A multicenter phase II study of personalized FOLFIRI-cetuximab for safe dose intensification.

Autor:	Boisdron-Celle M; Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France. Electronic address: michele.boisdron@ico.unicancer.fr., Metges JP; CHU Morvan, Brest, France., Capitain O; Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France., Adenis A; CRLCC Oscar Lambret, Lille, France., Raoul JL; CRLCC Centre Paoli - Calmettes, Marseille, France., Lecomte T; CHU Trousseau, Tours, France., Lam YH; CH Cholet, France., Faroux R; CHD Les Oudairies, La Roche sur Yon, France., Masliah C; Clinique Mutualiste de l׳Estuaire Cité Sanitaire, Saint Nazaire, France., Poirier AL; Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France., Berger V; Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France., Morel A; Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France., Gamelin E; Oncopharmacology - Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l'Ouest site Paul Papin, Angers, France.
Jazyk:	angličtina
Zdroj:	Seminars in oncology [Semin Oncol] 2017 Feb; Vol. 44 (1), pp. 24-33. Date of Electronic Publication: 2017 Feb 09.
DOI:	10.1053/j.seminoncol.2017.02.007
Abstrakt:	We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FU ^{ODPM Tox} ) followed by PK-guided dose optimization (5-FU ^{ODPM Protocol} ). An advanced cetuximab PK/pharmacodynamics (PD) study was performed but dosage remained unchanged. Eighty-five patients receiving second-line chemotherapy were enrolled. Mean irinotecan doses at 3 months were 247 ± 50, 210 ± 53 and 140 ± 21 mg/m ² for those with 6/6 (33), 6/7 (26), and 7/7 (7) TATA repeats in the UGT1A1 promoter region, respectively. The 5-FU dose was initially reduced in four patients with DPD deficiency, but mean 5-FU dose at 3 months was 2,412 ± 364 mg/m ² (1,615-3,170 mg/m ² ). Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8%, 5.9%, and 0% of patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes. The objective response rate was 25.8% among the 85 patients, 57.3% in patients with tumors wild type (WT) for KRAS, and 25% in those whose tumor harbored a mutant-KRAS. Secondary resection of hepatic metastases was performed in 31.7% of patients. Median progression-free survival (PFS) for all 85 patients was 181 days and 200, 132, and 121 days for patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes, respectively; these differences were not statistically different. In parallel, a strong relationship was shown between cetuximab AUC and regimen efficacy. We conclude that personalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification. (Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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