A genotype-directed phase I–IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer

Abstract

Background:Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy.Patients and methods:Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m−2 for the *1/*1, 110 mg m−2 for the *1/*28 and 90 mg m−2 for the *28/*28 genotypes.Results:The dose of irinotecan was escalated to 450 mg m−2 in patients with the *1/*1 genotype, to 390 mg m−2 in those with the *1/*28 genotype and to 150 mg m−2 in those with the *28/*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities.Conclusions:Our results demonstrated that the recommended dose of 180 mg m−2 for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 *1/*1 and *1/*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 *28/*28 genotype is 30% lower than the standard dose of 180 mg m−2.

Dose-Finding and Pharmacokinetic Study to Optimize the Dosing of Irinotecan According to the UGT1A1 Genotype of Patients With Cancer

“…However, the patient populations are quite different between our study (heavily pretreated, different tumor types) and the FOLFIRI studies (first-line treatment of metastatic colorectal cancer). 19,22 Similar to this study, these studies with FOLFIRI also showed that the patients with the *1/*28 genotype tolerated a lower dose relative to the patients with the *1/*1 genotype, confirming the importance of individualized dosing by genotype. The *1/*28 genotype confers an intermediatemetabolizer phenotype 13,[23][24][25] and an intermediate risk of toxicity.…”

“…An irinotecan dose of 500 mg/m 2 has been shown to be tolerable in patients with refractory cancer who have favorable characteristics (eg, good risk, not heavily pretreated), 21 but UGT1A1*28 was not used for dose selection in that study. In other UGT1A1*28 genotypedirected studies of FOLFIRI, patients with the *1/*1 genotype tolerated approximately twice the dose recommended by the label, 19,22 probably because the therapeutic window is wider in the biweekly regimen of FOLFIRI (standard dose, 180 mg/m 2 ) than in the regimen administered once every 3 weeks (standard dose, 350 mg/m 2 ). However, the patient populations are quite different between our study (heavily pretreated, different tumor types) and the FOLFIRI studies (first-line treatment of metastatic colorectal cancer).…”

“…In the FOLFIRI regimen (irinotecan with infusional fluorouracil and leucovorin), a 30% dose reduction appears safe for patients with the *28/*28 genotype. 19 Our study, for the first time to our knowledge, provides information about the safe doses of irinotecan in the every-3-week regimen in the patients with the highest risk of severe toxicity.…”

Clinical usefulness of testing for UDP glucuronosyltransferase 1 family, polypeptide A1 polymorphism prior to the inititation of irinotecan-based chemotherapy

“…In 2005, the US Food and Drug Administration recommended testing for UGT1A1 * 28 polymorphism for dose regulation of irinotecan. As regards colorectal cancer, studies on the optimal dose of irinotecan for the treatment of patients with low enzyme activity have been conducted (19,20). However, the optimal dose of irinotecan for lung cancer patients with low enzyme activity has not been determined and remains a subject of controversy.…”

710: Clinical implication of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab combined with FOLFIRI in the first-line setting

“…However, this dose is insufficient in patients with the UGT1A1*1 allele and contributes to a poorer clinical outcome [7][8][9][10]. Conversely, 180 mg/m 2 of irinotecan in patients with homozygous UGT1A1*28 is associated with a greater number of severe adverse events (AEs) [7,11].…”