Abstract B54: A phase 1 study to assess the safety, tolerability and pharmacokinetics of the ErbB-family inhibitor ARRY-334543 in patients with advanced solid tumors
Notice bibliographique
Résumé
Abstract Background: ARRY-334543 is an oral, potent, ATP-competitive, selective, reversible ErbB family inhibitor. ARRY-334543 has evolved from a ditosylate salt in capsule to a smaller freebase tablet which eases swallowing. This study (ARRAY-543-103) was initiated to assess the safety and maximum tolerated dose (MTD) of the ARRY-334543 tablet. Effect of food on plasma pharmacokinetics (PK) of ARRY-334543 and intrapatient exposure with the capsule and tablet also were assessed. Methods: Sequential cohorts of patients with advanced solid tumors were enrolled. Doses were escalated with a 3+3 design. For Cycle 1 only: to evaluate potential food effects, patients received single doses of the tablet on Day 1 (fasting) and Day 8 (with high-fat meal); to explore intrapatient exposure between capsule and tablet formulations, 6 additional patients were enrolled at the 300 mg dose only and received a single dose of the capsule on Day 1 and a single dose of the tablet on Day 8 after high-fat meals. In both scenarios, PK was assessed on Days 1 and 8 and starting on Day 10, all patients began twice-daily (BID) dosing regardless of food. All subsequent cycles were BID dosing for 28 days regardless of food. Additional PK assessments were performed on Day 24 at steady state. Preliminary Results: To date, 29 patients (16 females/13 males) have been treated at 4 dose levels ranging from 300 to 600 mg BID. Dose-limiting toxicities (DLTs) occurred in 3 of 10 patients in the 300 mg cohort (1 patient had a Grade 4 AST/Grade 3 ALT increase, 2 patients had Grade 3 fatigue). No DLTs were observed in the 400 mg cohort. Two of 4 patients in the 600 mg cohort had DLTs (1 patient: Grade 3 thrombosis and a Grade 3 AST/ALT increase; 1 patient: Grade 3 anorexia) so a 500 mg cohort was opened. One DLT has been observed at 500 mg BID (1 patient had Grade 3 weakness and Grade 4 ALT/Grade 3 AST) and expansion at this dose level is ongoing. Frequent drug-related adverse events (AEs) were fatigue (65%), diarrhea (35%), rash (35%) and anorexia (31%) with most AEs being Grade 1 or 2. Three patients at doses = 300 mg BID have had stable disease for ≥ 6 cycles. One patient with cervical cancer and 1 patient with squamous cell carcinoma of the skin remain on study after 11+ and 6.8 months, respectively. Mean Cmax and AUC estimates were 1.5 and 2-fold higher, respectively, when tablets were administered with a high-fat meal. In the fed state, mean Cmax and AUC values associated with capsules were 2.6-fold higher than tablets. Steady state mean AUC values for tablets at 300 mg BID were similar to capsules at 400 mg BID in a previous Phase 1 study. Conclusions: ARRY-334543 tablets demonstrated acceptable safety; determination of the MTD is ongoing. Preliminary PK data for tablets indicate a modest food effect and a steady state exposure similar to that obtained with capsules. Based on these results, future studies of ARRY-334543 will be conducted with tablets. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B54.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
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.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».