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- Title
A UGT1A1 genotype‐guided dosing study of modified FOLFIRINOX in previously untreated patients with advanced gastrointestinal malignancies.
- Authors
Sharma, Manish R.; Joshi, Smita S.; Karrison, Theodore G.; Allen, Kenisha; Suh, Grace; Marsh, Robert; Kozloff, Mark F.; Polite, Blase N.; Catenacci, Daniel V. T.; Kindler, Hedy L.
- Abstract
Background: FOLFIRINOX (5‐fluorouracil [5‐FU], leucovorin, irinotecan, oxaliplatin) is an effective but toxic therapy for pancreatic cancer. UGT1A1 (UDP glucuronosyltransferase 1A1) eliminates the active metabolite of irinotecan. Polymorphisms reduce UGT1A1 activity, leading to toxicity. The primary objective was to determine the dose‐limiting toxicity (DLT) rate in cycle 1 of modified FOLFIRINOX (mFOLFIRINOX) using genotype‐guided dosing of irinotecan for the most common UGT1A1 genotypes (*1/*1, *1/*28) in advanced gastrointestinal malignancies, with expansion in pancreatic and biliary tract cancers. Method: 5‐FU (2400 mg/m2 over 46 hours), leucovorin (400 mg/m2), oxaliplatin (85 mg/m2), and irinotecan were given every 14 days. Irinotecan doses of 180, 135, and 90 mg/m2 were administered for UGT1A1 genotypes *1/*1, *1/*28, and *28/*28, respectively. Prophylactic pegfilgrastim was omitted in cycle 1 for cohort 1 (tolerability by genotype), but was given in cohort 2 (tolerability by tumor type). Doses were tolerable if the upper limit of a 2‐sided 80% confidence interval for DLT rate was ≤33%. Results: In cohort 1, DLTs (most commonly febrile neutropenia, fatigue, diarrhea) occurred in 2/15 (13%), 3/16 (19%), and 4/10 (40%) patients with *1/*1, *1/*28, and *28/*28 genotypes, respectively. In cohort 2, 6/19 (32%) pancreatic and 4/19 (21%) biliary tract cancer patients experienced DLTs (most commonly fatigue, diarrhea, nausea/vomiting). In cohort 2, upper confidence limits of DLT rates exceeded 33%. Response rates were 38% in pancreatic and 21% in biliary tract cancers. Conclusion: On the basis of our prespecified criteria, tolerability of UGT1A1 genotype‐guided mFOLFIRINOX was not established in pancreatic and biliary tract cancers. However, this regimen was effective. Modified FOLFIRINOX with UGT1A1 genotype‐guided dosing of irinotecan is not tolerable in advanced pancreatic or biliary tract cancer. However, this regimen is effective.
- Subjects
GALLBLADDER cancer; BILIARY tract; CONFIDENCE intervals; FEBRILE neutropenia; PANCREATIC cancer; CANCER treatment
- Publication
Cancer (0008543X), 2019, Vol 125, Issue 10, p1629
- ISSN
0008-543X
- Publication type
Article
- DOI
10.1002/cncr.31938