Randomized phase 2 study of pegylated SN‐38 (EZN‐2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer

BACKGROUND Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN‐38 (10‐hydroxy‐7‐ethyl‐camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN‐38 (EZN‐2208) increases the solubility, exposure, and half‐l...

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Published in:Cancer 2013-12, Vol.119 (24), p.4223-4230
Main Authors: Garrett, Christopher R., Bekaii‐Saab, Tanios S., Ryan, Theresa, Fisher, George A., Clive, Sally, Kavan, Petr, Shacham‐Shmueli, Einat, Buchbinder, Aby, Goldberg, Richard M.
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized - administration & dosage
Antineoplastic Agents, Phytogenic - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Camptothecin - administration & dosage
Camptothecin - analogs & derivatives
Camptothecin - therapeutic use
Cell Line, Tumor
Cetuximab
colorectal cancer
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Disease-Free Survival
EZN‐2208
Female
Gastroenterology. Liver. Pancreas. Abdomen
Genes, ras
Humans
Male
Medical sciences
Middle Aged
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Mutation
Neoplasm Recurrence, Local - drug therapy
Neoplasm Recurrence, Local - genetics
pegylated
Polyethylene Glycols - administration & dosage
Polyethylene Glycols - therapeutic use
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins p21(ras)
randomized phase 2
ras Proteins - genetics
SN‐38
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
Young Adult
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Summary:BACKGROUND Irinotecan is cytotoxic in patients with advanced colorectal cancer (CRC). SN‐38 (10‐hydroxy‐7‐ethyl‐camptothecin) is the active metabolite of irinotecan. Attachment of polyethylene glycol (PEG) polymer chains (pegylation) to SN‐38 (EZN‐2208) increases the solubility, exposure, and half‐life of SN‐38. Preclinical studies demonstrated superior in vitro efficacy of EZN‐2208 when it was tested in irinotecan‐refractory human CRC cell lines. METHODS Patients with metastatic or locally recurrent CRC who had previously received 5‐flurouracil (5‐FU), oxaliplatin, and irinotecan were assigned to receive EZN‐2208 monotherapy (9 mg/m2 on days 1, 8, and 15 every 28 days for patients with KRAS‐mutant tumors only [arm A]), and patients with KRAS wild‐type tumors were randomized (2:1) to receive either EZN‐2208 plus cetuximab (400 mg/m2 loading dose on day 1 followed by 250 mg/m2 weekly starting on day 8 [arm B]) or irinotecan 125 mg/m2 on days 1 and 8 every 21 days plus cetuximab at the same doses indicated above (arm C). RESULTS The overall response rate and progression‐free survival were 0% and 1.8 months, respectively, in arm A; 10.7% and 4.9 months (95% confidence interval [CI], 3.2‐5.8 months), respectively, in arm B; and 14.3% and 3.7 months (95% CI, 2.1‐5.8 months), respectively, in arm C. EZN‐2208 was well tolerated in combination with cetuximab. No statistically significant difference in survival was observed between arm B (9.8 months; 95% CI, 7.2‐11.2 months) and arm C (9.1 months; 95% CI, 6.0‐13.0 months). CONCLUSIONS EZN‐2208, either as monotherapy or in combination with cetuximab, was well tolerated in patients with refractory CRC. Overall survival and progression‐free survival were similar in the cetuximab plus irinotecan arm and the EZN‐2208 arm. Cancer 2013;119:4223–4230. © 2013 American Cancer Society. The pegylated formulation of the active moiety of irinotecan SN‐38 (10‐hydroxy‐7‐ethyl‐camptothecin), called EZN‐2208, when used in combination with cetuximab in patients with metastatic KRAS wild‐type colorectal cancer, is well tolerated; in a randomized phase 2 study, treatment with EZN‐2208 plus cetuximab is not associated with improved progression‐free survival compared with irinotecan plus cetuximab. Objective radiographic responses are not observed in EZN‐2208‐treated patients with metastatic, KRAS‐mutant colorectal cancer who received prior irinotecan chemotherapy.
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.28358