Abstract P3-07-10: CCTG IND.236: A Phase 1b trial of combined CFI-402257 and weekly paclitaxel in patients with HER2-negative (HER2-) advanced breast cancer (aBC)
Notice bibliographique
Résumé
Abstract CCTG IND.236: A Phase 1b trial of combined CFI-402257 and weekly paclitaxel in patients with HER2-negative (HER2-) advanced breast cancer (aBC) Philippe L. Bedard, Mihaela Mates, John Hilton, Nathalie Levasseur, Arif Awan, Amirrtha Srikanthan, David Cescon, Karen Gelmon, Andrew Robinson, Nancy Drummond-Ivars, Irene Li, Laleh Rastgou, Jackie Edwards, Linda Hagerman, Siwei Zhang, Mark Bray, Lesley Seymour, Moira Rushton-Marovac, Pierre-Olivier Gaudreau Background: CFI-402257 is a selective oral inhibitor of TTK protein kinase, a critical regulator of the mitotic spindle assembly checkpoint overexpressed in breast cancer (BC). CFI-402257 monotherapy has anti-proliferative and cytotoxic activity and enhances antitumor activity of paclitaxel in BC xenograft models. Material and methods: Primary objectives were to establish safety and Recommended Phase 2 dose (RP2D) of CFI-402257 combined with weekly paclitaxel (Phase 1b) and Overall Response Rate (ORR) as per RECIST 1.1 (Phase 2). Patients with HER2- aBC with adequate organ function, PS 0-1, previously treated with >1 non-taxane chemotherapy, were eligible. A 3+3 design was used for Phase 1b, with dose limiting toxicities (DLTs) assessed during cycle 1 (28 days). Starting dose CFI-402257 was 84mg (DL1 = 84mg, DL2 = 112mg, DL3 = 168mg, DL4 = 210mg and DL5 = 252mg) on a 2-day on, 5-day off schedule with paclitaxel 80mg/m2 day 1, 8, 15. Safety assessments were performed weekly (CTCAE v5.0) and response every 2 cycles. A Simon 2-stage design was used for Phase 2 (stage 2 required ≥4 responses in 17 evaluable patients from stage 1). Results: 37 patients received a total of 260 cycles including all 5 dose levels. Median age was 59; 92% ER+/HER2-; 49% PS1; 22% 3 prior chemotherapy lines; 41% 4 sites of metastatic disease, and 81% had received prior CDK4/6 inhibitors. Grade 3 hematological adverse events (AEs, all dose levels) were neutropenia (70%), lymphopenia (41%) and anemia (14%). Six DLTs occurred: 5 dose-related grade 4 neutropenia and 1 febrile neutropenia. Three DLTs occurred at DL3, two at DL4, and one at DL5. Three serious AEs (two at DL3, and one at DL4) at least possibly related to treatment were seen: 2 febrile neutropenia and 1 skin infection (all grade 3). Frequent AEs (˃5%; all dose levels) considered at least possibly related to treatment were: diarrhea (38%), nausea (30%), fatigue (27%), vomiting (16%), anorexia (14%), maculo-papular rash (14%), oral mucositis (11%), alopecia (11%) and pruritus (8%). DL3 (168mg) was selected as RP2D. ORR was 3/36=8% and 1/17=5.9% in all vs Phase 2 evaluable patients, respectively. Clinical Benefit Rate (CBR; defined as complete response, partial response or stable disease ˃16 weeks in duration) was 18/33=54.6% and 10/17=58.8% in all vs Phase 2 evaluable patients, respectively. During Phase 2, the 17 evaluable patients from stage 1 did not meet pre-specified threshold for anti-tumor activity to proceed to stage 2. Conclusions: CFI-402257 and paclitaxel was well tolerated, with neutropenia as the main toxicity. DL3 (168mg) was selected as RP2D. Phase 2 ORR and CBR was 5.9% and 58.8%, respectively; during Phase 2, the 17 evaluable patients from stage 1 did not meet the pre-specified threshold for anti-tumor activity to proceed to stage 2 and the trial was closed to accrual on April 7, 2022. Final analysis and correlative analyses are ongoing. Acknowledgements: Coordinated by the CCTG. Funding supported by SU2C Canada - Canadian Cancer Society Breast Cancer Dream Team Research Funding (SU2C-AACR-DT-18-15) and OICR. CFI-402257 provided by Treadwell Therapeutics. Citation Format: Philippe Bedard, Mihaela Mates, John Hilton, Nathalie Levasseur, Arif Awan, Amirrtha Srikanthan, David W. Cescon, Karen Gelmon, Andrew Robinson, Nancy Drummond-Ivars, Irene Li, Laleh Rastgou, Jackie Edwards, Linda Hagerman, Siwei Zhang, Mark Bray, Lesley Seymour, Moira Rushton, Pierre-Olivier Gaudreau. CCTG IND.236: A Phase 1b trial of combined CFI-402257 and weekly paclitaxel in patients with HER2-negative (HER2-) advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-10.
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 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 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,017 | 0,003 |
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 ».