title: A phase Ib dose-escalation study of everolimus combined with cisplatin and etoposide as first-line therapy in patients with extensive-stage small-cell lung cancer.
abstract: BACKGROUND
  This phase Ib study aimed to establish the feasible everolimus dose given with standard-dose etoposide plus cisplatin (EP) for extensive-stage small-cell lung cancer (SCLC).
  
  
  METHODS
  An adaptive Bayesian dose-escalation model and investigator opinion were used to identify feasible daily or weekly everolimus doses given with EP in adults with treatment-naive extensive-stage SCLC. A protocol amendment mandated prophylactic granulocyte colony-stimulating factor (G-CSF). Primary end point was cycle 1 dose-limiting toxicity (DLT) rate. Secondary end points included safety, relative EP dose intensity, pharmacokinetics, and tumor response.
  
  
  RESULTS
  Patients received everolimus 2.5 or 5 mg/day without G-CSF (n=10; cohort A), 20 or 30 mg/week without G-CSF (n=18; cohort B), or 2.5 or 5 mg/day with G-CSF (n=12; cohort C); all received EP. Cycle 1 DLT rates were 50.0%, 22.2%, and 16.7% in cohorts A, B, and C, respectively. Cycle 1 DLTs were neutropenia (cohorts A and B), febrile neutropenia (all cohorts), and thrombocytopenia (cohorts A and C). The most common grade 3/4 adverse events were hematologic. Best overall response was partial response (40.0%, 61.1%, and 58.3% in cohorts A, B, and C, respectively).
  
  
  CONCLUSIONS
  Everolimus 2.5 mg/day plus G-CSF was the only feasible dose given with standard-dose EP in untreated extensive-stage SCLC.
authors.affiliation: Department of Cancer Medicine/Thoracic Unit, Institut Gustave Roussy, Villejuif, France.
authors.forename: B
authors.initials: B
authors.lastname: Besse
authors.forename: R S
authors.initials: RS
authors.lastname: Heist
authors.forename: V A
authors.initials: VA
authors.lastname: Papadmitrakopoulou
authors.forename: D R
authors.initials: DR
authors.lastname: Camidge
authors.forename: J T
authors.initials: JT
authors.lastname: Beck
authors.forename: P
authors.initials: P
authors.lastname: Schmid
authors.forename: C
authors.initials: C
authors.lastname: Mulatero
authors.forename: N
authors.initials: N
authors.lastname: Miller
authors.forename: S
authors.initials: S
authors.lastname: Dimitrijevic
authors.forename: S
authors.initials: S
authors.lastname: Urva
authors.forename: I
authors.initials: I
authors.lastname: Pylvaenaeinen
authors.forename: K
authors.initials: K
authors.lastname: Petrovic
authors.forename: B E
authors.initials: BE
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D000068338:Everolimus; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D005047:Etoposide; D000068338:Everolimus; D002945:Cisplatin; D020123:Sirolimus
keywords: cisplatin; etoposide; everolimus; phase I; small-cell lung cancer