title: Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI 48109-5848, United States. scotschu@med.umich.edu
authors.forename: Scott M
authors.initials: SM
authors.lastname: Schuetze
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: David R
authors.initials: DR
authors.lastname: Lucas
authors.forename: Gino
authors.initials: G
authors.lastname: Metko
authors.forename: Mark M
authors.initials: MM
authors.lastname: Zalupski
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Baker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012509:Sarcoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D008055:Lipids; D042461:Vascular Endothelial Growth Factor A; D003520:Cyclophosphamide; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus