Reference Detail

Ref Type

Journal Article

PMID

(25902900)

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	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	33	3	2015 Jun	710-9	Invest New Drugs

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
LY2780301	LY2780301	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
LY2780301		LY 2780301\|LY-2780301	Akt Inhibitor (Pan) 21 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	predicted - sensitive	LY2780301	Case Reports/Case Series	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