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Ref Type Journal Article
PMID (21831956)
Authors Hong DS, Kurzrock R, Oh Y, Wheler J, Naing A, Brail L, Callies S, André V, Kadam SK, Nasir A, Holzer TR, Meric-Bernstam F, Fishman M, Simon G
Title A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 17 20 2011 Oct 15 6582-91 Clin Cancer Res
URL
Abstract Text The antisense oligonucleotide LY2275796 blocks expression of cap-binding protein eukaryotic initiation factor 4E (eIF-4E), an mRNA translation regulator upregulated in tumors. This phase I study sought an appropriate LY2275796 dose in patients with advanced tumors.A 3-day loading dose, then weekly maintenance doses, were given to 1 to 3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations and tumor biopsies to quantify eIF-4E mRNA/protein.Thirty patients with stage 4 disease received 1 or more LY2275796 dose. A dose-limiting toxicity was observed at 1,200 mg, with 1,000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1 to 2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and postdose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and 7 patients achieved stable disease (minimum of 6 weeks) as best response, with 2 patients on therapy for more than 3 months (one with melanoma, one with cystadenocarcinoma of the head/neck).LY2275796 was well tolerated up to 1,000 mg. Because tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.

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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
LY2275796 LY2275796 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
LY2275796 ISIS 183750|LY-2275796|LY 2275796 Antisense Therapy 13 LY2275796 is an antisense oligonucleotide targeted against eukaryotic initiation factor 4E (eIF-4E), which results in decreased eIF-4E expression and potentially leads to reduced growth of eIF-4E-expressing tumors (PMID: 17786246, PMID: 21831956, PMID: 27194579).
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