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CHMP Assessment Report 25 September 2014 EMA/CHMP/726072/2014 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report Vargatef International non-proprietary name: nintedanib Procedure No.: EMEA/H/C/002569/0000 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union Administrative information Name of the medicinal product: Vargatef Applicant: Boehringer Ingelheim International GmbH Binger Strasse 173 55216 Ingelheim GERMANY Active substance: NINTEDANIB International Nonproprietary Name/Common Name: NINTEDANIB Pharmaco-therapeutic group (ATC Code): Not yet assigned Therapeutic indication: In combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first line chemotherapy. Pharmaceutical form: Capsule, soft Strengths: 100 mg and 150 mg Route of administration: Oral use Packaging: Blister (Alu/Alu) Package sizes: 120 (60 x 2) capsules (multipack), 120 capsules and 60 capsules CHMP assessment report EMA/CHMP/726072/2014 Page 2/138 Table of contents Administrative information ......................................................................... 2 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ..................................................................................... 8 1.2. Manufacturers ..................................................................................................... 9 1.3. Steps taken for the assessment of the product ........................................................ 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction ...................................................................................................... 10 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction.................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 14 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16 2.3. Non-clinical aspects ............................................................................................ 16 2.3.1. Introduction.................................................................................................... 16 2.3.2. Pharmacology ................................................................................................. 17 2.3.3. Pharmacokinetics ............................................................................................ 24 2.3.4. Toxicology ...................................................................................................... 26 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 41 2.3.6. Discussion on non-clinical aspects ..................................................................... 42 2.3.7. Conclusion on the non-clinical aspects ............................................................... 48 2.4. Clinical aspects .................................................................................................. 49 2.4.1. Introduction.................................................................................................... 49 2.4.2. Pharmacokinetics ............................................................................................ 50 2.4.3. Pharmacodynamics .......................................................................................... 54 2.4.4. Discussion on clinical pharmacology ................................................................... 55 2.4.5. Conclusions on clinical pharmacology ................................................................. 57 2.5. Clinical efficacy .................................................................................................. 57 2.5.1. Dose response study(ies) ................................................................................. 58 2.5.2. Main study ..................................................................................................... 58 2.5.3. Discussion on clinical efficacy ............................................................................ 87 2.5.4. Conclusions on the clinical efficacy .................................................................... 91 2.6. Clinical safety .................................................................................................... 92 2.6.1. Discussion on clinical safety ............................................................................ 122 2.6.2. Conclusions on the clinical safety .................................................................... 129 2.7. Pharmacovigilance ........................................................................................... 129 2.8. Risk Management Plan ...................................................................................... 129 2.9. Product information .......................................................................................... 133 2.9.1. User consultation .......................................................................................... 133 CHMP assessment report EMA/CHMP/726072/2014 Page 3/138 3. Benefit-Risk Balance ........................................................................... 133 4. Recommendations ............................................................................... 136 CHMP assessment report EMA/CHMP/726072/2014 Page 4/138 List of abbreviations 14C Carbon 14 ADCA Patients with adenocarcinoma ADCA <9months Patients with adenocarcinoma and <9 months since start of first-line therapy ADME Absorption, distribution, metabolism, elimination AE Adverse event AESI Adverse event of special interest AJCC American Joint Committee on Cancer ALKP Alkaline phosphatase ALT Alanine transaminase ANC Absolute neutrophil count ANOVA Analysis of variance aPTT Increased activated partial thromboplastin time AR Assessment Report AST Aspartate transaminase ATC Anatomical Therapeutic Chemical classification system ATP Adenosine triphosphate AUC Area under the time concentration curve b.i.d. Bis in die, twice daily BCRP Breast cancer resistance protein BfArM Bundesinstitut für Arzneimittel und Medizinprodukte, German Health Authority BI Boehringer Ingelheim BIBF 1120 Nintedanib bid Twice daily BMI Body mass index BSA Body surface area CEA Carcinoembryonic antigen CI Confidence interval CIOMS Council for International Organizations of Medical Sciences CL/F Apparent clearance CL/Fss Apparent clearance at steady state Cmax Maximum observed plasma concentration COPD Chronic obstructive pulmonary disease CP Carboplatin/paclitaxel CR Complete response CRA Clinical research associate CRC Colorectal cancer CRF Case report form CT Computed tomography CTCAE Common Terminology Criteria for Adverse Events CTR Clinical trial report CV Coefficient of variance CYFRA-21-1 Cytokeratin Subunit 19 CYP Cytochrome P450 DCE-MRI Dynamic Contrast-enhanced Magnetic Resonance Imaging DHC Ductus hepaticus communis DIC Disseminated intravascular coagulation DLT Dose limiting toxicity DMC Data monitoring committee ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group CHMP assessment report EMA/CHMP/726072/2014 Page 5/138 ECOG PS ECOG performance score EGFR Epidermal growth factor receptor EORTC European Organisation for Research and Treatment of Cancer EOT End of treatment EQ-5D Health Status Self-Assessment Questionnaire F Absolute bioavailability FF Final formulation FGF Fibroblast growth factor FGFR Fibroblast growth factor receptor Flt-3 FMS-like tyrosine kinase 3 fT3 Free triiodothyronine fT4 Free thyroxine FU Follow-up GCP Good clinical practice G-CSF Granulocyte colony stimulating factor gCV Geometric coefficient of variation GFR Glomerular filtration rate GGT γ-Glutamyl transferase GLUT1 Glucose transporter 1 gMean Geometric mean h Hour(s) HPLC-MS/MS High performance liquid chromatography, tandem mass spectroscopy HR Hazard ratio HRPC Hormone refractory prostate cancer HRQoL Health related quality of life HSA Human serum albumin ICH International Conference on Harmonisation IEC Independent Ethics Committee INR International normalised ratio IPF Idiopathic pulmonary fibrosis IRB Institutional Review Board ITT Intention-to-treat IV Intravenous administration IVRS/IWRS Interactive voice/web-based response system Ka First order absorption constant kg kilogram KM Kaplan-Meier L Litre LC-MS/MS Liquid chromatography-tandem mass spectrometry LDH Lactate dehydrogenase LoQ List of Questions LVSI Laboratory values of special interest MCT4 Monocarboxylate transporter 4 MedDRA Medical Dictionary for Drug Regulatory Activities MRI Magnetic resonance imaging MTD Maximum tolerated dose N Sample size N/A Not applicable na Not available NC Not calculated NONMEM Non-linear mixed effect modelling NSCLC Non-small cell lung cancer NYHA New York Heart Association CHMP assessment report
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