Document Detail

A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma.
MedLine Citation:
PMID:  23382028     Owner:  NLM     Status:  MEDLINE    
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.
K A Thornton; A R Chen; M M Trucco; P Shah; B A Wilky; N Gul; M A Carrera-Haro; M Fogle Ferreira; U Shafique; J D Powell; C F Meyer; D M Loeb
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Publication Detail:
Type:  Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-03-04
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  133     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-06-11     Completed Date:  2013-08-12     Revised Date:  2014-08-17    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  997-1005     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 UICC.
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MeSH Terms
Antineoplastic Agents / administration & dosage,  pharmacokinetics,  therapeutic use*
Bone Neoplasms / drug therapy*
Dose-Response Relationship, Drug
Doxorubicin / administration & dosage,  pharmacokinetics,  therapeutic use*
Middle Aged
Sarcoma / drug therapy*
Sirolimus / administration & dosage,  analogs & derivatives*,  pharmacokinetics,  therapeutic use
Young Adult
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/temsirolimus; 80168379AG/Doxorubicin; W36ZG6FT64/Sirolimus

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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