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Leukemia & Lymphoma Volume 55, 2014 - Issue 6
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Research Article

Phase I study of GTI-2040, a ribonucleotide reductase antisense, with high dose cytarabine in patients with relapsed/refractory acute myeloid leukemia

Rebecca B. KlisovicDivision of Hematology, Department of Medicine
,
William BlumDivision of Hematology, Department of Medicine;The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
,
Zhongfa LiuDivision of Pharmaceutics, College of Pharmacy
,
Zhiliang XieDivision of Pharmaceutics, College of Pharmacy
,
Cheryl KefauverThe Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
,
Lenguyen HuynhDivision of Hematology, Department of Medicine
,
James A. ZwiebelNational Cancer Institute, Bethesda, MD, USA
,
Steven M. DevineDivision of Hematology, Department of Medicine;The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
,
John C. ByrdDivision of Hematology, Department of Medicine;The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
,
Michael R. GreverDivision of Hematology, Department of Medicine;The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
,
Kenneth K. ChanDivision of Pharmaceutics, College of Pharmacy;The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
&
Guido MarcucciDivision of Hematology, Department of Medicine;The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USACorrespondence[email protected]
 show all
Pages 1332-1336 | Received 22 May 2013, Accepted 23 Aug 2013, Published online: 01 Nov 2013
 
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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.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

This study was supported by NCI U01 CA 076576-10 and NCI R21 CA 105879.

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