Genetic Polymorphism oriented PhaseI Study of Irinotecan and Doxifluridine for Unresectable or Recurrent Colorectal Cancer
- Conditions
- colorectal cancer
- Registration Number
- JPRN-UMIN000002092
- Lead Sponsor
- Department of Digestive Surgery and Surgical Oncology (Surgery II), and Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine
- Brief Summary
Although individuals carrying the UGT1A1 allele *28 have an increased risk of severe toxicities associated with irinotecan, no phase I study has been conducted based on the polymorphism. This report presents the recommended doses of irinotecan for patients with the respective genotypes. Twenty-seven patients with advanced colorectal cancer were enrolled in this study, and the UGT1A1*28 polymorphism was genotyped before chemotherapy. One course of chemotherapy consisted of irinotecan infused once every 2 weeks at 70, 100, 120, and 150 mg⁄m2 at dose levels 1, 2, 3, and 4, respectively, and doxifluridine was administered orally. This treatment continued for at least 12 weeks. The dose-limiting toxicity was determined as grade 3 hematological and non-hematological toxicities for the TA6 ⁄ TA6 (6 ⁄ 6) and TA6 ⁄ TA7 (6 ⁄ 7) genotypes. The pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide, was assessed at dose level 2. Eighteen and nine patients had the 6 ⁄ 6 and 6 ⁄ 7 genotypes, respectively. The maximum tolerated dose (MTD) was not observed up to dose level 4 in patients with the 6 ⁄ 6 genotype. In contrast, MTD was observed at dose level 2 (100 mg⁄m2) in patients with the 6 ⁄ 7 genotype. Patients with the 6 ⁄ 7 genotype had a significantly higher area under the plasma time–concentration curve 0-\ SN-38 (P = 0.022) and biliary index (P = 0.030) than those with 6 ⁄ 6. The recommended starting doses of biweekly irinotecan for phase II ⁄ III were 150 mg⁄m2 for patients with the UGT1A1 6 ⁄ 6 genotype and 70 mg⁄m2 for those with the 6 ⁄ 7 genotype, respectively. The gene polymorphism should be considered when determining the precise recommended doses to be administered in phase I studies. (Cancer Sci 2010; 101: 722-727)
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Complete: follow-up complete
- Sex
- All
- Target Recruitment
- 18
Not provided
Patients were ineligible if they had any of the following conditions: serious infectious disease or other severe complications (e.g., pulmonary fibrosis/interstitial pneumonia, uncontrollable diabetes); watery diarrhea, paralytic ileus, or intestinal obstruction; massive pleural effusion or ascitic fluid; symptomatic brain metastases; active concurrent malignancies; pregnancy or lactation, or desire for pregnancy; a history of drug allergy; and prior treatment with CPT-11.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method