PMID- 21898375
OWN - NLM
STAT- MEDLINE
DCOM- 20120507
LR  - 20220409
IS  - 1097-0142 (Electronic)
IS  - 0008-543X (Print)
IS  - 0008-543X (Linking)
VI  - 118
IP  - 7
DP  - 2012 Apr 1
TI  - Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell 
      carcinoma.
PG  - 1868-76
LID - 10.1002/cncr.26429 [doi]
AB  - BACKGROUND: Simultaneous inhibition of the vascular epithelial growth factor 
      (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment 
      response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR 
      inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are 
      standard agents in the management of metastatic RCC. METHODS: Sequential cohorts 
      of 3 to 6 patients with advanced RCC received dose-escalated combinations of 
      sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg 
      daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the 
      first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic 
      profiles were obtained. RESULTS: Twenty patients (13 clear cell and 7 nonclear 
      cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when 
      combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. 
      With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, 
      plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic 
      treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg 
      everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five 
      patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No 
      unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was 
      observed. CONCLUSIONS: The combination of everolimus and sunitinib is associated 
      with significant acute and chronic toxicities and is only tolerated at attenuated 
      doses. Responses were observed in nonclear cell and clear cell RCC.
CI  - Copyright (c) 2011 American Cancer Society.
FAU - Molina, Ana M
AU  - Molina AM
AD  - Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. 
      molinaa@mskcc.org
FAU - Feldman, Darren R
AU  - Feldman DR
FAU - Voss, Martin H
AU  - Voss MH
FAU - Ginsberg, Michelle S
AU  - Ginsberg MS
FAU - Baum, Michael S
AU  - Baum MS
FAU - Brocks, Dion R
AU  - Brocks DR
FAU - Fischer, Patricia M
AU  - Fischer PM
FAU - Trinos, Michael J
AU  - Trinos MJ
FAU - Patil, Sujata
AU  - Patil S
FAU - Motzer, Robert J
AU  - Motzer RJ
LA  - eng
GR  - R25 CA020449/CA/NCI NIH HHS/United States
GR  - T32 CA009207/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110906
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 0 (Indoles)
RN  - 0 (Pyrroles)
RN  - 9HW64Q8G6G (Everolimus)
RN  - V99T50803M (Sunitinib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Cancer. 2012 Apr 1;118(7):1744-6. PMID: 21898374
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
MH  - Carcinoma, Renal Cell/*drug therapy/secondary
MH  - Everolimus
MH  - Female
MH  - Humans
MH  - Indoles/*administration & dosage/pharmacokinetics
MH  - Kidney Neoplasms/*drug therapy/pathology
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Pyrroles/*administration & dosage/pharmacokinetics
MH  - Sirolimus/administration & dosage/*analogs & derivatives/pharmacokinetics
MH  - Sunitinib
PMC - PMC3609026
MID - NIHMS436893
EDAT- 2011/09/08 06:00
MHDA- 2012/05/09 06:00
PMCR- 2013/03/27
CRDT- 2011/09/08 06:00
PHST- 2011/03/31 00:00 [received]
PHST- 2011/05/16 00:00 [revised]
PHST- 2011/05/20 00:00 [accepted]
PHST- 2011/09/08 06:00 [entrez]
PHST- 2011/09/08 06:00 [pubmed]
PHST- 2012/05/09 06:00 [medline]
PHST- 2013/03/27 00:00 [pmc-release]
AID - 10.1002/cncr.26429 [doi]
PST - ppublish
SO  - Cancer. 2012 Apr 1;118(7):1868-76. doi: 10.1002/cncr.26429. Epub 2011 Sep 6.