title: Phase I/II Trial of Sorafenib in Combination with Vinorelbine as First-Line Chemotherapy for Metastatic Breast Cancer.
abstract: BACKGROUND
  Preclinical models have reported a synergistic interaction between sorafenib and vinorelbine. We investigated the toxicity, efficacy, and pharmacokinetics interaction of this combination as first-line treatment for patients with metastatic breast cancer.
  
  
  METHODS
  Patients were HER2-negative and treated with vinorelbine 30 mg/m2 IV days 1,8 every 21 plus daily oral sorafenib. In the phase I portion (3+3 design) patients received sorafenib 200 mg BID (cohort 1) or 400 mg BID (cohort 2). In the phase II expansion, 21 more evaluable patients were planned to receive the maximum tolerated dose (MTD). Pharmacokinetic analysis was performed in 6 patients: blood concentrations were compared for each drug in the presence or absence of the other drug.
  
  
  RESULTS
  In cohort 1, one patient experienced a dose-limiting toxicity (DLT) (grade 3 pancreatitis), requiring the expansion of this cohort to 6 patients, without further documented DLTs. In cohort 2, one patient of six experienced a grade 4 DLT (asymptomatic rise in amylase not requiring drug discontinuation), establishing this dose level as the MTD (sorafenib 400 mg BID). After expansion at the MTD, a total of 27 patients (median age 57) were treated for a median of 8 cycles. One grade 5 febrile neutropenia occurred. With repeated cycles, 52% of patients required at least 1 dose reduction of either drug. One patient experienced a sustained grade 3 fatigue resulting in treatment discontinuation. The response rate was 30%. Median PFS was 5.7 months (95% CI 4.4-7.6), and clinical benefit (absence of disease progression at 6 months) was 48%. PK analysis showed a significant interaction between the two drugs, resulting in a higher Cmax of vinorelbine in the presence of sorafenib.
  
  
  CONCLUSIONS
  The combination of sorafenib and vinorelbine at full doses is feasible but not devoid of toxicity, likely also due to a significant PK interaction.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00764972.
authors.affiliation: Department of Medical Oncology, McGill University, Montreal, Canada.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ferrario
authors.affiliation: Department of Cell Therapeutics, Sede Secondaria Della Cell Therapeutics, Bresso, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Strepponi
authors.affiliation: Department of Medical Oncology, McGill University, Montreal, Canada.
authors.forename: Khashayar
authors.identifier: http://orcid.org/0000-0003-2221-3755
authors.initials: K
authors.lastname: Esfahani
authors.affiliation: Department of Medical Oncology, McGill University, Montreal, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: Charamis
authors.affiliation: Department of Medical Oncology, McGill University, Montreal, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Langleben
authors.affiliation: Department of statistics, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.affiliation: Department of statistics, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Rome, Italy.
authors.forename: Oriana
authors.initials: O
authors.lastname: Nanni
authors.affiliation: Department of Medical Oncology, McGill University, Montreal, Canada.
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.affiliation: Department of Medical Oncology, McGill University, Montreal, Canada.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Panasci
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077157:Sorafenib; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077235:Vinorelbine
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D014747:Vinblastine; D000077157:Sorafenib; D000077235:Vinorelbine