title: A phase I pharmacodynamic study of GTI-2040, an antisense oligonucleotide against ribonuclotide reductase, in acute leukemias: a California Cancer Consortium study.
abstract: We performed a phase I study of GTI-2040, an antisense oligonucleotide against ribonucleotide reductase mRNA, on a novel dosing schedule of days 1-4 and 15-18 by continuous infusion to examine efficacy and tolerability in patients with leukemia. A dose of 11 mg/kg/d was safely reached. Dose-limiting toxicities (DLTs) at the higher levels included elevated troponin I and liver function enzymes. There were no objective responses to GTI-2040 in this study; 7/24 patients were able to complete the predetermined three infusion cycles. Pharmacokinetic and pharmacodynamic studies were performed, indicating a trend towards increasing intracellular drug levels and decreasing RRM2 gene expression with increasing doses. This dose schedule may be considered if appropriate combinations are identified in preclinical studies.
authors.affiliation: a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kirschbaum
authors.affiliation: a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Paul
authors.initials: P
authors.lastname: Frankel
authors.affiliation: a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.affiliation: b Ohio State University Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Xie
authors.affiliation: a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Leslie
authors.initials: L
authors.lastname: Popplewell
authors.affiliation: a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.affiliation: a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Omar
authors.initials: O
authors.lastname: Aljitawi
authors.affiliation: c Davis Comprehensive Cancer Center, University of California , Sacramento , CA , USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Tuscano
authors.affiliation: b Ohio State University Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.affiliation: a City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Edward M
authors.initials: EM
authors.lastname: Newman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology* / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D009838:Oligodeoxyribonucleotides; C464617:GTI2040; D012264:Ribonucleotide Reductases
keywords: Acute leukemia; GTI-2040; intermittent infusion; pharmacodynamics; pharmacokinetics; phase I trial; ribonucleotide reductase