26 November 2015 EMA/826135/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report Oncaspar International non-proprietary name: pegaspargase Procedure No. EMEA/H/C/003789/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged. 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 ........................................................ 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction ........................................................................................................ 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction ................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 11 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 2.2.6. Recommendations for future quality development ............................................... 16 2.3. Non-clinical aspects ............................................................................................ 16 2.3.1. Introduction ................................................................................................... 16 2.3.2. Pharmacology ................................................................................................. 17 2.3.3. Pharmacokinetics ............................................................................................ 20 2.3.4. Toxicology ...................................................................................................... 25 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 31 2.3.6. Discussion on non-clinical aspects ..................................................................... 31 2.3.7. Conclusion on the non-clinical aspects ............................................................... 34 2.4. Clinical aspects .................................................................................................. 34 2.4.1. Introduction ................................................................................................... 34 2.4.2. Pharmacokinetics ............................................................................................ 37 2.4.3. Pharmacodynamics .......................................................................................... 53 2.4.4. Discussion on clinical pharmacology .................................................................. 56 2.4.5. Conclusions on clinical pharmacology ................................................................. 59 2.5. Clinical efficacy .................................................................................................. 59 2.5.1. Dose response studies ..................................................................................... 59 2.5.2. Main studies ................................................................................................... 60 2.5.3. Discussion on clinical efficacy............................................................................ 93 2.5.4. Conclusions on the clinical efficacy .................................................................... 96 2.6. Clinical safety .................................................................................................... 96 2.6.1. Discussion on clinical safety ............................................................................ 109 2.6.2. Conclusions on the clinical safety .................................................................... 115 2.7. Pharmacovigilance ........................................................................................... 115 2.8. Risk Management Plan ...................................................................................... 115 2.9. Product information .......................................................................................... 117 2.9.1. User consultation .......................................................................................... 117 3. Benefit-Risk Balance ........................................................................... 118 4. Recommendations ............................................................................... 121 Assessment Report EMA/826135/2016 Page 2/122 List of abbreviations 6-MP 6-Mercaptopurine Ab Antibody ADR Adverse Drug Reaction AE Adverse Event ALL Acute Lymphoblastic Leukaemia ALT Alanine Amino Transferase AML Acute Myeloid Leukemia ANLL Acute Non-Lhymphoblastic Leukaemia API Active Pharmaceutical Ingredient Ara-C Cytosine Arabinoside AS Asparagine Synthetase ASNase Asparaginase AST Aspartate Amino Transferase AUC Area Under the Curve AUL Acute Undifferentiated Leukaemia BFM Berlin-Frankfurt-Münster Bid Bis in die BMT Bone Marrow Transplantation BUN Blood Urea Nitrogen BW Body Weight CALLA+ Reactive to common ALL antigen CCR Continuous Complete remission CHOP Cyclophosphamide adriamycin, vincristine, prednisone CIOMS Council for International Organizations of Medical Sciences CL Total Clearance CL/F Total Clearance for extravascular administration CMED Cyclophosphamide, methotrexate, etoposide, decadron CML Chronic Myelogenous Leukemia CNS Central Nervous System CON Consolidation CR Complete remission CSF Cerebrospinal Fluid CT Computed chromography CTC Common Toxicity Criteria CTD Common Technical Document CTEP Cancer Therapy Evaluation Program d Day DDP Cisplatin DI Delayed Intensification DIC Disseminated Intravascular Coagulation E. coli Escherichia Coli EEG Electroencephalogram EFS Event Free Survival ELISA Enzyme-Linked Immunosorbent Assay EU European Unit F Female F Absolute Bioavailability FAB French–American–British classification Assessment Report EMA/826135/2016 Page 3/122 FDA Food and Drug Administration FL Fluorescent (detection) FSR Final Study Report GGT Gamma Glutamyl Transferase GI Gastrointestinal GLP Good Laboratory Practice GOT see AST h Hour Hb Haemoglobin HD High Dose HI Haematologic Improvement HLA Human Leukocyte Antigen HPLC High Performance Liquid Chromatography HR High Risk i.m. Intramuscular i.p. Intraperitoneal i.v. Intravenous IC50 Half Maximal Inhibitory Concentration Im Intensification Maintenance IM intramuscular IND Induction INN International Nonproprietary Names INR International Normalised Ratio IPII Increased Intensity Post-Induction intensification ISS Integarted Summary of Safety IT Intratecal ITT Intention To Treat IU International Unit IU International Unit IV intravenous KDa Kilo Dalton Km Michaelis-Menten constant L-asp L-asparaginase LD50 Dose causing 50% Lethality LDH Lactate Dehydrogenase LDL Low Density Lipoprotein LE Leukaemic Event LFS Leukaemia Free Survival M Male MAA Marketing Authorization Application MAH Marketing Authorization Holder MDH Malic dehydrogenase MDR Multi Drug Resistance MedDRA Medical Dictionary for Regulatory Activities MIME Methilgag, ifosfamide, methotrexate, etoposide MR Minor Response MRD Minimal Residual Disease MRI Magnetic Resonance Image MS/MS Tandem Mass Spectrometry MTD Maximum Tolerated Dose MTX Methotrexate Assessment Report EMA/826135/2016 Page 4/122 NADH Nicotinamide Adenine Dinucleotide NCI National Cancer Institute NHL Non-Hodgkin’s Lymphoma NOEL No Observed Effect Level NR No Response OAP-Bleo Vincristine, cytarabine, prednisone, bleomycin ORR Overall Response Rate OS Overall survival p.o. Per os PBS Phosphate Buffer Saline PD Pharmacodynamic PEG Polyethylene Glycol PEG-L-asp PEG-L-asparaginase PI Patient Information PII Post-Induction Intensification PK Pharmacokinetics POG Pediatric Oncology Group PR Partial Response PRD Progressive Disease PSUR Periodic Safety Update Report PT Prothrombine Time Pts Patients PTT Partial Thromboplastin Time q Every (quaue) qd Every day (quaque die) RER Rapid Early Responders RES Reticuloendothelial System RPLS Reversible Posterior Leukoencephalopathy Syndrom S. typhimurium Salmonella typhimurium s.c. Subcutaneous SD Stable Disease SE Standard Error SEM Standard Error of Mean SER Slow Early Responders sGOT Serum Glutamate Oxaloacetate Transaminase SGPT Serum Glutamate Pyruvic Transaminase SmPC Summary of Product Characteristics SOC System Organ Classification SPII Standard Intensity Post-Induction intensification SR Standard Risk STD Standard Deviation t1/2 Apparent elimination half-life TE Therapeutic Effect TEAE Treatment Emergent Adverse Event TH Transient hyperglycaemia US United States VCR Vincristine VLDL Very Low Density Lipoprotein VP-16 Etoposide Vss Volume of distribution at steady state Vz Terminal