Intensive first-line FIr-C/FOx-C association of triplet chemotherapy plus cetuximab in wild-type metastatic colorectal cancer patients: preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers

Background: Intensive triplet chemotherapy/bevacizumab significantly increased metastatic colorectal cancer (MCRC) outcome. This phase II study investigated the safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line RAS wild-type and the prediction of individual limiting toxicity syndromes (LTS) by pharmacogenomic biomarkers. Methods: A Simon two-step design was used: p0 70%, p1 85%, power 80%, α5%, β20%; projected objective response rate (ORR) I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-timed flat infusion 900 mg/m 2 d1–2, 8–9, 15–16, 22–23; irinotecan (CPT-11) 160 mg/m 2 d1 and 15, oxaliplatin 80 mg/m 2 d8 and 22; CET 400mg/m 2 then 250 mg/m 2 d1, 8, 15, 22; every 28 days. Toxicity, and individual LTS were evaluated, compared by a Chi-square test; and activity/efficacy by log-rank. 5-FU/CPT-11 pharmacogenomic biomarkers, 5-FU degradation rate (5-FUDR), single nucleotide polymorphisms (SNPs) ABCB1, CYP3A4, DYPD , UGT1A1 were evaluated in patients with LTS and at a recommended dose. Results: A total of 29 patients 80%), grade 3–4 toxicities were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS 19 (65.5%), with 83% in yE patients. LTS prevalently multiple (ms) versus single site were 59% versus 7% ( p = 0.006). The prevalence of reduced FUDR was 56%, SNPs CYP3A4 22%, UGT1A1 71%, and of >2 positive pharmacogenomics biomarkers was 78%, prevalently reported in patients who developed gastrointestinal LTS. Conclusions: FIr-C/FOx-C is highly active and tolerable at recommended doses in non-elderly RAS wild-type MCRC patients. LTS provided an evaluation of the toxicity burden in individual patients. Reduced FUDR, CYP3A4 , and UGT1A1 SNPs may predict individual LTS-ms in patients at risk of limiting gastrointestinal toxicity. Trial registration: The trial was registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009-016793-32.