Abstract P035: A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591)
Notice bibliographique
Résumé
Abstract Background Trametinib (Mekinist ®) is an oral bioavailable MEK 1/2 inhibitor that is FDA approved in combination with BRAF inhibitor Dabrafenib for BRAFV600 mutant solid tumors. The single agent recommended phase 2 dose (RP2D) is 2 mg daily (QD). No clinical data is available on recommendation of trametinib dosing in various degrees of hepatic dysfunction (HD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib as primary endpoints in patients (pts) with genomically unselected advanced solid tumors with various degrees of HD. Methods Advanced cancer pts with ECOG ≤2, adequate renal and bone marrow functions, were stratified (NCI ODWG Criteria) into 4 HD groups: normal (NO), mild (ML), moderate (MD), severe (SV). NO group was enrolled as control subjects and was not evaluable for dose limiting toxicity (DLT). Trametinib was given QD on a 28-days cycle, with dose escalation based on a “3+3” design within each HD group (starting dose: NO, ML: 2mg; MD: 1.5 mg; SV: 1mg). Due to the long half-life of trametinib, PK samples were collected at days 15-16 in cycle 1. Differences in PK parameters among liver function groups were evaluated using analysis of variance (ANOVA). Results Out of 46 pts enrolled (2 pts ineligible), 44 (NO=17, ML=7, MD (1.5mg)=4, MD (2mg)=5, SV (1mg)=9, SV (1.5mg)=2) were evaluable for safety and 22 for PK analysis. The most common cancer type was GI-non CRC cancer (n=16, 36%). The most common all-grade treatment related adverse events (TRAEs) were acneiform rash (NO=53%, HD=48% of pts), nausea (NO=65%, HD=22%), diarrhea (NO=53%, HD=26%) and fatigue (NO=59%, HD=15%). Grade 3/4 TRAEs occurred in 27% (n=12) of pts (NO=8, 47%; HD=4, 15%). No treatment related deaths occurred. DLT was evaluable in 15 pts (ML=6, MD (1.5mg)=3, MD (2mg)=2, SV (1mg)=3 and SV (1.5mg)=1). One DLT (grade 3 acneiform rash) was observed in an SV pt (1.5mg). Dose interruptions or reductions due to TRAEs occurred in 15 pts (34%) [NO=9, 53%; ML=2, 29%; MD (1.5mg)=1, 33%; MD (2mg)=2, 33%; SV (1mg)=1, 11%; SV (1.5mg)=1; 50%]. Best response was stable disease in all HD groups (33 to 75%) and 54% in NO group. There were no significant differences for PK parameters of Cmax (p=0.18), Cmin (p=0.16), Cavg (p=0.62), or AUC0-24 (p=0.11) (NO vs ML, NO vs MD, NO vs SV, ML vs MD, ML vs SV, MD vs SV), when trametinib was normalized to 2 mg dose. However, only limited PK data were available for the MD (n=3) and SV (n=3) groups compared to NO (n=10) and ML (n=6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p=0.26). Conclusion RP2D for trametinib in ML pts is 2 mg QD. There are insufficient number of evaluable pts to declare RP2D for MD and SV HD groups. No DLTs were noted in the highest dose cohorts that reached 3 evaluable pts: 1.5 mg QD in MD group, and 1 mg QD in SV group. It may be appropriate for pts with MD and SV HD to start trametinib at 1.5 mg QD and 1 mg QD respectively, and monitored closely for toxicity. Citation Format: Pei Jye Voon, Eric X. Chen, Helen X. Chen, Albert C. Lockhart, Solmaz Sahebjam, Karen Kelly, Ulka N. Vaishampayan, Vivek Subbiah, Albiruni R. Razak, Daniel J. Renouf, Sebastien J. Hotte, Arti Singh, Philippe L. Bedard, Aaron R. Hansen, Ivy S. Percy, Lisa Wang, Lee-Anne Stayner, Lillian L. Siu, Anna Spreafico. A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P035.
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) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 ».