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

ABSTRACT: 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.

SUBMITTER: Hong DS

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

REPOSITORIES: biostudies-literature

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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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Project description:Background and objectives: Teverelix drug product (DP) is a gonadotropin-releasing hormone antagonist in development for the treatment of patients with prostate cancer in whom androgen deprivation therapy is indicated. The aim of this paper is to present the results of five Phase 2 studies that assessed the pharmacokinetics, pharmacodynamics, efficacy and safety of different loading dose regimens of teverelix DP. Methods: Five single-arm, uncontrolled clinical trials were conducted in patients with advanced prostate cancer. The five different loading dose regimens of teverelix DP tested were (a) a single 90 mg subcutaneous (SC) injection of teverelix DP given on 3 consecutive days (Days 0, 1 and 2); (b) a single 90 mg intramuscular (IM) injection of teverelix DP given 7 days apart (Days 0 and 7); (c) a single 120 mg SC injection of teverelix DP given on 2 consecutive days (Days 0 and 1); (d) 2 × 60 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2), and (e) 2 × 90 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2). The primary efficacy parameter was the duration of action of an initial loading dose regimen in terms of suppression of testosterone to below the castration level (0.5 ng/mL). Results: Eighty-two patients were treated with teverelix DP. Two regimens (90 mg and 180 mg SC on 3 consecutive days) had a mean duration of castration of 55.32 days and 68.95 days with >90% of patients having testosterone levels < 0.5 ng/mL at Day 28. The mean onset of castration for the SC regimens ranged from 1.10 to 1.77 days, while it was slower (2.4 days) with IM administration. The most common adverse event (AE) was injection site reaction. No AEs of severe intensity were reported. Conclusions: Teverelix DP is safe and well tolerated. Castrate levels of testosterone can be rapidly achieved following the subcutaneous injection of teverelix DP on 3 consecutive days. Streamlining of the administration of the loading dose and identifying a suitable maintenance dose will be investigated in future trials.

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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.

Publications

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

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