TY - JOUR
T1 - A first-in-human phase 1 study of LY3023414, an Oral PI3K/mTOR dual inhibitor, in patients with advanced cancer
AU - Bendell, Johanna C.
AU - Varghese, Anna M.
AU - Hyman, David M.
AU - Bauer, Todd M.
AU - Pant, Shubham
AU - Callies, Sophie
AU - Lin, Ji
AU - Martinez, Ricardo
AU - Wickremsinhe, Enaksha
AU - Fink, Aaron
AU - Wacheck, Volker
AU - Moore, Kathleen N.
N1 - Funding Information:
We thank the patients, their families and the study personnel across all sites for participating in this study. The authors would like to thank Christine Martersteck for reviewing biomarker data, Elizabeth Smith Labell for her work on the pharmacokinetic analysis, and Gregory P. Donoho for critical review of the manuscript and editorial assistance. Anindya Chatterjee provided writing assistance funded by Eli Lilly and Company. C.M., E.S.L., G.P.D, A.C. are employees of Eli Lilly and Company. The study was sponsored by Eli Lilly and Company.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/7/15
Y1 - 2018/7/15
N2 - Purpose: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. Patients and Methods: A 3þ3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug–drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Results: Forty-seven patients with solid tumors received LY3023414 at once-daily (20–450 mg) or twice-daily dosing (150–250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with 90% target inhibition at doses 150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. Conclusions: LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data.
AB - Purpose: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. Patients and Methods: A 3þ3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug–drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Results: Forty-seven patients with solid tumors received LY3023414 at once-daily (20–450 mg) or twice-daily dosing (150–250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with 90% target inhibition at doses 150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. Conclusions: LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data.
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U2 - 10.1158/1078-0432.CCR-17-3421
DO - 10.1158/1078-0432.CCR-17-3421
M3 - Article
C2 - 29636360
AN - SCOPUS:85050078078
SN - 1078-0432
VL - 24
SP - 3253
EP - 3262
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -