First-In-Human Phase I Study of a ...
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Article dans une revue scientifique: Article original
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Title :
First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer
Author(s) :
Yap, Timothy A. [Auteur]
The University of Texas M.D. Anderson Cancer Center [Houston]
Vieito, Maria [Auteur]
Vall d'Hebron University Hospital [Barcelona]
Baldini, Capucine [Auteur]
Institut Gustave Roussy [IGR]
Sepulveda-Sanchez, Juan Manuel [Auteur]
Hospital Universitario 12 de Octubre [Madrid]
Kondo, Shunsuke [Auteur]
National Cancer Center Research Institute [Tokyo]
Simonelli, Matteo [Auteur]
Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan]
Humanitas University [Milan] [Hunimed]
Cosman, Rasha [Auteur]
St. Vincent's Hospital, Sydney
Van Der Westhuizen, Andre [Auteur]
Calvary Mater Newcastle Hospital
Atkinson, Victoria [Auteur]
Carpentier, Antoine F. [Auteur]
Hopital Saint-Louis [AP-HP] [AP-HP]
Lohr, Mario [Auteur]
University Hospital Wuerzburg / Universitätsklinikum Würzburg
Redman, Rebecca [Auteur]
University of Louisville
Mason, Warren [Auteur]
Princess Margaret Hospital
Cervantes, Andres [Auteur]
Centro de Investigación Biomédica en Red de Cáncer [CIBERONC]
Universitat de València = University of Valencia [UV]
Le Rhun, Emilie [Auteur]
CIC CHU ( Lille)/inserm
Ochsenreither, Sebastian [Auteur]
Charité - UniversitätsMedizin = Berlin University Medicine
Warren, Louise [Auteur]
Zhao, Yumin [Auteur]
Eli Lilly and Company [Indianapolis]
Callies, Sophie [Auteur]
Estrem, Shawn T. [Auteur]
Man, Michael [Auteur]
Gandhi, Leena [Auteur]
Avsar, Emin [Auteur]
Melisi, Davide [Auteur]
Università degli studi di Verona = University of Verona [UNIVR]
The University of Texas M.D. Anderson Cancer Center [Houston]
Vieito, Maria [Auteur]
Vall d'Hebron University Hospital [Barcelona]
Baldini, Capucine [Auteur]
Institut Gustave Roussy [IGR]
Sepulveda-Sanchez, Juan Manuel [Auteur]
Hospital Universitario 12 de Octubre [Madrid]
Kondo, Shunsuke [Auteur]
National Cancer Center Research Institute [Tokyo]
Simonelli, Matteo [Auteur]
Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan]
Humanitas University [Milan] [Hunimed]
Cosman, Rasha [Auteur]
St. Vincent's Hospital, Sydney
Van Der Westhuizen, Andre [Auteur]
Calvary Mater Newcastle Hospital
Atkinson, Victoria [Auteur]
Carpentier, Antoine F. [Auteur]
Hopital Saint-Louis [AP-HP] [AP-HP]
Lohr, Mario [Auteur]
University Hospital Wuerzburg / Universitätsklinikum Würzburg
Redman, Rebecca [Auteur]
University of Louisville
Mason, Warren [Auteur]
Princess Margaret Hospital
Cervantes, Andres [Auteur]
Centro de Investigación Biomédica en Red de Cáncer [CIBERONC]
Universitat de València = University of Valencia [UV]
Le Rhun, Emilie [Auteur]

CIC CHU ( Lille)/inserm
Ochsenreither, Sebastian [Auteur]
Charité - UniversitätsMedizin = Berlin University Medicine
Warren, Louise [Auteur]
Zhao, Yumin [Auteur]
Eli Lilly and Company [Indianapolis]
Callies, Sophie [Auteur]
Estrem, Shawn T. [Auteur]
Man, Michael [Auteur]
Gandhi, Leena [Auteur]
Avsar, Emin [Auteur]
Melisi, Davide [Auteur]
Università degli studi di Verona = University of Verona [UNIVR]
Journal title :
Clinical Cancer Research
Abbreviated title :
Clin Cancer Res
Volume number :
27
Pages :
6666-6676
Publisher :
American Association for Cancer Research
Publication date :
2021-09-21
ISSN :
1557-3265
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [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, ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
INSERM
Université de Lille
Université de Lille
Submission date :
2022-06-15T13:58:20Z
2023-03-21T09:12:01Z
2023-03-21T09:12:01Z
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