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 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 1–3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations; tumor biopsies, to quantify eIF-4E mRNA/protein. Results Thirty patients with Stage 4 disease received ≥1 LY2275796 dose. A dose-limiting toxicity was observed at 1200 mg, with 1000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1–2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and post-dose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and seven patients achieved stable disease (minimum of 6 weeks) as best response, with two patients on therapy >3 months (one with melanoma, one with cystadenocarcinoma of the head/neck). Conclusions LY2275796 was well tolerated up to 1000 mg. Since tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.

Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells

“…It is believed that antitumor effects with 4EASO would be enhanced in combination with chemotherapy or radiation. 29 The results presented here demonstrate that 4EASO potently sensitizes NSCLC cells to gemcitabine and support the notion of enhanced chemosensitivity with 4EASO in NSCLC. With this in mind, 4EASO is being examined for the treatment of patients with stage IV non-small-cell lung cancer NSCLC in combination with chemotherapy in phase I/II trials.…”

“…27 A phase 1 clinical trial of 4EASO (LY2275796) in advanced human cancer was carried out owing to the promising findings from these preclinical investigations and the results recently published. 29 The maximum tolerated dose and biological effective dose of 1000 mg 4EASO was determined employing a dose escalation experimental design. When comparing pre-and posttreatment tumor biopsies, a decrease in eIF4E expression was observed in the majority of patients.…”

“…28 In addition, results from a phase I/II clinical trial of 4EASO in patients with advanced cancer has recently been published. 29 A reduction of up to 80% of eIF4E mRNA was realized in patient tumors but did not result in tumor response. It was suggested that 4EASO be examined with combined therapies.…”

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

“…A phase I clinical trial showed reduction of eIF4E protein by up to 65% by an antisense oligonucleotide (LY2275796) in most of the 30 patients tested (43). Other targets of eIFs include PI3K and mTOR inhibitors.…”

Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors

“…a phase 1 trial, of the 30 patients who received at least 1 dose of the eIF4E antisense oligonucleotide, 7 patients had stable disease of at least 6 weeks duration and 2 patients had disease control for over 3 months. 31 Other efforts have included the use of the ribavirin, an antiviral drug that may mimic the m 7 G cap to block eIF4E activity. 27 A clinical trial of ribavirin was conducted in patients with AML, and among the 11 evaluable patients, there was 1 complete remission and 2 partial remissions.…”