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1 1 von :00 EU-CTR Version: Home Search About Glossary Data Quality Joining a trial Contacts EudraPharm Clinicaltrialsregister.eu Search for Clinical Trials Summary EudraCT Number: Sponsor's Protocol Code Number: AMLSG15-10 National Competent Authority: Germany - BfArM Clinical Trial Type: EEA CTA Trial Status: Ongoing Date on which this record was first entered in the EudraCT database: Index A. PROTOCOL INFORMATION B. SPONSOR INFORMATION C. APPLICANT IDENTIFICATION D. IMP IDENTIFICATION D.8 INFORMATION ON PLACEBO E. GENERAL INFORMATION ON THE TRIAL F. POPULATION OF TRIAL SUBJECTS G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED P. END OF TRIAL A. Protocol Information A.1 Member State Concerned Germany - BfArM A.2 EudraCT number A.3 Full title of the trial Randomized Phase III Study of Low-Dose Cytarabine and Etoposide with or without All-Trans Retinoic Acid in Older Patients not Eligible for Intensive Chemotherapy with Acute Myeloid Leukemia and NPM1 Mutation A.3.1 Title of the trial for lay people, in easily understood, i.e. non-technical, language Randomisierte Phase III Studie zu niedrig dosiertem Cytarabin und Etoposid mit oder ohne All-trans Retinsäure bei älteren, für eine intensive Chemotherapie ungeeigneten Patienten mit einer akuten myeloischen Leukämie und NPM1-Genmutation A.3.2 Name or abbreviated title of the trial where available AMLSG A.4.1 Sponsor's protocol code number AMLSG15-10 A.5.2 A.7 A.8 US NCT (ClinicalTrials.gov registry) number Trial is part of a Paediatric Investigation Plan EMA Decision number of Paediatric Investigation Plan NCT B. Sponsor Information B.Sponsor: 1 B.1.1 Name of Sponsor University Hospital Ulm B Country Germany B.3.1 and B.3.2 Status of the sponsor n-commercial B.4 Source(s) of Monetary or Material Support for the clinical trial: B.4.1 Name of organisation providing support University Hospital Ulm B.4.2 Country Germany B.4.1 Name of organisation providing support Bundesministerium für Bildung und Forschung B.4.2 Country Germany B.5 Contact point designated by the sponsor for further information on the trial B.5.1 Name of organisation University Hospital Ulm B.5.2 Functional name of contact point AMLSG Clinical Trials Office B.5.3 Address: B Street Address Albert-Einstein-Allee 23 B Town/ city Ulm B Post code B Country Germany B.5.4 Telephone number

2 2 von :00 B. Sponsor Information B.5.5 Fax number B.5.6 richard.schlenk@uniklinik-ulm.de D. IMP Identification D.IMP: 1 D.1.2 and IMP Role Test D.1.3 D.2 Status of the IMP to be used in the clinical trial D.2.1 IMP to be used in the trial has a marketing authorisation Yes D Trade name Vesanoid D D Name of the Marketing Authorisation holder Country which granted the Marketing Authorisation Roche Pharma AG European Union D.2.5 The IMP has been designated in this indication as an orphan drug in the Community D Orphan drug designation number D.3 Description of the IMP D.3.1 Product name all-trans retinoic acid D.3.2 Product code ATRA D.3.4 Pharmaceutical form Capsule D Specific paediatric formulation D.3.7 Routes of administration for this IMP Oral use D.3.8 to D.3.10 IMP Identification Details (Active Substances) D.3.8 INN - Proposed INN Tretinoin D CAS number D.3.10 Strength D Concentration unit mg milligram(s) D Concentration type equal D Concentration number 10 D.3.11 The IMP contains an: D Active substance of chemical origin Yes D Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) The IMP is a: D Advanced Therapy IMP (ATIMP) D Somatic cell therapy medicinal product D Gene therapy medical product D Tissue Engineered Product D D Combination ATIMP (i.e. one involving a medical device) Committee on Advanced therapies (CAT) has issued a classification for this product D Combination product that includes a device, but does not involve an Advanced Therapy D Radiopharmaceutical medicinal product D Immunological medicinal product (such as vaccine, allergen, immune serum) D Plasma derived medicinal product D Extractive medicinal product D Recombinant medicinal product Medicinal product containing genetically D modified organisms D Herbal medicinal product D Homeopathic medicinal product D Another type of medicinal product D.8 Information on Placebo E.1 Medical condition or disease under investigation

