PMID- 30889492 OWN - NLM STAT- MEDLINE DCOM- 20200519 LR - 20201210 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 112 DP - 2019 May TI - Phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in patients with metastatic colorectal cancer. PG - 12-19 LID - S0959-8049(19)30138-8 [pii] LID - 10.1016/j.ejca.2019.01.101 [doi] AB - 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(2) twice daily, days 1-5, q14 days, together with a fixed dose of 85 mg/m(2) of oxaliplatin day 1, q14 days. An intermediate cohort with a lower oxaliplatin dose (65 mg/m(2)) was also investigated. After MTD determination, additional patients were treated to define the RD. 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(2) of trifluridine/tipiracil twice daily, days 1-5, q14 days and 85 mg/m(2) of oxaliplatin day 1, q14 CLINICALTRIALS. GOV NUMBER: NCT02848443. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Argiles, Guillem AU - Argiles G AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Spain. Electronic address: gargiles@vhio.net. FAU - Andre, Thierry AU - Andre T AD - Sorbonne Universite et Hopital Saint-Antoine, Service d'Oncologie Medicale, 184, rue du Faubourg-Saint-Antoine, Paris, France. FAU - Hollebecque, Antoine AU - Hollebecque A AD - Drug Development Department (DITEP: Departement d'Innovations Therapeutiques et Essais Precoces), Gustave Roussy Cancer Campus, Villejuif, France. FAU - Calvo, Aitana AU - Calvo A AD - Gregorio Maranon University General Hospital, Madrid, Spain. FAU - Dahan, Laetitia AU - Dahan L AD - Aix Marseille University; Assistance Publique Hopitaux de Marseille, Centre d'Essais Precoces en Cancerologie de Marseille CLIP(2), Marseille, France. FAU - Cervantes, Andres AU - Cervantes A AD - CIBERONC, Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain. FAU - Leger, Catherine AU - Leger C AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Amellal, Nadia AU - Amellal N AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Fougeray, Ronan AU - Fougeray R AD - Institut de Recherches Internationales Servier, Suresnes, France. FAU - Tabernero, Josep AU - Tabernero J AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Spain. LA - eng SI - ClinicalTrials.gov/NCT02848443 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190316 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (Drug Combinations) RN - 0 (Pyrrolidines) RN - 0 (trifluridine tipiracil drug combination) RN - 04ZR38536J (Oxaliplatin) RN - 56HH86ZVCT (Uracil) RN - NGO10K751P (tipiracil) RN - QR26YLT7LT (Thymine) RN - RMW9V5RW38 (Trifluridine) SB - IM MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects MH - Colorectal Neoplasms/*drug therapy MH - Drug Combinations MH - Female MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Oxaliplatin/*administration & dosage/adverse effects MH - Pyrrolidines/*administration & dosage/adverse effects MH - Thymine/*administration & dosage/adverse effects MH - Trifluridine/*administration & dosage/adverse effects MH - Uracil/administration & dosage/adverse effects/*analogs & derivatives OTO - NOTNLM OT - Fluoropyrimidines OT - Metastatic colorectal cancer OT - Oxaliplatin OT - Trifluridine/tipiracil EDAT- 2019/03/20 06:00 MHDA- 2020/05/20 06:00 CRDT- 2019/03/20 06:00 PHST- 2018/12/05 00:00 [received] PHST- 2019/01/18 00:00 [revised] PHST- 2019/01/25 00:00 [accepted] PHST- 2019/03/20 06:00 [pubmed] PHST- 2020/05/20 06:00 [medline] PHST- 2019/03/20 06:00 [entrez] AID - S0959-8049(19)30138-8 [pii] AID - 10.1016/j.ejca.2019.01.101 [doi] PST - ppublish SO - Eur J Cancer. 2019 May;112:12-19. doi: 10.1016/j.ejca.2019.01.101. Epub 2019 Mar 16.