PMID- 26272806
OWN - NLM
STAT- MEDLINE
DCOM- 20160707
LR  - 20200206
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Linking)
VI  - 26
IP  - 10
DP  - 2015 Oct
TI  - A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus 
      bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients.
PG  - 2085-91
LID - 10.1093/annonc/mdv286 [doi]
AB  - BACKGROUND: This randomised, open-label, phase I/II study evaluated the efficacy 
      and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with 
      chemotherapy, relative to bevacizumab plus chemotherapy as first-line therapy in 
      patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients 
      with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative 
      Oncology Group performance status </= 2 and adequate organ function were included. 
      Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.i.d. plus 
      mFOLFOX6 (oxaliplatin 85 mg/m(2), l-leucovorin 200 mg/m(2) or d,l-leucovorin 400 
      mg/m(2), 5-fluoruracil bolus 400 mg/m(2) followed by 2400 mg/m(2), every 2 weeks) 
      or bevacizumab (5 mg/kg every 2 weeks) plus mFOLFOX6. During phase I, patients 
      underwent a 3 + 3 dose-escalation schema to determine the maximum tolerated dose 
      (MTD) of nintedanib in combination with mFOLFOX6. The primary end point was 
      progression-free survival (PFS) rate at 9 months. Objective response (OR) was a 
      secondary end point. RESULTS: The nintedanib recommended phase II dose was 200 mg 
      b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients 
      randomised in the phase II part, 126 received treatment (nintedanib plus 
      mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% 
      with nintedanib and 70.2% with bevacizumab [difference: -8.1% (95% confidence 
      interval -27.8 to 11.5)]. Confirmed ORs were recorded in 63.5% and 56.1% of 
      patients in the nintedanib and bevacizumab groups, respectively. The incidence of 
      adverse events (AEs) considered related to treatment was 98.8% with nintedanib 
      and 97.6% with bevacizumab; the incidence of serious AEs was 37.6% with 
      nintedanib and 53.7% with bevacizumab. The pharmacokinetics of nintedanib and the 
      components of mFOLFOX6 were unaffected by their combination. CONCLUSIONS: 
      Nintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in 
      patients with mCRC with a manageable safety profile and further studies in this 
      population are warranted.
CI  - (c) The Author 2015. Published by Oxford University Press on behalf of the European 
      Society for Medical Oncology. All rights reserved. For permissions, please email: 
      journals.permissions@oup.com.
FAU - Van Cutsem, E
AU  - Van Cutsem E
AD  - Digestive Oncology, University Hospitals Leuven and KULeuven, Leuven, Belgium 
      eric.vancutsem@uzleuven.be.
FAU - Prenen, H
AU  - Prenen H
AD  - Digestive Oncology, University Hospitals Leuven and KULeuven, Leuven, Belgium.
FAU - D'Haens, G
AU  - D'Haens G
AD  - Department of Gastroenterology and Hepatology, Academic Medical Centre, 
      Amsterdam, The Netherlands Imelda GI Clinical Research Centre, Bonheiden, 
      Belgium.
FAU - Bennouna, J
AU  - Bennouna J
AD  - Department of Medical Oncology, Centre Rene Gauducheau, Nantes, France.
FAU - Carrato, A
AU  - Carrato A
AD  - Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain.
FAU - Ducreux, M
AU  - Ducreux M
AD  - Gustave-Roussy Cancer Campus, Institut Gustave Roussy, Paris University of 
      Paris-Sud, Le Kremlin Bicetre, Paris.
FAU - Bouche, O
AU  - Bouche O
AD  - Department of Digestive Oncology, CHU Reims, Reims, France.
FAU - Sobrero, A
AU  - Sobrero A
AD  - Department of Medical Oncology, San Martino Hospital, Genoa.
FAU - Latini, L
AU  - Latini L
AD  - Oncology Unit, Macerata Hospital, Macerata, Italy.
FAU - Staines, H
AU  - Staines H
AD  - Medical and Drug Regulatory Affairs, Boehringer Ingelheim France S.A.S., Reims, 
      France.
FAU - Oum'Hamed, Z
AU  - Oum'Hamed Z
AD  - Medical and Drug Regulatory Affairs, Boehringer Ingelheim France S.A.S., Reims, 
      France.
FAU - Dressler, H
AU  - Dressler H
AD  - Global Pharmacovigilance, Boehringer Ingelheim, Ingelheim, Germany.
FAU - Studeny, M
AU  - Studeny M
AD  - Division of Medicine/Department of Clinical Development, Boehringer Ingelheim, 
      Vienna, Austria.
FAU - Capdevila, J
AU  - Capdevila J
AD  - Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), 
      Barcelona, Spain.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20150812
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (Indoles)
RN  - 0 (Organoplatinum Compounds)
RN  - 04ZR38536J (Oxaliplatin)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - G6HRD2P839 (nintedanib)
RN  - Q573I9DVLP (Leucovorin)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Adenocarcinoma/*drug therapy/mortality/secondary
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Bevacizumab/administration & dosage
MH  - Colorectal Neoplasms/*drug therapy/mortality/pathology
MH  - Female
MH  - Fluorouracil/administration & dosage
MH  - Follow-Up Studies
MH  - Humans
MH  - Indoles/administration & dosage
MH  - Leucovorin/administration & dosage
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Metastasis
MH  - Neoplasm Staging
MH  - Organoplatinum Compounds/administration & dosage
MH  - Oxaliplatin
MH  - Prognosis
MH  - Survival Rate
OTO - NOTNLM
OT  - CRC
OT  - FOLFOX
OT  - VEGF
OT  - angiogenesis
OT  - nintedanib
EDAT- 2015/08/15 06:00
MHDA- 2016/07/09 06:00
CRDT- 2015/08/15 06:00
PHST- 2015/02/16 00:00 [received]
PHST- 2015/06/27 00:00 [accepted]
PHST- 2015/08/15 06:00 [entrez]
PHST- 2015/08/15 06:00 [pubmed]
PHST- 2016/07/09 06:00 [medline]
AID - S0923-7534(19)35784-9 [pii]
AID - 10.1093/annonc/mdv286 [doi]
PST - ppublish
SO  - Ann Oncol. 2015 Oct;26(10):2085-91. doi: 10.1093/annonc/mdv286. Epub 2015 Aug 12.