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|Ref Type||Journal Article|
|Authors||Azaro A, Rodon J, Calles A, Brana I, Hidalgo M, Lopez-Casas PP, Munoz M, Westwood P, Miller J, Moser BA, Ohnmacht U, Bumgardner W, Benhadji KA, Calvo E|
|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.|
|Journal||Investigational new drugs|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|LY2780301||Akt Inhibitor (Pan) 20 S6 Kinase Inhibitor 5||LY2780301 is an inhibitor of AKT and P70S6 kinases, which prevents signaling of the PI3K/AKT pathway thereby possibly resulting in antitumor activity (PMID: 25902900, PMID: 28877935).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA E545K||colon cancer||sensitive||LY2780301||Phase I||Actionable||In a Phase I trial, a colon cancer patient harboring PIK3CA E545K was sensitive to LY2780301, demonstrating stable disease for approximately 125 days (PMID: 25902900).||25902900|