title: A phase I study of mTOR inhibitor everolimus in association with cisplatin and radiotherapy for the treatment of locally advanced cervix cancer: PHOENIX I.
abstract: BACKGROUND
  Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cisplatin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhibits its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cisplatin and radiotherapy.
  
  
  METHODS
  In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiotherapy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day -7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radiotherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives.
  
  
  RESULTS
  Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs-1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and C max.
  
  
  CONCLUSIONS
  The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support further studies.
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil. andreia.melo@inca.gov.br.
authors.forename: Andréia Cristina
authors.initials: AC
authors.lastname: de Melo
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Rachele
authors.initials: R
authors.lastname: Grazziotin-Reisner
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Felipe
authors.initials: F
authors.lastname: Erlich
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Mariane S
authors.initials: MS
authors.lastname: Fontes Dias
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Giulliana
authors.initials: G
authors.lastname: Moralez
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Michel
authors.initials: M
authors.lastname: Carneiro
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Álvaro Henrique
authors.initials: ÁH
authors.lastname: Ingles Garces
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Flávia Vieira
authors.initials: FV
authors.lastname: Guerra Alves
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Bruna
authors.initials: B
authors.lastname: Novaes Neto
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Mateus
authors.initials: M
authors.lastname: Fuchshuber-Moraes
authors.affiliation: Novartis, São Paulo, Brazil.
authors.forename: Juliane
authors.initials: J
authors.lastname: Morando
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Suarez-Kurtz
authors.affiliation: Brazilian Clinical Cancer Research Network (RNPCC) - INCA/Decit/MS, D'or Institute of Research and Education (IDOR), Rio de Janeiro, Brazil.
authors.forename: Carlos Gil
authors.initials: CG
authors.lastname: Ferreira
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001918:Brachytherapy / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000628:therapy*
chemical_list: D000068338:Everolimus; D002945:Cisplatin
keywords: Cervix cancer; Cisplatin; Everolimus; Phase I; Radiotherapy