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PURPOSE: Enhanced tumor cell survival through expression of inhibitors of apoptosis (IAP) is a hallmark of cancer. Survivin, an IAP absent from most normal tissues, is overexpressed in many malignancies and associated with a poorer prognosis. We report the first-in-human dose study of LY2181308, a second-generation antisense oligonucleotide (ASO) directed against survivin mRNA. PATIENTS AND METHODS: A dose-escalation study evaluating the safety, pharmacokinetics, and pharmacodynamics of LY2181308 administered intravenously for 3 hours as a loading dose on 3 consecutive days and followed by weekly maintenance doses. Patients were eligible after signing informed consent, had exhausted approved anticancer therapies and agreed to undergo pre- and posttreatment tumor biopsies to evaluate reduction of survivin protein and gene expression. RESULTS: A total of 40 patients were treated with LY2181308 at doses of 100 to 1,000 mg. Twenty-six patients were evaluated at the recommended phase 2 dose of 750 mg, at which level serial tumor sampling and [(11)C]LY2183108 PET (positron emission tomography) imaging demonstrated that ASO accumulated within tumor tissue, reduced survivin gene and protein expression by 20% and restored apoptotic signaling in tumor cells in vivo. Pharmacokinetics were consistent with preclinical modeling, exhibiting rapid tissue distribution, and terminal half-life of 31 days. CONCLUSIONS: The tumor-specific, molecularly targeted effects demonstrated by this ASO in man underpin confirmatory studies evaluating its therapeutic efficacy in cancer.

Original publication

DOI

10.1158/1078-0432.CCR-10-1932

Type

Journal article

Journal

Clin Cancer Res

Publication Date

15/12/2010

Volume

16

Pages

6150 - 6158

Keywords

Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Dose-Response Relationship, Drug, Down-Regulation, Evidence-Based Practice, Female, Gene Expression Regulation, Neoplastic, Genetic Therapy, Humans, Inhibitor of Apoptosis Proteins, Male, Microtubule-Associated Proteins, Middle Aged, Molecular Targeted Therapy, Neoplasms, Oligonucleotides, Oligonucleotides, Antisense, Pilot Projects, Survivin