London, 17 January 2013 EMA/70979/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Bosulif International non-proprietary name: bosutinib Procedure No. EMEA/H/C/002373 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Product information Name of the medicinal product: Bosulif Applicant: Pfizer Ltd. Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom Active substance: bosutinib monohydrate International Nonproprietary Name/Common Name: bosutinib Pharmaco-therapeutic group Protein kinase inhibitors (ATC Code): (L01XE14) Bosulif is indicated for the treatment of adult Therapeutic indication: patients with chronic phase (CP), accelerated phase (AP), and blast phase (BP) Philadelphia chromosome positive chronic myelogenous leukaemia (Ph+ CML) previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. Pharmaceutical form: Film-coated tablet Strengths: 100 mg, 500 mg Route of administration: Oral use Packaging: Blister (PVC/ACLAR/PVC) Package sizes: 28 tablets, 30 tablets Bosulif CHMP assessment report Page 2/87 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction....................................................................................................... 10 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 13 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 15 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 15 2.3. Non-clinical aspects ............................................................................................ 16 2.3.1. Introduction .................................................................................................... 16 2.3.2. Pharmacology ................................................................................................. 16 2.3.3. Pharmacokinetics............................................................................................. 17 2.3.4. Toxicology ...................................................................................................... 18 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 28 2.3.6. Discussion on non-clinical aspects...................................................................... 29 2.3.7. Conclusion on the non-clinical aspects ................................................................ 30 2.4. Clinical aspects .................................................................................................. 30 2.4.1. Introduction .................................................................................................... 30 2.4.2. Pharmacokinetics............................................................................................. 35 2.4.3. Pharmacodynamics .......................................................................................... 40 2.4.4. Discussion on clinical pharmacology ................................................................... 41 2.4.5. Conclusions on clinical pharmacology ................................................................. 43 2.5. Clinical efficacy .................................................................................................. 43 2.5.1. Dose response studies...................................................................................... 44 2.5.2. Main studies ................................................................................................... 45 Supportive studies .................................................................................................... 56 2.5.3. Discussion on clinical efficacy ............................................................................ 60 2.5.4. Conclusions on the clinical efficacy ..................................................................... 64 2.6. Clinical safety .................................................................................................... 65 2.6.1. Discussion on clinical safety .............................................................................. 75 2.6.2. Conclusions on the clinical safety ....................................................................... 78 2.7. Pharmacovigilance .............................................................................................. 78 2.8. User consultation ............................................................................................... 81 3. Benefit-Risk Balance.............................................................................. 81 4. Recommendations ................................................................................. 85 Bosulif CHMP assessment report Page 3/87 List of abbreviations AE adverse event ALT aspartate aminotransferase AP accelerated phase ASMT advanced solid malignant tumours AST alanine aminotransferase AUC total area under the concentration-versus-time curve (AUCT + CT/λz) AUCT area under the concentration-time curve to the last observable concentration (CT) at time T BA bioavailability BC blast crisis BCR-ABL breakpoint cluster region-abelson BE bioequivalence BMI body mass index BP blast phase BSA body surface area CCyR complete cytogenetic response CHMP Committee for Human Medicinal Products CHR complete haematologic response CI confidence interval c-KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog CL/F apparent oral clearance CLCR creatinine clearance CLR renal clearance Cmax peak/maximum concentration CMH Cochran-Mantel-Haenszel Cmin minimum concentration CML chronic myelogenous leukaemia CMR complete molecular response CNS Central nervous system CP chronic phase CrkL v-crk sarcoma virus CT10 oncogene homolog (avian)-like CSR clinical study report CV coefficient of variation CYP cytochrome P450 DLT dose limiting toxicity DOE Design of experiments DSC Differential Scanning Calorimetry ECOG Eastern Cooperative Oncology Group EFS event-free survival ER estrogen receptor Bosulif CHMP assessment report Page 4/87 erbB2 erythroblastic leukaemia viral oncogene homolog 2 FID Flame Ionization Detector FISH fluorescence in situ hybridization GC Gas chromatography GI Gastrointestinal GLP Good laboratory practice GRAS Generally Recognised As Safe hERG Human ether-à-go-go related gene HPLC High Performance Liquid Chromatography HRQOL health-related quality of life HSCT haemopoietic stem cell transplantation IC50 Concentration of drug required for 50% inhibition ICH International conference on harmonization INN International Non-Proprietary Name IR Infrared spectroscopy IRIS International Randomised Study of Interferon versus STI571 ITT intent-to-treat IV Intravenous K–M Kaplan-Meier L/h liters per hour Lyn Yamaguchi sarcoma viral (v-yes-1) oncogene homolog M2 oxydechlorinated bosutinib M5 N-desmethyl bosutinib MCyR major cytogenetic response MHR major haematologic response MMR major molecular response msec millisecond(s) MTD maximum tolerated dose NA not applicable NOAEL No observed adverse effect level NOEL No observed effect level OHR overall haematologic response OS overall survival PCyR partial cytogenetic response PD pharmacodynamic(s) PDCO Paediatric Committee PDGFR platelet-derived growth factor receptor PFS progression-free survival Pgp P-glycoprotein PgR progesterone receptor Ph+ Philadelphia chromosome positive Ph. Eur. Pharmacopoeia Europea Bosulif CHMP assessment report Page 5/87 PK pharmacokinetic(s) PRO patient-reported outcomes PVC Polyvinul chloride QD once daily QT interval measure of time between the start of the Q wave and end of the T wave in the heart’s electrical cycle QTc QT interval, corrected QTcF interval Fridericia’s correction of QT interval R accumulation ratio RH relative humidity RPT report RRT Relative Retention Time RT-PCR reverse transcriptase-polymerase chain reaction SAE serious adverse event SD standard deviation SE standard error SFK Src family kinase SR slow release Stat5 signal transducer and activator of transcription 5A τ time of the dosing interval t1/2 apparent terminal half-life TEAE treatment-emergent adverse event TEC Tyrosin protein kinase TKI tyrosine kinase inhibitor tlag absorption lag time tmax time to maximum or peak concentration TR target release UV ultraviolet Vz/F apparent volume of distribution