title: Phase I study of GTI-2040, a ribonucleotide reductase antisense, with high dose cytarabine in patients with relapsed/refractory acute myeloid leukemia.
abstract: We hypothesized that GTI-2040, a 20-mer oligonucleotide complementary to the R2 subunit mRNA of ribonucleotide reductase, combined with high dose cytarabine (HiDAC) would result in enhanced cytotoxicity by favoring Ara-CTP DNA incorporation. In a phase I dose escalation trial, adults (≥ 60 years) with refractory or relapsed acute myeloid leukemia (AML) received daily HiDAC plus infusional GTI-2040. Using a novel assay, evidence of intracellular drug accumulation and target R2 down-regulation was observed. GTI-2040/HiDAC can be administered safely. However, with no complete remissions observed, alternative doses and schedules may need to be investigated to achieve clinical activity in older patients with AML.
authors.affiliation: Division of Hematology, Department of Medicine.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Klisovic
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Xie
authors.forename: Cheryl
authors.initials: C
authors.lastname: Kefauver
authors.forename: Lenguyen
authors.initials: L
authors.lastname: Huynh
authors.forename: James A
authors.initials: JA
authors.lastname: Zwiebel
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D009838:Oligodeoxyribonucleotides; D003561:Cytarabine; C464617:GTI2040
keywords: Acute myeloid leukemia; GTI-2040; antisense therapy; phase I study; ribonucleotide reductase