Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma

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 200 mg 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. (C) 2012 Elsevier Ltd. All rights reserved.