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, 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.

Conflict of interest statement

Disclosure

The authors have declared no conflicts of interest.

Copyright © 2013 UICC.

Figures

Figure 1

A) MHH-ES cells were treated with the indicated concentration of doxorubicin with (dotted line) or without (solid line) 200 nM sirolimus (Rapamycin). Cell survival was quantified using an MTT assay. The difference between the curves was statistically significantly different by 2-way ANOVA (p high), a population depleted of stem cells (ALDHlow), and an unsorted population (Flow Through). Cells were incubated for 48 hours with 250 nM doxorubicin and the indicated concentration of sirolimus (Rapamycin), and cell viability was determined using the MTT assay. The ALDHhigh cells were resistant to doxorubicin, and this resistance was overcome by sirolimus in a dose-dependent manner. Experiments were performed in triplicate and repeated twice, and error bars represent standard error of the mean.

Figure 2

Progression-free Survival of patients treated at the MTD. A Kaplan-Meier curve indicating the time from the beginning of treatment until the first objective evidence of disease progression, censored at discontinuation of drug.