title: Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population.
  
  
  METHODS
  Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated.
  
  
  RESULTS
  Twenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m2/dose; and topotecan 0.8 mg/m2/dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 (p=0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline.
  
  
  CONCLUSIONS
  The combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen.
authors: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Kieuhoa T
authors: KT
authors: Vo
authors: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Erin E
authors: EE
authors: Karski
authors: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Nicole M
authors: NM
authors: Nasholm
authors: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Shelly
authors: S
authors: Allen
authors: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Fabienne
authors: F
authors: Hollinger
authors: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: W Clay
authors: WC
authors: Gustafson
authors: Department of Clinical Pharmacy, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Janel R
authors: JR
authors: Long-Boyle
authors: Department of Epidemiology and Biostatistics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Stephen
authors: S
authors: Shiboski
authors: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Katherine K
authors: KK
authors: Matthay
authors: Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA.
authors: Steven G
authors: SG
authors: DuBois
mesh_terms: D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D019772:Topotecan; D003520:Cyclophosphamide; D020123:Sirolimus
keywords: cyclophosphamide; mTOR; phase 1; sirolimus; topotecan