title: Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck.
abstract: BACKGROUND
  Platinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN.
  
  
  METHODS
  Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m(2) and then 250 mg/m(2) weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2.
  
  
  RESULTS
  The study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival.
  
  
  CONCLUSIONS
  The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck.
authors.affiliation: Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Saba
authors.forename: Selwyn J
authors.initials: SJ
authors.lastname: Hurwitz
authors.forename: Kelly
authors.initials: K
authors.lastname: Magliocca
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: Donald
authors.initials: D
authors.lastname: Harvey
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.forename: Jackie
authors.initials: J
authors.lastname: Rogerio
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mendel
authors.forename: Scott A
authors.initials: SA
authors.lastname: Kono
authors.forename: Colleen
authors.initials: C
authors.lastname: Lewis
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Chen
authors.forename: Kristin
authors.initials: K
authors.lastname: Higgins
authors.forename: Mark
authors.initials: M
authors.lastname: El-Deiry
authors.forename: Trad
authors.initials: T
authors.lastname: Wadsworth
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Beitler
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068818:Cetuximab; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068338:Everolimus; D016190:Carboplatin; D000068818:Cetuximab; D020123:Sirolimus
keywords: everolimus in head and neck cancer; everolimus in squamous cell carcinoma; everolimus, cetuximab, and carboplatin; mTOR inhibition in head and neck cancer; mTOR inhibition in squamous cell carcinoma; pharmacokinetics, and NONMEM