PMID- 26296295 OWN - NLM STAT- MEDLINE DCOM- 20160130 LR - 20181202 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 51 IP - 16 DP - 2015 Nov TI - A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours. PG - 2275-84 LID - S0959-8049(15)00747-9 [pii] LID - 10.1016/j.ejca.2015.07.041 [doi] AB - 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. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00809133. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Suder, A AU - Suder A AD - Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: anetasuder@hotmail.com. FAU - Ang, J E AU - Ang JE AD - Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK. Electronic address: jooern.ang@icr.ac.uk. FAU - Kyle, F AU - Kyle F AD - Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: fiona.kyle@gstt.nhs.uk. FAU - Harris, D AU - Harris D AD - The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Electronic address: dean.harris@cdhb.health.nz. FAU - Rudman, S AU - Rudman S AD - Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: sarah.rudman@gstt.nhs.uk. FAU - Kristeleit, R AU - Kristeleit R AD - The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Electronic address: r.kristeleit@ucl.ac.uk. FAU - Solca, F AU - Solca F AD - 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. FAU - Uttenreuther-Fischer, M AU - Uttenreuther-Fischer M AD - 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. FAU - Pemberton, K AU - Pemberton K AD - Medical Department, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK. Electronic address: karine.pemberton@boehringer-ingelheim.com. FAU - Pelling, K AU - Pelling K AD - Biometrics and Data Management, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK. Electronic address: katy.pelling@boehringer-ingelheim.com. FAU - Schnell, D AU - Schnell D AD - 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. FAU - de Bono, J AU - de Bono J AD - Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK. Electronic address: johann.de-Bono@icr.ac.uk. FAU - Spicer, J AU - Spicer J AD - 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. LA - eng SI - ClinicalTrials.gov/NCT00809133 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20150818 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (Protein Kinase Inhibitors) RN - 0 (Quinazolines) RN - 41UD74L59M (Afatinib) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (ERBB3 protein, human) RN - EC 2.7.10.1 (ERBB4 protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) RN - EC 2.7.10.1 (Receptor, ErbB-4) RN - P88XT4IS4D (Paclitaxel) SB - IM MH - Administration, Intravenous MH - Administration, Oral MH - Adult MH - Afatinib MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/adverse effects/pharmacokinetics MH - Drug Administration Schedule MH - ErbB Receptors/antagonists & inhibitors/metabolism MH - Female MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasms/*drug therapy/enzymology/pathology MH - Paclitaxel/*administration & dosage/adverse effects MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects/pharmacokinetics MH - Quinazolines/*administration & dosage/adverse effects/pharmacokinetics MH - Receptor, ErbB-2/antagonists & inhibitors/metabolism MH - Receptor, ErbB-3/antagonists & inhibitors/metabolism MH - Receptor, ErbB-4/antagonists & inhibitors/metabolism MH - Time Factors MH - Treatment Outcome MH - United Kingdom OTO - NOTNLM OT - Afatinib OT - Clinical trial phase I OT - ErbB receptors OT - Neoplasms OT - Paclitaxel EDAT- 2015/08/25 06:00 MHDA- 2016/01/31 06:00 CRDT- 2015/08/23 06:00 PHST- 2015/03/05 00:00 [received] PHST- 2015/07/08 00:00 [revised] PHST- 2015/07/23 00:00 [accepted] PHST- 2015/08/23 06:00 [entrez] PHST- 2015/08/25 06:00 [pubmed] PHST- 2016/01/31 06:00 [medline] AID - S0959-8049(15)00747-9 [pii] AID - 10.1016/j.ejca.2015.07.041 [doi] PST - ppublish SO - Eur J Cancer. 2015 Nov;51(16):2275-84. doi: 10.1016/j.ejca.2015.07.041. Epub 2015 Aug 18.