Etirinotecan pegol: development of a novel conjugated topoisomerase I inhibitor

Abstract

Irinotecan is a very active chemotherapeutic agent used for the treatment of several malignancies, including colorectal cancer, gastroesophageal tumors, lung cancer, breast cancer, ovarian cancer, and primary brain tumors. Irinotecan exerts its antineoplastic effects through its active metabolite 7-ethyl-10-hydroxycamptothecin. This metabolite is also responsible for the classic side effects associated with irinotecan that include diarrhea and neutropenia. A pegylated form of this agent, etirinotecan pegol, is undergoing clinical development with the main goal of increasing its therapeutic efficacy and its safety. This agent decreases the maximal exposure to 7-ethyl-10-hydroxycamptothecin while providing continuous exposure to the treated tumor. The half-life of etirinotecan pegol is 50 days and it has been studied in different schedules: weekly, every other week, and once every 3 weeks. The maximum tolerated dose of etirinotecan pegol was found to be 145 mg/m(2). There have already been two phase II clinical trials published showing the efficacy of this novel agent in the treatment of metastatic ovarian and breast cancer. The side effect profile was acceptable for most patients, with a number of patients experiencing diarrhea and even neutropenia.