title: Metronomic treatment of advanced non-small-cell lung cancer with daily oral vinorelbine - a Phase I trial.
abstract: In a Phase I dose-finding study of metronomic daily oral vinorelbine in advanced non-small-cell lung cancer, a recommended dose was established for this therapeutic approach. In addition, this trial revealed promising efficacy data and an acceptable tolerability profile. The observed vinorelbine blood concentrations suggest continuous anti-angiogenic coverage.
  
  
  BACKGROUND
  We present a Phase I dose-finding study investigating metronomic daily oral vinorelbine (Navelbine®Oral, NVBo) in advanced non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Patients with stage III/IV NSCLC received daily NVBo at fixed dose levels of 20-50 mg/d for 21 days of each 4-week cycle. Primary end point was the maximum tolerated dose. Secondary end points included tumor response, time to progression (TTP), overall survival (OS) and tolerability.
  
  
  RESULTS
  Twenty-seven patients with advanced NSCLC were enrolled. Most of them were extensively pretreated. Daily NVBo was well tolerated up to 30 mg/d. At 40 mg/d, two of five patients experienced dose-limiting toxicities (DLTs). Three of six patients had DLTs at the 50 mg/d level. The recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2, if tolerated. Pharmacokinetic analyses showed continuous blood exposure over 21 days and only marginal accumulation. The tolerability profile was acceptable (all dose levels - all grades: decreased appetite 33%, diarrhea 33%, leukopenia 33%, nausea 30%, vomiting 26%; ≥grade 3: leukopenia 30%, lymphopenia 19%, neutropenia 19%, febrile neutropenia 15%). Disease control rate, OS and TTP signaled a treatment effect.
  
  
  CONCLUSIONS
  Daily metronomic NVBo therapy in extensively pretreated patients with advanced NSCLC is feasible and safe at the recommended dose of 30 mg/d. Escalation to 40 mg/d in the second cycle is possible. The blood concentrations of vinorelbine after daily metronomic dosing reached lower peaks than intravenous or oral conventional dosing. Blood concentrations were consistent with anti-angiogenic or immune modulating pharmacologic properties of vinorelbine. Further studies are warranted to evaluate the safety and efficacy of this novel approach in specific patient populations.
authors.affiliation: Ev. Diakonissenkrankenhaus Leipzig, Leipzig.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Guetz
authors.affiliation: University Hospital Munich and Thoracic Oncology Centre Munich, Member of the German Center for Lung Research, Comprehensive Pneumology Center Munich (DZL CPC-M), Munich.
authors.forename: Amanda
authors.initials: A
authors.lastname: Tufman
authors.affiliation: Asklepios Fachkliniken Muenchen-Gauting, Gauting.
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.affiliation: Lungenfachklinik Immenhausen, Immenhausen, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Rittmeyer
authors.affiliation: University Hospital Munich and Thoracic Oncology Centre Munich, Member of the German Center for Lung Research, Comprehensive Pneumology Center Munich (DZL CPC-M), Munich.
authors.forename: Astrid
authors.initials: A
authors.lastname: Borgmeier
authors.affiliation: Pierre Fabre Pharmaceuticals, Oncology Research and Development Center, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Ferré
authors.affiliation: Pierre Fabre Pharma GmbH, Freiburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Edlich
authors.affiliation: University Hospital Munich and Thoracic Oncology Centre Munich, Member of the German Center for Lung Research, Comprehensive Pneumology Center Munich (DZL CPC-M), Munich.
authors.forename: Rudolf Maria
authors.initials: RM
authors.lastname: Huber
keywords: NSCLC; anti-angiogenic treatment; cytotoxic therapy; dose escalation; lung carcinoma; vinca-alkaloid; vinorelbine capsules