First-in-human phase i study of a ...
Type de document :
Article dans une revue scientifique: Article original
PMID :
URL permanente :
Titre :
First-in-human phase i study of a next-generation, oral, transforming growth factor-beta receptor 1 inhibitor, ly3200882 in patients with advanced cancer
Auteur(s) :
Yap, Timothy A. [Auteur]
Vieito, Maria [Auteur]
Baldini, Capucine [Auteur]
Sepulveda-Sanchez, Juan Manuel [Auteur]
Kondo, Shunsuke [Auteur]
Simonelli, Matteo [Auteur]
Cosman, Rasha [Auteur]
Van Der Westhuizen, Andre [Auteur]
Atkinson, Victoria [Auteur]
Carpentier, Antoine F. [Auteur]
Lohr, Mario [Auteur]
Redman, Rebecca [Auteur]
Mason, Warren [Auteur]
Cervantes, Andres [Auteur]
Le Rhun, Emilie [Auteur]
Ochsenreither, Sebastian [Auteur]
Warren, Louise [Auteur]
Zhao, Yumin [Auteur]
Callies, Sophie [Auteur]
Estrem, Shawn T. [Auteur]
Man, Michael [Auteur]
Gandhi, Leena [Auteur]
Avsar, Emin [Auteur]
Melisi, Davide [Auteur]
Vieito, Maria [Auteur]
Baldini, Capucine [Auteur]
Sepulveda-Sanchez, Juan Manuel [Auteur]
Kondo, Shunsuke [Auteur]
Simonelli, Matteo [Auteur]
Cosman, Rasha [Auteur]
Van Der Westhuizen, Andre [Auteur]
Atkinson, Victoria [Auteur]
Carpentier, Antoine F. [Auteur]
Lohr, Mario [Auteur]
Redman, Rebecca [Auteur]
Mason, Warren [Auteur]
Cervantes, Andres [Auteur]
Le Rhun, Emilie [Auteur]
Ochsenreither, Sebastian [Auteur]
Warren, Louise [Auteur]
Zhao, Yumin [Auteur]
Callies, Sophie [Auteur]
Estrem, Shawn T. [Auteur]
Man, Michael [Auteur]
Gandhi, Leena [Auteur]
Avsar, Emin [Auteur]
Melisi, Davide [Auteur]
Titre de la revue :
Clinical cancer research . an official journal of the American Association for Cancer Research
Nom court de la revue :
Clin Cancer Res
Date de publication :
2021-09-21
ISSN :
1557-3265
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
PURPOSE: A novel, selective, next-generation transforming growth factor beta (TGFbeta) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, ...
Lire la suite >PURPOSE: A novel, selective, next-generation transforming growth factor beta (TGFbeta) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. PATIENTS AND METHODS: This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). RESULTS: Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced >/=1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naive patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. CONCLUSIONS: LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.Lire moins >
Lire la suite >PURPOSE: A novel, selective, next-generation transforming growth factor beta (TGFbeta) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. PATIENTS AND METHODS: This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). RESULTS: Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced >/=1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naive patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. CONCLUSIONS: LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
INSERM
Université de Lille
Université de Lille
Date de dépôt :
2022-06-15T13:58:20Z
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