A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma

K. A. Thornton, Allen R Chen, M. M. Trucco, P. Shah, B. A. Wilky, N. Gul, M. A. Carrera-Haro, M. Fogle Ferreira, U. Shafique, Jonathan Powell, Christian Meyer, D. M. Loeb

Research output: Contribution to journalArticle

Abstract

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/m2 monthly with temsirolimus 20 mg/m2 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. What's new? Despite promising evidence from in vitro experiments, inhibition of mammalian target of rapamycin (mTOR) has been largely ineffective at preventing the recurrence of sarcoma in patients following cytotoxic chemotherapy. The results of a Phase I/II clinical trial reported here, however, reveal that concurrent administration of the mTOR inhibitor temsirolimus with liposomal doxorubicin may result in increased tumor exposure to the active temsirolimus metabolite, sirolimus. The combination of drugs appeared to be relatively safe for heavily pretreated sarcoma patients. The approach could change existing treatment strategies for certain types of sarcoma.

Original languageEnglish (US)
Pages (from-to)997-1005
Number of pages9
JournalInternational Journal of Cancer
Volume133
Issue number4
DOIs
Publication statusPublished - Aug 15 2013

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Keywords

  • cancer stem cell
  • chemoresistance
  • clinical trial
  • mTOR
  • sarcoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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