TY - JOUR
T1 - First-In-Human Phase I Study of a Next-Generation, Oral, TGFb Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer
AU - Yap, Timothy A.
AU - Vieito, Maria
AU - Baldini, Capucine
AU - Sepúlveda-Sánchez, Juan Manuel
AU - Kondo, Shunsuke
AU - Simonelli, Matteo
AU - Cosman, Rasha
AU - van der Westhuizen, Andre
AU - Atkinson, Victoria
AU - Carpentier, Antoine F.
AU - Löhr, Mario
AU - Redman, Rebecca
AU - Mason, Warren
AU - Cervantes, Andres
AU - Le Rhun, Emilie
AU - Ochsenreither, Sebastian
AU - Warren, Louise
AU - Zhao, Yumin
AU - Callies, Sophie
AU - Estrem, Shawn T.
AU - Man, Michael
AU - Gandhi, Leena
AU - Avsar, Emin
AU - Melisi, Davide
N1 - Funding Information:
T.A. Yap reports grants from Eli Lilly during the conduct of the study. T.A. Yap also reports grants from Artios, Constellation, Cyteir, Forbius, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Ribon Therapeutics, Regeneron, Sanofi, Scholar Rock, Tesaro, Vertex Pharmaceuticals, and Novartis; grants and personal fees from AstraZeneca, Bayer, Clovis, EMD Serono, F-Star, Merck, Pfizer, Repare, and Seattle Genetics; and personal fees from Almac, Aduro, Atrin, Axiom, Bristol Myers Squibb, Calithera, Cybrexa, Guidepoint, Ignyta, I-Mab, Janssen, Roche, Rubius, Schrodinger, Varian, and Zai Labs outside the submitted work. M. Vieito reports personal fees from Roche, EMD Serono, and TFS outside the submitted work. S. Kondo reports other support from Eli Lilly during the conduct of the study; S. Kondo also reports personal fees from Chugai, as well as other support from Incyte and Eisai outside the submitted work. V. Atkinson reports personal fees and non-financial support from BMS, as well as personal fees from MSD, NEKTAR,
Funding Information:
This work was supported by grants from Eli Lilly and Company. We would like to thank Dan Kaplan for his consulting role on the pharmacodynamic assays and Shuaicheng Freeman Wang for his support. We would like to thank Collin Miles for his extensive contribution to the pharmacokinetics analysis. We would like to thank Shaleen Multani, an employee of Eli Lilly Services India Private Limited for providing writing support. T.A. Yap acknowledges the MD Anderson Cancer Center for support grant P30 CA016672 and the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy at the MD Anderson Cancer Center for support grant 1U01 CA180964. Work in the unit of D. Melisi was partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) Investigator Grant no. 23719 and 5 ⨯ 1000 Grant no. 12182, by the Italian Ministry of Health Ricerca Finalizzata 2016 GR-2016-02361134 grant, by the patients’ associations “Nastro Viola” and “Voglio il Massimo” donations.
Publisher Copyright:
© 2021 The Authors.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - Purpose: A novel, selective, next-generation transforming growth factor beta (TGFb) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-inhuman 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 treatmentemergent 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% diseasecontrol 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.
AB - Purpose: A novel, selective, next-generation transforming growth factor beta (TGFb) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-inhuman 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 treatmentemergent 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% diseasecontrol 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.
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U2 - 10.1158/1078-0432.CCR-21-1504
DO - 10.1158/1078-0432.CCR-21-1504
M3 - Article
C2 - 34548321
AN - SCOPUS:85122386288
SN - 1078-0432
VL - 27
SP - 6666
EP - 6676
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -