PMID- 23382028
OWN - NLM
STAT- MEDLINE
DCOM- 20130812
LR  - 20220402
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 133
IP  - 4
DP  - 2013 Aug 15
TI  - A dose-finding study of temsirolimus and liposomal doxorubicin for patients with 
      recurrent and refractory bone and soft tissue sarcoma.
PG  - 997-1005
LID - 10.1002/ijc.28083 [doi]
AB  - There are few effective therapies for high-risk sarcomas. Initial 
      chemosensitivity is often followed by relapse. In vitro, mammalian target of 
      rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant 
      sarcoma cells. Although sarcoma trials using mTOR inhibitors have been 
      disappointing, these drugs were used as maintenance. We conducted a Phase I/II 
      clinical trial to test the ability of temsirolimus to potentiate the cytotoxic 
      effect of liposomal doxorubicin and present here the dose-finding portion of this 
      study. Adult and pediatric patients with recurrent or refractory sarcomas were 
      treated with increasing doses of liposomal doxorubicin and temsirolimus using a 
      continual reassessment method for escalation, targeting a dose-limiting toxicity 
      rate of 20%. Blood samples were drawn before and after the first dose of 
      temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally 
      tolerated dose combination was liposomal doxorubicin 30 mg/m(2) monthly with 
      temsirolimus 20 mg/m(2) weekly. Hematologic toxicity was common but manageable. 
      Dose-limiting toxicities were primarily renal. Concurrent administration of 
      liposomal doxorubicin resulted in increased exposure to sirolimus, the active 
      metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and 
      temsirolimus is safe for heavily pretreated sarcoma patients. Co-administration 
      with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but 
      increased exposure to its active metabolite.
CI  - Copyright (c) 2013 UICC.
FAU - Thornton, K A
AU  - Thornton KA
AD  - Division of Medical Oncology, Department of Oncology, Sidney Kimmel Comprehensive 
      Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
FAU - Chen, A R
AU  - Chen AR
FAU - Trucco, M M
AU  - Trucco MM
FAU - Shah, P
AU  - Shah P
FAU - Wilky, B A
AU  - Wilky BA
FAU - Gul, N
AU  - Gul N
FAU - Carrera-Haro, M A
AU  - Carrera-Haro MA
FAU - Ferreira, M Fogle
AU  - Ferreira MF
FAU - Shafique, U
AU  - Shafique U
FAU - Powell, J D
AU  - Powell JD
FAU - Meyer, C F
AU  - Meyer CF
FAU - Loeb, D M
AU  - Loeb DM
LA  - eng
GR  - K12 CA090433/CA/NCI NIH HHS/United States
GR  - P30 CA006973/CA/NCI NIH HHS/United States
GR  - R01 AI077610/AI/NIAID NIH HHS/United States
GR  - T32 CA009071/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130304
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Antineoplastic Agents)
RN  - 624KN6GM2T (temsirolimus)
RN  - 80168379AG (Doxorubicin)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/administration & dosage/pharmacokinetics/*therapeutic use
MH  - Bone Neoplasms/*drug therapy
MH  - Child
MH  - Dose-Response Relationship, Drug
MH  - Doxorubicin/administration & dosage/pharmacokinetics/*therapeutic use
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Recurrence
MH  - Sarcoma/*drug therapy
MH  - Sirolimus/administration & dosage/*analogs & 
      derivatives/pharmacokinetics/therapeutic use
MH  - Young Adult
PMC - PMC3681832
MID - NIHMS455103
COIS- Disclosure The authors have declared no conflicts of interest.
EDAT- 2013/02/06 06:00
MHDA- 2013/08/13 06:00
PMCR- 2014/08/15
CRDT- 2013/02/06 06:00
PHST- 2012/09/14 00:00 [received]
PHST- 2013/01/23 00:00 [accepted]
PHST- 2013/02/06 06:00 [entrez]
PHST- 2013/02/06 06:00 [pubmed]
PHST- 2013/08/13 06:00 [medline]
PHST- 2014/08/15 00:00 [pmc-release]
AID - 10.1002/ijc.28083 [doi]
PST - ppublish
SO  - Int J Cancer. 2013 Aug 15;133(4):997-1005. doi: 10.1002/ijc.28083. Epub 2013 Mar 
      4.