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 syndr...
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doaj-22f2f413aa674d4985f539b6f7f03b0d2020-11-25T03:03:22ZengSAGE PublishingTherapeutic Advances in Medical Oncology1758-83592019-05-011110.1177/1758835919846421Intensive 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 biomarkersGemma BrueraSilvia MassaceseFrancesco PepeUmberto MalapelleAntonella Dal MasEugenio CiaccoGiuseppe CalvisiGiancarlo TronconeMaurizio SimmacoEnrico RicevutoBackground: 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 <75 years, with a primary/intermediate Cumulative Index Rating Scale were enrolled; the median age was 59 years; there were 7 young-elderly (yE; 24%). Recommended CPT-11/5-FU doses were 120/750 mg/m 2 . In the intent-to-treat analysis, the ORR was 58.6%. The primary endpoint was met in patients who received the planned three treatment cycles: the objective response (OR) was 14/18 (78%). At a median follow up of 18 months, progression-free survival (PFS) was 12, and overall survival (OS) was 23 months. At the recommended doses (received dose intensity >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.https://doi.org/10.1177/1758835919846421 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gemma Bruera Silvia Massacese Francesco Pepe Umberto Malapelle Antonella Dal Mas Eugenio Ciacco Giuseppe Calvisi Giancarlo Troncone Maurizio Simmaco Enrico Ricevuto |
spellingShingle |
Gemma Bruera Silvia Massacese Francesco Pepe Umberto Malapelle Antonella Dal Mas Eugenio Ciacco Giuseppe Calvisi Giancarlo Troncone Maurizio Simmaco Enrico Ricevuto 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 Therapeutic Advances in Medical Oncology |
author_facet |
Gemma Bruera Silvia Massacese Francesco Pepe Umberto Malapelle Antonella Dal Mas Eugenio Ciacco Giuseppe Calvisi Giancarlo Troncone Maurizio Simmaco Enrico Ricevuto |
author_sort |
Gemma Bruera |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publisher |
SAGE Publishing |
series |
Therapeutic Advances in Medical Oncology |
issn |
1758-8359 |
publishDate |
2019-05-01 |
description |
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 <75 years, with a primary/intermediate Cumulative Index Rating Scale were enrolled; the median age was 59 years; there were 7 young-elderly (yE; 24%). Recommended CPT-11/5-FU doses were 120/750 mg/m 2 . In the intent-to-treat analysis, the ORR was 58.6%. The primary endpoint was met in patients who received the planned three treatment cycles: the objective response (OR) was 14/18 (78%). At a median follow up of 18 months, progression-free survival (PFS) was 12, and overall survival (OS) was 23 months. At the recommended doses (received dose intensity >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. |
url |
https://doi.org/10.1177/1758835919846421 |
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