title: A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors.
abstract: OBJECTIVE
  The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors.
  
  
  METHODS
  This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel and bevacizumab. Safety, pharmacokinetics, and anti-tumor activity were also assessed. The starting dose was oral afatinib 40 mg once daily plus intravenous paclitaxel (fixed dose 80 mg/m2, Days 1, 8, and 15 of a 4-week cycle) and intravenous bevacizumab 5 mg/kg every 2 weeks.
  
  
  RESULTS
  Twenty-nine patients were enroled. The afatinib dose was de-escalated to 30 mg and then 20 mg after 2/6 and 2/5 evaluable patients developed dose-limiting toxicities at 40 and 30 mg, respectively, when combined with paclitaxel and bevacizumab 5 mg/kg. The bevacizumab dose was subsequently escalated to 10 mg/kg, and MTD was defined as afatinib 20 mg plus paclitaxel 80 mg/m2and bevacizumab 10 mg/kg. Frequent (any grade) treatment-related adverse events (AEs) included diarrhea (83%), rash/acne (83%), fatigue (79%), mucosal inflammation (59%), and nausea (59%). Based on overall safety, bevacizumab was amended to 7.5 mg/kg for the recommended phase II dose. Pharmacokinetic analyses suggested no relevant drug-drug interactions. Three (10%) confirmed partial responses were observed; 15 (52%) patients had stable disease.
  
  
  CONCLUSIONS
  The recommended phase II dose schedule was afatinib 20 mg/day with paclitaxel 80 mg/m2(Days 1, 8, and 15 every 4 weeks) and bevacizumab 7.5 mg/kg every 2 weeks. At this dose schedule, AEs were manageable, and anti-tumor activity was observed.
authors.affiliation: King's College London, Guy's Hospital, 3rd Floor, Bermondsey Wing, Great Maze Pond, London, SE1 9RT, UK. james.spicer@kcl.ac.uk.
authors.forename: James
authors.initials: J
authors.lastname: Spicer
authors.affiliation: King's College London, Guy's Hospital, 3rd Floor, Bermondsey Wing, Great Maze Pond, London, SE1 9RT, UK.
authors.forename: Sheeba
authors.initials: S
authors.lastname: Irshad
authors.affiliation: Royal Marsden NHS Foundation Trust, Surrey, UK.
authors.forename: Joo Ern
authors.initials: JE
authors.lastname: Ang
authors.affiliation: King's College London, Guy's Hospital, 3rd Floor, Bermondsey Wing, Great Maze Pond, London, SE1 9RT, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Enting
authors.affiliation: Royal Marsden NHS Foundation Trust, Surrey, UK.|University College London Cancer Institute, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kristeleit
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.affiliation: Boehringer Ingelheim Ltd, Bracknell, UK.
authors.forename: Karine
authors.initials: K
authors.lastname: Pemberton
authors.affiliation: Boehringer Ingelheim Ltd, Bracknell, UK.
authors.forename: Katy
authors.initials: K
authors.lastname: Pelling
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Schnell
authors.affiliation: Royal Marsden NHS Foundation Trust, Surrey, UK.
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D011799:Quinazolines; D000068258:Bevacizumab; D000077716:Afatinib; D017239:Paclitaxel
keywords: Afatinib; Bevacizumab; Paclitaxel; Phase I; Solid tumors