A Suder1, J E Ang2, F Kyle3, D Harris4, S Rudman5, R Kristeleit6, F Solca7, M Uttenreuther-Fischer8, K Pemberton9, K Pelling10, D Schnell11, J de Bono12, J Spicer13. 1. Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: anetasuder@hotmail.com. 2. Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK. Electronic address: jooern.ang@icr.ac.uk. 3. Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: fiona.kyle@gstt.nhs.uk. 4. The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Electronic address: dean.harris@cdhb.health.nz. 5. Department of Medical Oncology, Guys and St Thomas' NHS Foundation, Great Maze Pond, London SE1 9RT, UK. Electronic address: sarah.rudman@gstt.nhs.uk. 6. The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Electronic address: r.kristeleit@ucl.ac.uk. 7. 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. 8. 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. 9. Medical Department, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK. Electronic address: karine.pemberton@boehringer-ingelheim.com. 10. Biometrics and Data Management, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK. Electronic address: katy.pelling@boehringer-ingelheim.com. 11. 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. 12. Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK. Electronic address: johann.de-Bono@icr.ac.uk. 13. 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.
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. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00809133.
BACKGROUND: This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express humanepidermal 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.
Authors: Bob T Li; Adrian Lee; Sandra O'Toole; Wendy Cooper; Bing Yu; Jamie E Chaft; Maria E Arcila; Mark G Kris; Nick Pavlakis Journal: Lung Cancer Date: 2015-10-29 Impact factor: 5.705
Authors: Salvatore Galdy; Angela Lamarca; Mairéad G McNamara; Richard A Hubner; Chiara A Cella; Nicola Fazio; Juan W Valle Journal: Cancer Metastasis Rev Date: 2017-03 Impact factor: 9.264
Authors: Mary E R O'Brien; Debashis Sarker; Jaishree Bhosle; Kiruthikah Thillai; Timothy A Yap; Martina Uttenreuther-Fischer; Karine Pemberton; Xidong Jin; Sabrina Wiebe; Johann de Bono; James Spicer Journal: Cancer Chemother Pharmacol Date: 2018-08-07 Impact factor: 3.333