title: A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE).
abstract: OBJECTIVE
  VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination.
  
  
  METHODS
  Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily. Erlotinib 75 mg daily was added to the phase II dose recommended phase II dose (RPTD) of bevacizumab and everolimus. Dose-limiting toxicity (DLT) was assessed in cycle 1.
  
  
  RESULTS
  Forty-eight patients with advanced solid malignancies were evaluable for DLT and efficacy. No DLTs were observed in the doublet dose escalation. Two DLTs (grade 3 mucositis and grade 3 rash) were observed with the addition of erlotinib 75 mg daily. Consequently, triplet doses were adjusted and were better tolerated. Four patients had a partial response. Median progression-free survival (PFS) for the doublet therapy was 6.0 months (0.5 to 32+ months) and 5.5 months (0.8 to 27+ months) for the triplet therapy. Systemic exposure of everolimus was significantly higher in combination with erlotinib (476 ± 161 ng h/mL) compared to when given alone (393 ± 156 ng h/mL; P = 0.020).
  
  
  CONCLUSIONS
  The RPTD for the doublet therapy is bevacizumab 10 mg/kg every 14 days and everolimus 10 mg daily, and the RPTD for the triplet therapy is bevacizumab 5 mg/kg every 14 days, everolimus 5 mg and erlotinib 75 mg daily. Prolonged disease stability was demonstrated in tumors known to respond to mTOR inhibition and potentially resistant to VEGF blockade.
authors.affiliation: Duke University Medical Center, Seeley G. Mudd Bldg, 10 Bryan Searle Drive, Box 3052, Durham, NC 27710, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Bullock
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
authors.forename: Islam
authors.initials: I
authors.lastname: Younis
authors.forename: Hope E
authors.initials: HE
authors.lastname: Uronis
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
authors.forename: S Yousuf
authors.initials: SY
authors.lastname: Zafar
authors.forename: Jon P
authors.initials: JP
authors.lastname: Gockerman
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Lager
authors.forename: Roxanne
authors.initials: R
authors.lastname: Truax
authors.forename: Kellen L
authors.initials: KL
authors.lastname: Meadows
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Howard
authors.forename: Margot M
authors.initials: MM
authors.lastname: O'Neill
authors.forename: Gloria
authors.initials: G
authors.lastname: Broadwater
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068258:Bevacizumab; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068258:Bevacizumab; D000068338:Everolimus; D000069347:Erlotinib Hydrochloride; D020123:Sirolimus