217. doi:10.1158/1538-7445.AM2015-CT217
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,003 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».