Darinaparsin a Novel Organic Arsenic Molecule Active in Lymphoma: Development of An Oral Form.
Notice bibliographique
Résumé
Abstract Abstract 4759 Introduction Darinaparsin is an organic arsenic molecule constructed of dimethylated arsenic linked to glutathione (N-[S-(dimethylarsino)-N-L-gamma-glutamyl-L-cysteinyl]-glycine). It has a multifaceted mechanism of action, inducing G2/M cell cycle arrest and apoptosis mediated through disruption of mitochondrial functions, increased reactive oxygen species production, and modulation of signal transduction pathways. In addition, darinaparsin has anti-angiogenic activity. It has significant activity in a broad spectrum of hematologic and solid tumors in preclinical models, including human cell lines resistant to arsenic trioxide. It is active in heavily treated patients with refractory lymphoma when administered IV 300 mg/m2 for 5 days on a 28 day cycle, and is very well tolerated. Preclinically it is orally highly bioavailable. Oral administration may be of importance in potential utility in lymphoma in continuous metronomic dosing. Methods Two Phase I studies of oral darinaparsin are being conducted in patients diagnosed with relapsed or refractory advanced tumors. The first protocol is a Phase I, dose-escalation, oral administration study designed to determine the MTD of darinaparsin capsules. The dosing schedule is a regimen of 2 doses per week for 3 weeks followed by 1 week of rest, starting at 300 mg twice weekly. A second Phase I study, having a similar design and objective, evaluates several dosing regimens, including dosing capsules three times per week increasing dosing frequency to daily dosing for 3 weeks, with 1 week of rest. For each study 28 days constitutes one cycle. Standard methods for evaluation of toxicity, escalation and efficacy are being used. Results These two studies have thus far enrolled 19 and 17 patients, respectively. In total there are 24 male and 12 female patients. The median age is 59 years, with a range from 38 to 82 years. To date, MTD has not been reached in either study. The dose continues to be escalated and is currently at 900mg / day twice weekly in the 1st study, and 300 mg daily every day in the 2nd study. Bioavailability has been very high (>75%). All patients were heavily pretreated and refractory. Of 27 evaluable patients thus far in the two trials, 2 had a partial response and 15 had prolonged stable disease, including lymphoma (NHL), head and neck, colon, and pancreatic cancers. The duration of responses has been 3 – 8 + months. Safety and tolerability has been very good and comparable to that of IV darinaparsin. SAEs were atrial fibrillation and congestive heart failure, each occurring in one patient, and dyspnea, occurring in two patients. No QT prolongation has been observed. Dose escalation continues in both studies and updated results will be presented. Conclusion Darinaparsin is a novel organic arsenic molecule that has demonstrated clinical activity in refractory lymphoma when given IV. When given orally by capsule, the drug is well tolerated and demonstrates early signs of activity. Disclosures: Buck: ZIOPHARM Oncology: Employment. Wallner:ZIOPHARM Oncology: Employment. Lewis:ZIOPHARM Oncology: Employment, Membership on an entity's Board of Directors or advisory committees.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, pas un consensus.
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