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Published on: October 2, 2015
Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma
Scott M Schuetze1, Lili Zhao, Rashmi Chugh
1Division of Hematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI 48109-5848, United States. scotschu@med.umich.edu
Background:
Activation of the mammalian target of rapamycin (mTOR) pathway has been demonstrated in sarcoma. Trials using mTOR inhibitor in sarcoma have shown low objective response rates but progression-free survival (PFS) rates suggest cytostatic effects. The combination of sirolimus and cyclophosphamide demonstrated synergistic anti-sarcoma activity in preclinical models; therefore, we conducted a phase II trial of sirolimus and cyclophosphamide in patients with advanced sarcoma.
Methods:
Patients received 4 mg sirolimus daily and 200mg cyclophosphamide d1-7 and 15-21 every 28 days. The primary objective was to estimate the 24-week PFS rate with a target of ≥ 25%. Patients were followed for World Health Organisation (WHO) criteria tumour response by imaging every 8 weeks. Serum levels of sirolimus, lipids and vascular endothelial growth factor were measured. Tumour tissue was analysed for mTOR, S6 ribosomal protein and cytochrome P450 3A4/5 by quantitative immunofluorescence.
Results:
Forty-nine eligible patients were enrolled from September 2008 to December 2009. Patients received a median of four cycles of therapy. Starting doses of drugs were tolerated in 79%. One patient achieved partial tumour response, 10 were progression-free for ≥ 24 weeks and two completed 12 cycles of treatment. Median PFS and overall survival (OS) were 3.4 and 9.9 months, respectively. Serious adverse events attributed to therapy occurred in 11% and included infection, pneumonitis and thrombosis. Hypertriglyceridaemia from treatment and lower tumour phosphorylated-mTOR are associated with longer survival.
Conclusions:
Sirolimus and cyclophosphamide were tolerated by the majority of patients. About 20% of patients had stable sarcoma for at least 6 months but objective tumour response was infrequent.
Insights
This phase II trial investigated sirolimus and cyclophosphamide for advanced sarcoma. While objective responses were rare, about 20% of patients showed stable disease for at least six months, indicating potential cytostatic effects.
Area of Science:
- Oncology
- Pharmacology
Background:
- The mammalian target of rapamycin (mTOR) pathway is activated in sarcoma.
- Previous mTOR inhibitor trials showed limited objective response rates but suggested cytostatic effects.
- Preclinical models indicated synergistic anti-sarcoma activity with sirolimus and cyclophosphamide.
Purpose of the Study:
- To evaluate the efficacy and safety of combining sirolimus and cyclophosphamide in patients with advanced sarcoma.
- To estimate the 24-week progression-free survival (PFS) rate.
Main Methods:
- A phase II trial involving 49 patients with advanced sarcoma.
- Patients received daily sirolimus and intermittent cyclophosphamide.
- Tumor response, serum levels of sirolimus and VEGF, and tumor markers were assessed.
Main Results:
- Median PFS was 3.4 months and median overall survival was 9.9 months.
- 10 out of 49 patients (approximately 20%) were progression-free for ≥ 24 weeks.
- Treatment was generally tolerated, with serious adverse events in 11% of patients.
Conclusions:
- The combination of sirolimus and cyclophosphamide was tolerated by most advanced sarcoma patients.
- Approximately 20% of patients experienced stable disease for at least six months.
- Objective tumor response was infrequent, but the combination showed potential cytostatic activity.
