title: A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours.
abstract: BACKGROUND
  This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2.
  
  
  METHODS
  Oral afatinib was combined with intravenous paclitaxel (80mg/m(2); days 1, 8 and 15 every four weeks) starting at 20mg once daily and escalated to 40 and 50mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity.
  
  
  RESULTS
  Sixteen patients were treated. Dose-limiting toxicities with afatinib 50mg were fatigue and mucositis. The MTD was determined as afatinib 40mg with paclitaxel 80mg/m(2), which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n=3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination.
  
  
  CONCLUSIONS
  The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80mg/m(2) (days 1, 8 and 15 every four weeks) was 40mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity.
  
  
  BACKGROUND
  ClinicalTrials.gov, NCT00809133.
authors: Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: anetasuder@hotmail.com.
authors: A
authors: A
authors: Suder
authors: Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK. Electronic address: jooern.ang@icr.ac.uk.
authors: J E
authors: JE
authors: Ang
authors: Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: fiona.kyle@gstt.nhs.uk.
authors: F
authors: F
authors: Kyle
authors: The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Electronic address: dean.harris@cdhb.health.nz.
authors: D
authors: D
authors: Harris
authors: Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: sarah.rudman@gstt.nhs.uk.
authors: S
authors: S
authors: Rudman
authors: The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Electronic address: r.kristeleit@ucl.ac.uk.
authors: R
authors: R
authors: Kristeleit
authors: Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer Gasse 5-11, A1120 Vienna, Austria. Electronic address: flavio.solca@boehringer-ingelheim.com.
authors: F
authors: F
authors: Solca
authors: Therapeutic Area Oncology, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str 65, Biberach an der Riss 88397, Germany. Electronic address: martina.uttenreuther-fischer@boehringer-ingelheim.com.
authors: M
authors: M
authors: Uttenreuther-Fischer
authors: Medical Department, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK. Electronic address: karine.pemberton@boehringer-ingelheim.com.
authors: K
authors: K
authors: Pemberton
authors: Biometrics and Data Management, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK. Electronic address: katy.pelling@boehringer-ingelheim.com.
authors: K
authors: K
authors: Pelling
authors: Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim GmbH & Co KG, Birkendorfer Str 65, Biberach an der Riss, 88397 Biberach an der Riss, Germany. Electronic address: david.schnell@boehringer-ingelheim.com.
authors: D
authors: D
authors: Schnell
authors: Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK. Electronic address: johann.de-Bono@icr.ac.uk.
authors: J
authors: J
authors: de Bono
authors: King's College London - Division of Cancer Studies, 3rd Floor, Bermondsey Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK. Electronic address: james.spicer@kcl.ac.uk.
authors: J
authors: J
authors: Spicer
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D000077716:Afatinib; D066246:ErbB Receptors; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C587689:ERBB4 protein, human
keywords: Afatinib; Clinical trial phase I; ErbB receptors; Neoplasms; Paclitaxel