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Safety, pharmacokinetics, and activity of EZN-2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies.
- Source :
-
Cancer [Cancer] 2012 Dec 15; Vol. 118 (24), pp. 6144-51. Date of Electronic Publication: 2012 Jun 06. - Publication Year :
- 2012
-
Abstract
- Background: EZN-2208 is a water-soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN-2208 in adult patients with advanced solid tumors.<br />Methods: Patients in sequential cohorts (3 + 3 design) received intravenous EZN-2208 at doses between 1.25 mg/m(2) and 25 mg/m(2) once every 21 days.<br />Results: Thirty-nine patients received EZN-2208. The median number of prior therapies was 2 (range, 0-10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN-2208 with (16.5 mg/m(2)) and without (10 mg/m(2)) granulocyte-colony-stimulating factor (G-CSF). The dose-limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m(2) with G-CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m(2)). PK analysis indicated a mean terminal half-life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥ 4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short-lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥ 4 months, 3 had received prior irinotecan, and 1 had KRAS-positive colorectal cancer.<br />Conclusions: EZN-2208 was well tolerated and produced stable disease that lasted for ≥ 4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy.<br /> (Copyright © 2012 American Cancer Society.)
- Subjects :
- Adult
Aged
Camptothecin pharmacokinetics
Camptothecin therapeutic use
DNA, Neoplasm genetics
Female
Follow-Up Studies
Glucuronosyltransferase blood
Glucuronosyltransferase genetics
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Staging
Neoplasms genetics
Polymerase Chain Reaction
Polymorphism, Genetic genetics
Prognosis
Safety
Tissue Distribution
Camptothecin analogs & derivatives
Neoplasms drug therapy
Polyethylene Glycols pharmacokinetics
Polyethylene Glycols therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0142
- Volume :
- 118
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 22674635
- Full Text :
- https://doi.org/10.1002/cncr.27647