A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and
K A Thornton1, A R Chen, M M Trucco
1Division of Medical Oncology, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
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.
Insights
This study found that combining liposomal doxorubicin with temsirolimus is a safe treatment option for advanced sarcoma patients. The maximally tolerated doses were determined for this chemotherapy combination.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- High-risk sarcomas often relapse after initial chemotherapy.
- Mammalian target of rapamycin (mTOR) inhibition shows potential in overcoming chemotherapy resistance in vitro.
- Previous trials with mTOR inhibitors in sarcoma yielded disappointing results when used as maintenance therapy.
Purpose of the Study:
- To determine the safety and maximally tolerated dose (MTD) of combining liposomal doxorubicin with temsirolimus in patients with recurrent or refractory sarcomas.
- To evaluate the pharmacokinetic interaction between liposomal doxorubicin and temsirolimus.
Main Methods:
- A Phase I/II clinical trial using a continual reassessment method for dose escalation.
- Adult and pediatric patients received escalating doses of liposomal doxorubicin and temsirolimus.
- Pharmacokinetic analyses were performed to assess drug exposure.
Main Results:
- The MTD was identified as liposomal doxorubicin 30 mg/m(2) monthly and temsirolimus 20 mg/m(2) weekly.
- Common toxicities were hematologic and manageable; dose-limiting toxicities were primarily renal.
- Concurrent liposomal doxorubicin increased exposure to sirolimus, the active metabolite of temsirolimus.
Conclusions:
- The combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients.
- This combination therapy warrants further investigation for efficacy in sarcoma treatment.
- Liposomal doxorubicin co-administration impacts temsirolimus metabolite exposure but not temsirolimus pharmacokinetics.
