Phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in patients with metastatic colorectal cancer.
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Colorectal Neoplasms
/ drug therapy
Drug Combinations
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Oxaliplatin
/ administration & dosage
Pyrrolidines
/ administration & dosage
Thymine
/ administration & dosage
Trifluridine
/ administration & dosage
Uracil
/ administration & dosage
Fluoropyrimidines
Metastatic colorectal cancer
Oxaliplatin
Trifluridine/tipiracil
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
05
12
2018
revised:
18
01
2019
accepted:
25
01
2019
pubmed:
20
3
2019
medline:
20
5
2020
entrez:
20
3
2019
Statut:
ppublish
Résumé
Pre-clinical data have shown that combining trifluridine/tipiracil with oxaliplatin enhances anti-tumour activity compared with either monotherapy. A phase I dose-escalation study was conducted to determine the maximum tolerated dose (MTD), recommended dose (RD) for phase II and pharmacokinetic profile of this combination in patients with metastatic colorectal cancer (mCRC) who had progressed after at least 1 prior line of treatment. Using a 3 + 3 design, patients received escalating trifluridine/tipiracil doses from 25, then 30 and to 35 mg/m Twenty-four patients were enrolled. One dose-limiting toxicity of grade 3 febrile neutropenia was observed at the highest dose level, which was established as the MTD and subsequently the RD. The most common drug-related adverse events (AEs) were asthenia, nausea, diarrhoea, peripheral neuropathy, neutropenia, decreased appetite, thrombocytopenia, vomiting, anaemia and peripheral sensory neuropathy. Most drug-related AEs (93.0%) were of grade 1-2. Pharmacokinetic parameters of trifluridine/tipiracil were not influenced by oxaliplatin co-administration. Best overall responses at the RD (n = 14) included 1 patient with partial response (7.1%) and 7 patients with stable disease (50.0%). The combination of trifluridine/tipiracil and oxaliplatin in patients with mCRC has a manageable safety profile with some efficacy. The RD is 35 mg/m NCT02848443.
Sections du résumé
BACKGROUND AND OBJECTIVES
Pre-clinical data have shown that combining trifluridine/tipiracil with oxaliplatin enhances anti-tumour activity compared with either monotherapy. A phase I dose-escalation study was conducted to determine the maximum tolerated dose (MTD), recommended dose (RD) for phase II and pharmacokinetic profile of this combination in patients with metastatic colorectal cancer (mCRC) who had progressed after at least 1 prior line of treatment.
METHODS
Using a 3 + 3 design, patients received escalating trifluridine/tipiracil doses from 25, then 30 and to 35 mg/m
RESULTS
Twenty-four patients were enrolled. One dose-limiting toxicity of grade 3 febrile neutropenia was observed at the highest dose level, which was established as the MTD and subsequently the RD. The most common drug-related adverse events (AEs) were asthenia, nausea, diarrhoea, peripheral neuropathy, neutropenia, decreased appetite, thrombocytopenia, vomiting, anaemia and peripheral sensory neuropathy. Most drug-related AEs (93.0%) were of grade 1-2. Pharmacokinetic parameters of trifluridine/tipiracil were not influenced by oxaliplatin co-administration. Best overall responses at the RD (n = 14) included 1 patient with partial response (7.1%) and 7 patients with stable disease (50.0%).
CONCLUSION
The combination of trifluridine/tipiracil and oxaliplatin in patients with mCRC has a manageable safety profile with some efficacy. The RD is 35 mg/m
GOV NUMBER
NCT02848443.
Identifiants
pubmed: 30889492
pii: S0959-8049(19)30138-8
doi: 10.1016/j.ejca.2019.01.101
pii:
doi:
Substances chimiques
Drug Combinations
0
Pyrrolidines
0
trifluridine tipiracil drug combination
0
Oxaliplatin
04ZR38536J
Uracil
56HH86ZVCT
tipiracil
NGO10K751P
Thymine
QR26YLT7LT
Trifluridine
RMW9V5RW38
Banques de données
ClinicalTrials.gov
['NCT02848443']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12-19Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.