Abstract CT029: Pharmacokinetic (PK), safety, and tolerability profile of DCC-2618 in a phase I trial supports 150mg QD selected for a pivotal phase III trial in gastrointestinal stromal tumor (GIST)
Notice bibliographique
Résumé
Abstract Background: DCC-2618, a pan-KIT and PDGFRα kinase switch control inhibitor, is being studied in a pivotal, randomized phase 3 trial, INVICTUS (NCT03353753), based on encouraging disease control observed in a phase 1 trial (NCT02571036) in heavily pretreated GIST patients (pts). In the phase 1 trial, escalating doses of DCC-2618 up to 400 mg per day did not result in a DLT or MTD dose level. The RP2D of 150 mg QD was selected based on PK, efficacy and safety observed across the dose escalation cohorts before enrolling pts into expansion cohorts. Methods: Dose escalation in the phase 1 study is complete, and this study is now enrolling pts into 6 expansion cohorts, including 3 GIST cohorts. DCC-2618 was administered in 28-day cycles at daily oral doses of 20 to 200 mg BID or 100 to 250 mg QD in pts with advanced solid tumors, including GIST. The safety and tolerability of DCC-2618 will be reviewed as a function of exposure to study drug. We report PK results from all dose-escalation cohorts and the expansion phase. The impact of dose modifications including intra-patient dose escalation was assessed based on PK. Results: As of Jan 18, 2018, a total of 168 patients had been treated including 141 GIST patients. The most common treatment-emergent adverse effects (TEAE; all grades, ≥10% of patients) for the overall population across all dose levels included fatigue, myalgia, lipase increase (↑), alopecia, constipation, decreased appetite, nausea, hand-foot-syndrome, anaemia, diarrhea, dyspnea, abdominal pain, weight decrease, arthralgia, and hypertension (HTN). The most common TEAEs for the RP2D of 150 mg QD, based on 106 pts, included fatigue, myalgia, lipase ↑, alopecia, constipation and hand-foot-syndrome. G3 or G4 TEAE, regardless of attribution, occurring in ≥2% pts across all dose levels included included lipase ↑, anemia and HTN. 7.2% of patients underwent dose reductions. All patients who could have received at least 1 cycle prior to Dec 1, 2017 were included for further analysis (127 total, 114 GIST). Among these 114 GIST patients, 83 (73%) remain active on treatment, and 27, 14, 9 and 6 patients have been on DCC-2618 for more than 6, 9, 12, or 15 mo, respectively (15 pts were treated beyond progression per RECIST; a total of 21 were allowed to dose escalate while on study). The median follow up is 3.7 months with a range from 1 to 20 months. Population PK modeling using data from 67 patients demonstrated that combined exposures of DCC-2618 and its active metabolite, DP-5439, increase dose-proportionally. Dosing with a high fat meal increased exposure only slightly. The impact of dose escalation on plasma exposure will be shown. Conclusions: The PK, safety and tolerability data presented together with efficacy data from the phase 1 trial demonstrate a favorable profile and broad therapeutic window for DCC-2618 and support the selection of 150 mg QD as the RP2D for the ongoing pivotal phase 3 INVICTUS study of DCC-2618 in pts with >4th-line GIST. Citation Format: Filip Janku, Michael Heinrich, Albiruni Razak, Michael Gordon, Ping Chi, Kristen Ganjoo, Margaret von Mehren, Neeta Somaiah, Jongtae Lee, Keisuke Kuida, Rodrigo Ruiz Soto, Oliver Rosen, Suzanne George. Pharmacokinetic (PK), safety, and tolerability profile of DCC-2618 in a phase I trial supports 150mg QD selected for a pivotal phase III trial in gastrointestinal stromal tumor (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT029.
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 | 0,003 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».