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

Autor: Michèle Boisdron-Celle, Claude Masliah, Antoine Adenis, Jean Philippe Metges, Olivier Capitain, Virginie Berger, You Heng Lam, Jean-Luc Raoul, Erick Gamelin, Roger Faroux, Anne Lise Poirier, Thierry Lecomte, Alain Morel
Přispěvatelé: Laboratoire d'Oncopharmacologie (Département de Pharmacogénétique), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, CRLCC Centre Paoli - Calmettes [Marseille], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier de Cholet, CHD Vendée - Hôpital Les Oudairies [La Roche sur Yon], Clinique Mutualiste de l'Estuaire Cité Sanitaire [Saint Nazaire], Bernardo, Elizabeth, Université de Lille-UNICANCER, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée)
Rok vydání: 2017
Předmět:
Zdroj: Seminars in Oncology
Seminars in Oncology, WB Saunders, 2017, 44 (1), pp.24-33. ⟨10.1053/j.seminoncol.2017.02.007⟩
Seminars in Oncology, 2017, 44 (1), pp.24-33. ⟨10.1053/j.seminoncol.2017.02.007⟩
ISSN: 1532-8708
0093-7754
DOI: 10.1053/j.seminoncol.2017.02.007⟩
Popis: International audience; 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/m2 (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.
Databáze: OpenAIRE
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