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

Christopher R. Garrett, Tanios S. Bekaii-Saab, Theresa Ryan, George A. Fisher, Sally Clive, Petr Kavan, Einat Shacham-Shmueli, Aby Buchbinder, Richard M. Goldberg

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26 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4223-4230
Number of pages8
JournalCancer
Volume119
Issue number24
DOIs
StatePublished - Dec 15 2013

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Keywords

  • EZN-2208
  • SN-38
  • colorectal cancer
  • pegylated
  • randomized phase 2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Garrett, C. R., Bekaii-Saab, T. S., Ryan, T., Fisher, G. A., Clive, S., Kavan, P., Shacham-Shmueli, E., Buchbinder, A., & Goldberg, R. M. (2013). Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. Cancer, 119(24), 4223-4230. https://doi.org/10.1002/cncr.28358