PMID- 28886476
OWN - NLM
STAT- MEDLINE
DCOM- 20171023
LR  - 20181202
IS  - 1879-0852 (Electronic)
IS  - 0959-8049 (Linking)
VI  - 85
DP  - 2017 Nov
TI  - Phase I study of axitinib and everolimus in metastatic solid tumours and 
      extension to metastatic renal cell carcinoma: Results of EVAX study.
PG  - 39-48
LID - S0959-8049(17)31151-6 [pii]
LID - 10.1016/j.ejca.2017.07.031 [doi]
AB  - PURPOSE: Anti-angiogenic and mammalian target of rapamycin inhibitors have shown 
      efficacy in solid tumours. Reported combination of both drugs was deemed to be 
      too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase 
      I study combining everolimus (EV) and AX for solid tumours was explored. 
      EXPERIMENTAL DESIGN: Patients (pts) with advanced cancers were enrolled in an 
      escalation phase I study to investigate the safety of the combination. 
      Pharmacokinetic profile and functional vascular imaging were performed. An 
      extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored. 
      RESULTS: 15 pts were included over three different dose levels (DLs); DL 0: AX 
      3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and 
      DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was 
      reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. 
      Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, 
      recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was 
      level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, 
      diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial 
      responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st 
      line MRCC in the escalating phase. In the extension phase in naive MRCC treated 
      at MTD, five pts had a PR and one pt had a prolonged stable disease. CONCLUSION: 
      The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Ravaud, Alain
AU  - Ravaud A
AD  - Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France; 
      Clinical Investigational Center, CIC, INSERM CIC 1401, Bordeaux University 
      Hospital, Bordeaux, France; Bordeaux University, Bordeaux, France. Electronic 
      address: alain.ravaud@chu-bordeaux.fr.
FAU - Gomez-Roca, Carlos
AU  - Gomez-Roca C
AD  - Department of Medical Oncology, Cancer University Institute of Toulouse Oncopole, 
      Toulouse, France.
FAU - Picat, Marie-Quitterie
AU  - Picat MQ
AD  - Methodology Research Unit, Bordeaux University Hospital, Bordeaux, France.
FAU - Digue, Laurence
AU  - Digue L
AD  - Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France; 
      Clinical Investigational Center, CIC, INSERM CIC 1401, Bordeaux University 
      Hospital, Bordeaux, France.
FAU - Chevreau, Christine
AU  - Chevreau C
AD  - Department of Medical Oncology, Cancer University Institute of Toulouse Oncopole, 
      Toulouse, France.
FAU - Gimbert, Anne
AU  - Gimbert A
AD  - Pharmacovigilance Unit, Bordeaux University Hospital, Bordeaux, France.
FAU - Chauzit, Emmanuelle
AU  - Chauzit E
AD  - Clinical Pharmacology Unit, Bordeaux University Hospital, Bordeaux, France.
FAU - Sitta, Remi
AU  - Sitta R
AD  - Methodology Research Unit, Bordeaux University Hospital, Bordeaux, France.
FAU - Cornelis, Francois
AU  - Cornelis F
AD  - Department of Radiology, Bordeaux University Hospital, Bordeaux, France.
FAU - Asselineau, Julien
AU  - Asselineau J
AD  - Methodology Research Unit, Bordeaux University Hospital, Bordeaux, France.
FAU - Aziza, Richard
AU  - Aziza R
AD  - Department of Radiology, Cancer University Institute of Toulouse Oncopole, 
      Toulouse, France.
FAU - Daste, Amaury
AU  - Daste A
AD  - Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France; 
      Bordeaux University, Bordeaux, France.
FAU - Quemener, Cathy
AU  - Quemener C
AD  - INSERM U1029, Bordeaux, France.
FAU - Baud, Jessica
AU  - Baud J
AD  - INSERM U1029, Bordeaux, France.
FAU - Bikfalvi, Andreas
AU  - Bikfalvi A
AD  - INSERM U1029, Bordeaux, France.
FAU - Pedenon-Perichout, Delphine
AU  - Pedenon-Perichout D
AD  - Department of Medical Oncology, Bordeaux University Hospital, Bordeaux, France; 
      Bordeaux University, Bordeaux, France.
FAU - Doussau, Adelaide
AU  - Doussau A
AD  - Methodology Research Unit, Bordeaux University Hospital, Bordeaux, France.
FAU - Molimard, Mathieu
AU  - Molimard M
AD  - Clinical Pharmacology Unit, Bordeaux University Hospital, Bordeaux, France.
FAU - Delord, Jean-Pierre
AU  - Delord JP
AD  - Department of Medical Oncology, Cancer University Institute of Toulouse Oncopole, 
      Toulouse, France.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
DEP - 20170905
PL  - England
TA  - Eur J Cancer
JT  - European journal of cancer (Oxford, England : 1990)
JID - 9005373
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Indazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 9HW64Q8G6G (Everolimus)
RN  - C9LVQ0YUXG (Axitinib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Angiogenesis Inhibitors/*administration & dosage/adverse effects/pharmacokinetics
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Axitinib
MH  - Carcinoma, Renal Cell/diagnostic imaging/*drug therapy/secondary
MH  - Diffusion Magnetic Resonance Imaging
MH  - Drug Dosage Calculations
MH  - Everolimus/*administration & dosage/adverse effects/pharmacokinetics
MH  - Female
MH  - France
MH  - Humans
MH  - Imidazoles/*administration & dosage/adverse effects/pharmacokinetics
MH  - Indazoles/*administration & dosage/adverse effects/pharmacokinetics
MH  - Kidney Neoplasms/diagnostic imaging/*drug therapy/pathology
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Protein Kinase Inhibitors/*administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Time Factors
MH  - Treatment Outcome
OTO - NOTNLM
OT  - Axitinib
OT  - Everolimus
OT  - Phase I
OT  - Renal cell carcinoma
OT  - Solid tumours
EDAT- 2017/09/09 06:00
MHDA- 2017/10/24 06:00
CRDT- 2017/09/09 06:00
PHST- 2017/05/15 00:00 [received]
PHST- 2017/07/19 00:00 [accepted]
PHST- 2017/09/09 06:00 [pubmed]
PHST- 2017/10/24 06:00 [medline]
PHST- 2017/09/09 06:00 [entrez]
AID - S0959-8049(17)31151-6 [pii]
AID - 10.1016/j.ejca.2017.07.031 [doi]
PST - ppublish
SO  - Eur J Cancer. 2017 Nov;85:39-48. doi: 10.1016/j.ejca.2017.07.031. Epub 2017 Sep 
      5.