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

Abstract

There are few effective therapies for high-risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, 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 pediatrics 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. Coadministration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.

Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma

“…Considering the advanced disease stage and high level of previous therapy in this population, the efficacy of single-agent Myocet ® should be further explored. To our knowledge, Myocet ® has been used only twice in multi-agent regimen in children [26,27]. In the first study, the combination led to an encouraging remission rate in children with relapsed acute leukaemia.…”

“…Elsewhere, Myocet ® was administered in combination with fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG-Myocet ® regimen) in a very high-risk group of children with relapsed or refractory acute leukaemias at the dose of 50 mg/m 2 [26]. Lastly, a phase I trial of a combination of an mTOR inhibitor and Myocet ® was performed in adults and children with refractory/relapsing sarcoma [27]. Authors determined that the MTD of Myocet ® in this combination was 30 mg/m 2 every 4 weeks.…”

A sarcoma synoviale kezelési lehetőségei

“…E hatóanyaggal végzett másik vizsgálat során CR 0%, PR 6,3%, SD 18,8%, a PD 68,8% és a progresszióig eltelt idő 1,1 hónap (95% CI 1,0-4,1) volt (n = 16) [41]. Liposzomális doxorubicin és temsirolimus kombináció biztonságosan adható már kemoterápiával előkezelt sarcoma esetén [42]. A 4. táblázat mutatja a molekuláris célpontokra ható szereket és a klinikai vizsgálatokat.…”

Doxorubicin-Resistant Osteosarcoma: Novel Therapeutic Approaches in Sight?

“…The NCT00949325 phase I/II trial has been performed to test the ability of temsirolimus (CCI-779; an mTOR inhibitor) to potentiate the cytotoxic effect of liposomal doxorubicin [11]. This trial, which enrolled 15 bone and soft-tissue sarcoma patients (including one patient with HGOS),…”

“…showed that the combination of liposomal doxorubicin with temsirolimus can be safely administered to heavily pretreated patients with recurrent or refractory bone and soft tissue sarcomas and that the toxicity of this combination was manageable and reversible [11]. The NCT00019630 phase I trial has been completed, but no study results have been posted yet.…”