title: A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer.
abstract: 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.
authors.affiliation: Vall d'Hebron University Hospital and University of Autònoma, Barcelona, Spain.
authors.forename: Analia
authors.initials: A
authors.lastname: Azaro
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.forename: Irene
authors.initials: I
authors.lastname: Braña
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Pedro P
authors.initials: PP
authors.lastname: Lopez-Casas
authors.forename: Manuel
authors.initials: M
authors.lastname: Munoz
authors.forename: Paul
authors.initials: P
authors.lastname: Westwood
authors.forename: Joel
authors.initials: J
authors.lastname: Miller
authors.forename: Brian A
authors.initials: BA
authors.lastname: Moser
authors.forename: Ute
authors.initials: U
authors.lastname: Ohnmacht
authors.forename: William
authors.initials: W
authors.lastname: Bumgardner
authors.forename: Karim A
authors.initials: KA
authors.lastname: Benhadji
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa