PMID- 21177764
OWN - NLM
STAT- MEDLINE
DCOM- 20110815
LR  - 20211203
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 17
IP  - 4
DP  - 2011 Feb 15
TI  - Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and 
      figitumumab in patients with advanced sarcomas and other solid tumors.
PG  - 871-9
LID - 10.1158/1078-0432.CCR-10-2621 [doi]
AB  - PURPOSE: Preclinical models demonstrate synergistic antitumor activity with 
      combination blockade of mTOR and IGF-1R signaling. We aimed to determine the 
      safety, tolerability, and recommended phase II dose (RP2D) of the combination of 
      figitumumab, a fully human IgG(2) anti-insulin-like growth factor-1 receptor 
      (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus 
      (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination 
      were evaluated. EXPERIMENTAL DESIGN: Phase I trial in patients with advanced 
      sarcomas and other solid tumors. Initial cohort combined full phase 2 dose 
      figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally 
      once daily). Intercohort dose de-escalation was planned for unacceptable 
      toxicities. Dose modifications were allowed beyond cycle 1. RESULTS: No DLTs were 
      observed in the initial cohort during cycle one, therefore full dose figitumumab 
      and everolimus was declared the RP2D. In total, 21 patients were enrolled on 
      study. Most toxicities were grade 1 or 2, and were similar to reported toxicities 
      of the single agents. Mucositis was the most frequently observed grade 3 
      toxicity. Median time on study was 104 days (range 17-300). Of 18 patients 
      evaluable for response, best response was partial response in 1 patient with 
      malignant solitary fibrous tumor and, stable disease in 15 patients. There were 
      no apparent pharmacokinetic interactions between everolimus and figitumumab. 
      CONCLUSIONS: Combination figitumumab plus everolimus at full doses appears safe 
      and well tolerated with no unexpected toxicities. Dose reductions in everolimus 
      may be required after prolonged drug administration. This regimen exhibits 
      interesting antitumor activity warranting further investigation.
CI  - (c)2010 AACR.
FAU - Quek, Richard
AU  - Quek R
AD  - Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02115, USA,
FAU - Wang, Qian
AU  - Wang Q
FAU - Morgan, Jeffrey A
AU  - Morgan JA
FAU - Shapiro, Geoffrey I
AU  - Shapiro GI
FAU - Butrynski, James E
AU  - Butrynski JE
FAU - Ramaiya, Nikhil
AU  - Ramaiya N
FAU - Huftalen, Tarsha
AU  - Huftalen T
FAU - Jederlinic, Nicole
AU  - Jederlinic N
FAU - Manola, Judith
AU  - Manola J
FAU - Wagner, Andrew J
AU  - Wagner AJ
FAU - Demetri, George D
AU  - Demetri GD
FAU - George, Suzanne
AU  - George S
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101222
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Immunoglobulins, Intravenous)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - VE267FC2UB (figitumumab)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Everolimus
MH  - Female
MH  - Humans
MH  - Immunoglobulins, Intravenous
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/pathology
MH  - Receptor, IGF Type 1/*antagonists & inhibitors
MH  - Sarcoma/*drug therapy/pathology
MH  - Sirolimus/administration & dosage/analogs & derivatives
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Treatment Outcome
MH  - Tumor Burden/drug effects
MH  - Young Adult
EDAT- 2010/12/24 06:00
MHDA- 2011/08/16 06:00
CRDT- 2010/12/24 06:00
PHST- 2010/12/24 06:00 [entrez]
PHST- 2010/12/24 06:00 [pubmed]
PHST- 2011/08/16 06:00 [medline]
AID - 1078-0432.CCR-10-2621 [pii]
AID - 10.1158/1078-0432.CCR-10-2621 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2011 Feb 15;17(4):871-9. doi: 10.1158/1078-0432.CCR-10-2621. 
      Epub 2010 Dec 22.