TY - JOUR
T1 - A phase I study of LY3009120, a pan-RAF inhibitor, in patients with advanced or metastatic cancer
AU - Sullivan, Ryan J.
AU - Hollebecque, Antoine
AU - Flaherty, Keith T.
AU - Shapiro, Geoffrey I.
AU - Ahnert, Jordi Rodon
AU - Millward, Michael J.
AU - Zhang, Wei
AU - Gao, Ling
AU - Sykes, Amanda
AU - Willard, Melinda D.
AU - Yu, Danni
AU - Schade, Andrew E.
AU - Crowe, Kris Anne
AU - Flynn, Daniel L.
AU - Kaufman, Michael D.
AU - Henry, James R.
AU - Peng, Sheng Bin
AU - Benhadji, Karim A.
AU - Conti, Ilaria
AU - Gordon, Michael S.
AU - Tiu, Ramon V.
AU - Hong, David S.
N1 - Funding Information:
We would like to thank Dr. Nina Ramdas from Eli Lilly and Company in Indianapolis, Indiana, for her work on this study and for her input on the manuscript. Andrea Humphries, PhD, and Andrea Metti, PhD, MPH, of Syneos Health, provided writing support. Funding for the study was provided by Eli Lilly and Company. This study was funded by Eli Lilly and Company.
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2020/2
Y1 - 2020/2
N2 - Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N ¼ 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n ¼ 15), nausea (n ¼ 12), dermatitis acneiform (n ¼ 10), decreased appetite (n ¼ 7), and maculopapular rash (n ¼ 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.
AB - Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N ¼ 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n ¼ 15), nausea (n ¼ 12), dermatitis acneiform (n ¼ 10), decreased appetite (n ¼ 7), and maculopapular rash (n ¼ 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.
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U2 - 10.1158/1535-7163.MCT-19-0681
DO - 10.1158/1535-7163.MCT-19-0681
M3 - Article
C2 - 31645440
AN - SCOPUS:85079088235
SN - 1535-7163
VL - 19
SP - 460
EP - 467
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 2
ER -