title: A phase I study of sirolimus and bevacizumab in patients with advanced malignancies.
abstract: BACKGROUND
  We performed a single institution, phase I study of sirolimus and bevacizumab, in order to determine the dose limiting toxicity (DLT) and recommended phase II doses.
  
  
  METHODS
  Eligible patients had previously treated advanced malignancies and were enrolled in three cohorts. Sirolimus 90 mg PO weekly (45 mg on days 1 and 2) was combined with bevacizumab 7.5mg/kg (cohort #1) or bevacizumab 15 mg/kg (cohort #2) IV q3weeks. Sirolimus 4 mg PO daily was combined with bevacizumab 15 mg/kg IV q3weeks (cohort #3).
  
  
  RESULTS
  Twenty-eight patients enrolled. The most common tumour types were colorectal (21%), head/neck (14%), and renal cell (11%). No DLTs were observed in cohorts #1 (4 patients) and #2 (12 patients), while two DLTs (grade 3 confusion and grade 3 fatigue) were observed in the first six patients in cohort #3 (12 patients). The most common grade 3 toxicities were fatigue (18%), hypertension (14%) and anorexia (11%). There were no responses, but one patient has had stable disease for 78 weeks.
  
  
  CONCLUSIONS
  The combination of sirolimus and bevacizumab at full doses is tolerable in the majority of patients. The availability and cost of sirolimus compared with other mTOR inhibitors make this an attractive agent to combine with bevacizumab.
authors: Section of Hematology and Oncology, Department of Medicine, Comprehensive Cancer Center, Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA. ecohen@medicine.bsd.uchicago.edu
authors: E E W
authors: EE
authors: Cohen
authors: M R
authors: MR
authors: Sharma
authors: L
authors: L
authors: Janisch
authors: M
authors: M
authors: Llobrera
authors: L
authors: L
authors: House
authors: K
authors: K
authors: Wu
authors: J
authors: J
authors: Ramirez
authors: G F
authors: GF
authors: Fleming
authors: W M
authors: WM
authors: Stadler
authors: M J
authors: MJ
authors: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus