Safety, pharmacokinetics, and activity of EZN-2208, a novel conjugate of polyethylene glycol and SN38, in patients with advanced malignancies.
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.


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.


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.


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.
Department of Investigational Cancer Therapeutics Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. rkurzroc@mdanderson.org
Razelle
R
Kurzrock
Sanjay
S
Goel
Jennifer
J
Wheler
David
D
Hong
Siqing
S
Fu
Keyvan
K
Rezai
Sonia K
SK
Morgan-Linnell
Saik
S
Urien
Sridhar
S
Mani
Imran
I
Chaudhary
Mohammed H
MH
Ghalib
Aby
A
Buchbinder
François
F
Lokiec
Mary
M
Mulcahy
D000328:Adult; D000368:Aged; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D014453:Glucuronosyltransferase / Q000097:blood / Q000235:genetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011092:Polyethylene Glycols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D011379:Prognosis; D012449:Safety; D014018:Tissue Distribution; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D004273:DNA, Neoplasm; D014453:Glucuronosyltransferase; D011092:Polyethylene Glycols; D000099148:UGT1A1 Enzyme; C528970:EZN-2208