A phase I study of daily afatinib,an irreversible ErbB family blocker,in combination with weekly paclitaxel in patients with advanced solid tumours |
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| Institution: | 1. Department of Medical Oncology, Guys and St Thomas’ NHS Foundation, Great Maze Pond, London SE1 9RT, UK;2. Drug Development Unit, The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT UK;3. The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK;4. Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer Gasse 5-11, A1120 Vienna, Austria;5. Therapeutic Area Oncology, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Str 65, Biberach an der Riss 88397, Germany;6. Medical Department, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK;7. Biometrics and Data Management, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell RG12 8YS, UK;8. Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim GmbH & Co KG, Birkendorfer Str 65, Biberach an der Riss, 88397 Biberach an der Riss, Germany;9. King’s College London – Division of Cancer Studies, 3rd Floor, Bermondsey Wing, Guy’s Hospital, Great Maze Pond, London, SE1 9RT, UK;1. Medical Oncology, Cantonal Hospital Luzern, Luzern, Switzerland;2. Clinical Research Unit of the Dr. Dubois-Ferrière Dinu Lipatti Foundation, Oncology Center, Geneva University Hospital, Geneva, Switzerland;3. Medical Oncology, University Hospital Basel, Basel, Switzerland;4. SAKK Coordinating Center, Bern, Switzerland;5. Medical Oncology, University Hospital Zurich, Zurich, Switzerland;6. Medical Oncology, Cantonal Hospital Graubünden, Chur, Switzerland;7. Medical Oncology, Cantonal Hospital St Gallen, St Gallen, Switzerland;8. Medical Oncology, Cantonal Hospital Fribourg, Fribourg, Switzerland;9. Cancer Center, University Hospital Lausanne, Lausanne, Switzerland;10. Medical Oncology, Cantonal Hospital Thun, Thun, Switzerland;11. Medical Oncology, Cantonal Hospital Valais, Sion, Switzerland;12. Institute of Pathology, University Hospital Basel, Basel, Switzerland;13. Department of Clinical Research, University of Bern, Bern, Switzerland;14. Department of Hematology, University Hospital Bern, Bern, Switzerland;15. Laboratory of Clinical Chemistry, University Hospital Bern, Bern, Switzerland;16. Pulmonology, Cantonal Hospital St Gallen, St Gallen, Switzerland;17. Medical Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland;18. Medical Oncology, University Hospital Bern, Bern, Switzerland;1. Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;2. Department of Medical Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan;3. Department of Respiratory Medicine, Miyagi Cancer Center, Natori, Japan;4. Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan;5. Hirosaki Central Hospital, Hirosaki, Japan;6. Division of Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa, Japan;7. Obihiro-Kousei General Hospital, Obihiro, Japan;8. Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan;9. Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan;10. Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan;11. Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan;12. Division of Respirology, NTT Medical Center Tokyo, Tokyo, Japan;13. Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan;14. Division of Respiratory Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan;15. Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan;p. Department of Pathology, Miyagi Cancer Center, Natori, Japan;1. Department of General Surgery, Shandong University Qilu Hospital, Jinan, China;2. Department of General Surgery, Yishui Central Hospital, Linyi, China;3. Department of Pharmacy, Shandong Provincial Hospital, Jinan, China;4. Department of Pathology, Linyi People’s Hospital, Linyi, China;5. Department of Surgery, Jinan Central Hospital, Jinan, China;6. Department of Pathology, Shandong University Medical School, Jinan, China;7. Department of Pathology, Shandong University Qilu Hospital, Jinan, China;1. Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;2. Biometrics Department, The Netherlands Cancer Institute, Amsterdam, The Netherlands;3. Pathology Department, The Netherlands Cancer Institute, Amsterdam, The Netherlands;4. Pulmonary Medicine, Amphia Ziekenhuis Breda, The Netherlands;5. Department of Radiation Oncology, Verbeeten Institute, Tilburg, The Netherlands;6. Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;7. Pulmonary Medicine, Haga Ziekenhuis The Hague, The Netherlands;8. Pulmonary Medicine, Academic Medical Centre, Amsterdam, The Netherlands;9. Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands |
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| Abstract: | BackgroundThis 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.MethodsOral afatinib was combined with intravenous paclitaxel (80 mg/m2; days 1, 8 and 15 every four weeks) starting at 20 mg once daily and escalated to 40 and 50 mg 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.ResultsSixteen patients were treated. Dose-limiting toxicities with afatinib 50 mg were fatigue and mucositis. The MTD was determined as afatinib 40 mg with paclitaxel 80 mg/m2, 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 ?6 months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination.ConclusionsThe MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80 mg/m2 (days 1, 8 and 15 every four weeks) was 40 mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity.Trial registrationClinicalTrials.gov, NCT00809133. |
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| Keywords: | Afatinib Paclitaxel ErbB receptors Clinical trial phase I Neoplasms |
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