Dataset Information

A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer.

ABSTRACT:

Purpose

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.

Experimental design

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.

Results

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).

Conclusions

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.

SUBMITTER: Hong DS

PROVIDER: S-EPMC5036398 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Publications

A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer.

Hong David S DS Kurzrock Razelle R Oh Yun Y Wheler Jennifer J Naing Aung A Brail Les L Callies Sophie S André Valérie V Kadam Sunil K SK Nasir Aejaz A Holzer Timothy R TR Meric-Bernstam Funda F Fishman Mayer M Simon George G

Clinical cancer research : an official journal of the American Association for Cancer Research 20110810 20

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 concentra ...[more]

PMID: 21831956

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Dataset Information

A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer.

Purpose

Experimental design

Results

Conclusions

Publications

A phase 1 dose escalation, pharmacokinetic, and pharmacodynamic evaluation of eIF-4E antisense oligonucleotide LY2275796 in patients with advanced cancer.

Similar Datasets

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