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A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer

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Summary

The primary objective of this phase I study of LY2780301, a dual p70 S6 kinase and Akt inhibitor, was to determine the recommended phase II dose as a single agent in patients with advanced cancer. Secondary objectives included safety, pharmacokinetic, and pharmacodynamic analyses, and co-clinical analyses in Avatar models. Eligible patients received total daily doses of LY2780301 100–500 mg, given orally as a single dose or divided into 2 doses for 28-day cycles. Dose escalation followed 3 + 3 design. The primary pharmacodynamic endpoint was inhibition of S6 assessed by skin and tumor biopsy. Thirty-two patients were treated. Common toxicities possibly related to treatment included constipation (19 %), fatigue (13 %), nausea (9 %), and diarrhea (9 %). Grade 3/4 toxicities potentially related to treatment were anemia (n = 2), increased alanine aminotransferase/aspartate aminotransferase (ALT) (n = 1), and increased gamma-glutamyl transpeptidase (GGT) (n = 1). One patient experienced best overall response of prolonged stable disease for 6 cycles. Plasma exposures of LY2780301 exceeded predicted efficacious exposures, but were not dose proportional. Among patients receiving 500 mg daily >50 % exhibited reduced S6 in skin biopsies at Day 8 of treatment, but the effect was not maintained. Plasma concentrations of LY2780301 and/or its metabolites were not correlated with S6 expression in the epidermis. There was minimal antitumor activity against the model, CRC 019. Avatar models showed minimal pharmacodynamic effects consistent with the observed antitumor effects. This study suggests a dose of LY2780301 500 mg QD for future studies.

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Acknowledgments

The study was sponsored by Eli Lilly and Company. The authors acknowledge Suzanne R.L. Young, Ph.D., and Jennifer M. Harris, Pharm.D., employees of Eli Lilly and Company, for writing assistance. Antonio Calles is a “Rio Hortega” fellowship grant recipient from the Instituto de Salud Carlos III (CM09/00283).

Conflicts of interest

A.A., J.R., A.C., I.B., P.P.L.C., and J.M. have no conflicts of interest to report. W.B. is an employee and shareholder of Onyx Pharmaceuticals, a subsidiary of Amgen, and is a shareholder of Eli Lilly and Company. M.H. received research support and an honorarium from Eli Lilly and Company. E.C. received clinical research support and an honorarium (Advisory Board) from Eli Lilly and Company. P.W., B.A.M., U.O., and K.A.B... are employees and shareholders of Eli Lilly and Company.

Previous disclosure

Data from this study, NCT01115751, were communicated as an oral presentation at The American Society of Clinical Oncology (ASCO) 2012 [J Clin Oncol 30, 2012 (suppl; abstr 3005).

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Authors and Affiliations

  1. Vall d’Hebron University Hospital and University of Autònoma, Barcelona, Spain

    Analia Azaro, Jordi Rodon & Irene Braña

  2. Spanish National Cancer Research Center (CNIO), Madrid, Spain

    Antonio Calles, Manuel Hidalgo, Pedro P. Lopez-Casas & Manuel Munoz

  3. Eli Lilly and Company, Indianapolis, IN, USA

    Paul Westwood, Brian A. Moser, Ute Ohnmacht, William Bumgardner & Karim A. Benhadji

  4. Eli Lilly and Company, Bridgewater, NJ, USA

    Joel Miller

  5. START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain

    Antonio Calles, Manuel Hidalgo & Emiliano Calvo

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  1. Analia Azaro
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  2. Jordi Rodon
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  3. Antonio Calles
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  4. Irene Braña
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  7. Manuel Munoz
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  9. Joel Miller
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Corresponding author

Correspondence to Emiliano Calvo.

Additional information

At the time of this study, Dr. Miller and Mr. Bumgardner were employed by Eli Lilly and Company. Dr. Miller is currently employed by Everest Clinical Research, Little Falls, NJ, USA. Mr. Bumgardner is currently employed by Onyx Pharmaceuticals, a subsidiary of Amgen, South San Francisco, CA, USA.

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Azaro, A., Rodon, J., Calles, A. et al. A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer. Invest New Drugs 33, 710–719 (2015). https://doi.org/10.1007/s10637-015-0241-7

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