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A phase I study of the combination of temsirolimus with irinotecan for metastatic sarcoma
Claire F Verschraegen1, Sujana Movva, Yongli Ji
1Department of Hematology/Oncology, The University of Vermont Cancer Center, 89 Beaumont Ave., Burlington, VT 05405, USA. claire.verschraegen@vtmednet.org.
Abstract:
mTOR inhibitors are emerging as important anti-neoplastic agents with a wide range of clinical applications. The topoisomerase I inhibitor irinotecan is a potent DNA damaging drug, with a broad spectrum of anticancer activities. mTOR appears to enhance cancer cell survival following DNA damage, thus the inhibition of mTOR after irinotecan could theoretically show synergistic activities in patients. Both mTOR inhibitors and irinotecan have been used as single agents in soft tissue sarcomas with limited efficacy. We completed a phase I trial of the combination of the mTOR inhibitor, temsirolimus, and irinotecan in patients with advanced soft tissue sarcoma. Seventeen patients were recruited. The Phase II recommended dose is 20 mg of temsirolimus and 80 mg/m2 of irinotecan administered on weekly basis for three out of four weeks. Most frequently encountered toxicities include cytopenias, fatigue, and gastrointestinal toxicities. Two patients (one with leiomyosarcoma and one with high grade undifferentiated sarcoma) had stable disease for more than 12 months.
Insights
Combining temsirolimus (an mTOR inhibitor) with irinotecan shows potential for advanced soft tissue sarcoma. This phase I trial established a recommended dose and identified key toxicities, with some patients achieving long-term stable disease.
Area of Science:
- Oncology
- Pharmacology
Background:
- Mammalian target of rapamycin (mTOR) inhibitors are key anti-neoplastic agents.
- Irinotecan, a topoisomerase I inhibitor, is a potent DNA damaging anticancer drug.
- mTOR may promote cancer cell survival after DNA damage, suggesting potential synergy with irinotecan.
Purpose of the Study:
- To evaluate the safety and determine the recommended Phase II dose of combination temsirolimus and irinotecan in advanced soft tissue sarcoma.
- To explore preliminary efficacy of this combination therapy.
Main Methods:
- A Phase I clinical trial was conducted.
- Seventeen patients with advanced soft tissue sarcoma were recruited.
- Dose escalation determined the recommended Phase II dose.
Main Results:
- The recommended Phase II dose was identified as 20 mg of temsirolimus and 80 mg/m2 of irinotecan weekly for 3 weeks on a 4-week cycle.
- Common toxicities included cytopenias, fatigue, and gastrointestinal issues.
- Two patients (one with leiomyosarcoma, one with high-grade undifferentiated sarcoma) achieved stable disease for over 12 months.
Conclusions:
- The combination of temsirolimus and irinotecan is a feasible treatment option for advanced soft tissue sarcoma.
- Further investigation is warranted to confirm efficacy and optimize treatment strategies.
