UGT1A1 genotype-guided phase I study of irinotecan, oxaliplatin, and capecitabine

Abstract

Purpose We performed a UGT1A1 genotype-guided study to determine the maximum tolerated dose (MTD) and evaluate the toxicities and pharmacokinetics of the combination of capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRIN). Experimental Design Patients were screened for UGT1A1 *28 genotype prior to treatment. The starting dose (mg/m2) was IRIN (150), OX (85) and CAP (400), days 2-15. Doses were escalated or de-escalated within each genotype group (*28/*28, *1/*28 and *1/*1). IRIN pharmacokinetics was performed at the MTD. Results 50 patients were evaluable for toxicity [11 (*28/*28); 18 (*1/*28); 21 (*1/*1)]. UGT1A1 *28/*28 patients experienced hematologic dose limiting toxicity (DLT), requiring dose-de-escalation. The UGT1A1 *28/*28 recommended phase 2 dose (RP2D) was IRIN (75), OX (85), and CAP (400). In contrast, both UGT1A1 *1/*28 and *1/*1 tolerated higher doses of IRIN and non-hematologic toxicity was dose limiting for UGT1A1 *1/*1. The RP2D was IRIN (150), OX (85), and CAP (400) for UGT1A1*1/*28 and IRIN (150), OX (100), and CAP (1600) for UGT1A1 *1/*1. UGT1A1 *1/*28 and *1/*1 patients treated with IRIN (150) had similar AUCs for the active irinotecan metabolite, SN38 (366 +/− 278 and 350 +/− 159 ng/ml*hr, respectively). UGT1A1 *28/*28 patients (n=3) treated with a lower IRIN dose (100) had non-significantly higher mean SN38 exposures (604 +/− 289 ng/ml*hr, p=0.14). Antitumor activity was observed in all genotype groups. Conclusions UGT1A1 genotype affects the dose and pharmacokinetics of the CAPIRINOX regimen and UGT1A1 genotype-guided dosing of CAPIRINOX is ongoing in a phase II study of small bowel cancer (NCT00433550).

North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic‐based dosing of irinotecan, oxaliplatin, and capecitabine as first‐line therapy for patients with advanced small bowel adenocarcinoma

“…17,19 A phase 1 trial with genotype-dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX) was performed at the Mayo Clinic using UGT1A1 genotyping performed prospectively in parallel cohorts to determine the appropriate dose for the 3 common genotypes, with the identification of higher tolerable doses in patients with the 6/6 genotype compared with patients with the 6/7 and 7/7 genotypes with comparable total SN-38 exposure. 20 Using the doses identified in that study for each genotype (6/6, 6/7, and 7/7), the North Central Cancer Treatment Group (NCCTG) performed a pharmacogenetic-based phase 2 study (N0543) in patients with advanced SBA. The NCCTG is now a part of the Alliance for Clinical Trials in Oncology.…”

Different schedules of irinotecan administration: A meta-analysis

“…Several trials and a meta-analysis demonstrated that the UGT1A1 * 28/ * 28 genotype is associated with an increased risk of neutropenia and diarrhea, and that this association was dose-dependent (5,22). Genotype-directed dosing has been investigated by a series of studies (6)(7)(8); however, its integration into the clinical practice remains scant and this drug is still dosed by body surface area according to almost all guidelines. Furthermore, SN-38 accounts for only 14% of the total interindividual variability in the absolute neutrophil count nadir (9), suggesting that additional factors may lead to neutropenia.…”

“…Genotype UGT1A1 * 28 has been found to be associated with decreased SN-38 glucuronidation; thus, irinotecan-induced diarrhea and neutropenia may be increased in patients with the UGT1A1 * 28/ * 28 genotype (5). While several UGT1A1 genotype-directed administration schedules of irinotecan are currently under evaluation (6)(7)(8), the concept of heritable biological marker-guided dosing is new and requires further evaluation prior to introduction in clinical practice (9).…”

The evolving management of small bowel adenocarcinoma

“…It appears that a common polymorphism in the number of TA repeats (7 vs. 6) of the uridine diphosphate glucuronosyltransferase enzyme 1A1 (UGT1A1) is responsible for decreased inactivation of irinotecan's active metabolite SN-38 and hence increased hematological toxicity [67,68]. UGT1A1 genotype-guided drug dosage, i.e., standard irinotecan dosage for 6/6 UGT1A1 genotype and lower irinotecan dosage for heterozygous 6/7 UGT1A1 genotype and homozygous 7/7 UGT1A1 genotype may result in overall decreased systemic toxicity, while the exposure to SN-38 remains similar in all genotype groups [69,70]. In a most recent study [71], doses of capecitabine, irinotecan and oxaliplatin (CAPIRINOX) were administered according to the UGT1A1 genotype in 33 patients with advanced SBA.…”