3 3 von :00 E.1.1 Medical condition(s) being investigated Adult patients (>60) with AML and NPM1 mutation ineligible for intensive chemotherapy E Medical condition in easily understood language ältere, für eine intensive Chemotherapie ungeeignete Patienten (>60) mit einer akuten myeloischen Leukämie und NPM1-Genmutation E Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15] MedDRA Classification E.1.3 Condition being studied is a rare disease Yes E.2 Objective of the trial E.2.1 Main objective of the trial Primary Efficacy Objective Evaluation of overall survival after treatment with low-dose cytarabine and etoposide with or without all-trans retinoic acid (ATRA) in patients with acute myeloid leukemia (AML) and nucleophosmin-1 (NPM1) mutation ineligible for intensive treatment Secondary Efficacy Objectives Evaluation of efficacy based on complete remission (CR) rates, event-free survival (EFS), and cumulative incidences of relapse and deaths in CR E.2.2 Secondary objectives of the trial Safety and QoL Objectives Evaluation of safety based on toxicity Evaluation of safety based on duration of neutropenia and leukopenia after each treatment cycle, incidence of infections, duration of hospitalization Assessment of quality of live E.2.3 Trial contains a sub-study E.3 Principal inclusion criteria Patients with confirmed diagnosis of acute myeloid leukemia according to the World Health Organization (WHO) classification (including de novo AML, t-aml and s-aml) Presence of NPM1 mutation as assessed in one of the central AMLSG reference laboratories. Age > 60 years. There is no upper age limit. prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if needed for up to 10 days during the diagnostic screening phase. Signed written informed consent Men must give their informed consent that they do not father a baby and must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy while on therapy and for 3 month after the last dose of chemotherapy. WHO performance status 3 Patients not eligible for intensive chemotherapy according to at least one of the following criteria -HCT-CI Score >2 (see Appendix F) -Patient s decision -age 75 years E.4 Principal exclusion criteria All other AML subtypes, in particular those AML with other recurrent genetic changes (according to WHO 2008): - AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 - AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 - AML with t(15;17)(q22;q12); PML-RARA (or other translocations involving RARA) - AML with t(9;11)(p22;q23); MLLT3-MLL (or other translocations involving MLL) - AML with t(6;9)(p23;q34); DEK-NUP214 - AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 consent for registration, storage and processing of the individual diseasecharacteristics and course as well as information of the family physician and all other treating physicians about study participation Bleeding disorder independent of leukemia Uncontrolled infection Known positive for HIV, HBV or HCV Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or ALP >2.5x upper normal serum level, not attributable to AML; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder) Severe neurological or psychiatric disorder interfering with ability of giving an informed consent Patients with a currently active second malignancy other than non-melanoma skin cancers. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. E.5 End points E.5.1 E E.5.2 Primary end point(s) Timepoint(s) of evaluation of this end point Secondary end point(s) Primary Efficacy Endpoint Overall Survival (OS) at the end of the trial Secondary Efficacy Endpoints Rates of CR Cumulative incidences of relapse (CIR) and death in CR (CID) Event-free survival (EFS) Safety Endpoints Rate of early deaths (ED)/hypoplastic deaths (HD) Type, frequency, severity (graded using the National Cancer Institute Common

4 4 von :00 E Timepoint(s) of evaluation of this end point Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.0), timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during different treatment cycles Incidence of infection after each treatment cycle Duration of neutropenia and thrombocytopenia as well as duration of hospitalization after each treatment cycle QoL Endpoint Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics according to Messerer et al. Safety will be monitored by internal and external supervision. After cohorts of 25 patients, the analyses of the safety end points will be performed and results will be sent to the internal monitoring board (principle investigator, chairs of the AMLSG, biostatistician, AMLSG Steering Committee). Twelve-monthly, a study report comprising the safety end point report, a summary as well as a complete list of serious adverse events (SAE), results of blinded central versus on-site disease assessment and a summary of study con-duct to assess protocol adherence will be sent to the external Data Monitoring and Safety Board (DMSB). The DMSB will have to answer within 1 month with a common statement concerning the further conduct of the study. E.6 and E.7 Scope of the trial E.6 Scope of the trial E.6.1 Diagnosis E.6.2 Prophylaxis E.6.3 Therapy Yes E.6.4 Safety E.6.5 Efficacy Yes E.6.6 Pharmacokinetic E.6.7 Pharmacodynamic E.6.8 Bioequivalence E.6.9 Dose response E.6.10 Pharmacogenetic E.6.11 Pharmacogenomic E.6.12 Pharmacoeconomic E.6.13 Others E.7 Trial type and phase E.7.1 Human pharmacology (Phase I) E First administration to humans E Bioequivalence study E Other E Other trial type description E.7.2 Therapeutic exploratory (Phase II) E.7.3 Therapeutic confirmatory (Phase III) Yes E.7.4 Therapeutic use (Phase IV) E.8 Design of the trial E.8.1 Controlled Yes E Randomised Yes E Open Yes E Single blind E Double blind E Parallel group Yes E Cross over E Other E.8.2 Comparator of controlled trial E Other medicinal product(s) Yes E Placebo E Other E Number of treatment arms in the trial 2 E.8.3 E.8.4 E The trial involves single site in the Member State concerned The trial involves multiple sites in the Member State concerned Number of sites anticipated in Member State concerned Yes 45

5 5 von :00 E.8.5 The trial involves multiple Member States Yes E Number of sites anticipated in the EEA 50 E.8.6 Trial involving sites outside the EEA E Trial being conducted both within and outside the EEA Trial being conducted completely outside E of the EEA E.8.7 Trial has a data monitoring committee Yes E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial this information is provided in the protocol: 13.2, 11 E.8.9 Initial estimate of the duration of the trial E In the Member State concerned years 6 E In the Member State concerned months 0 E In the Member State concerned days 0 E E E In all countries concerned by the trial years In all countries concerned by the trial months In all countries concerned by the trial days F. Population of Trial Subjects F.1 Age Range F.1.1 Trial has subjects under 18 F.1.1 Number of subjects for this age range: 0 F In Utero F Number of subjects for this age range: 0 Preterm newborn infants (up to F gestational age < 37 weeks) F Number of subjects for this age range: 0 F Newborns (0-27 days) F Number of subjects for this age range: 0 F Infants and toddlers (28 days-23 months) F Number of subjects for this age range: 0 F Children (2-11years) F Number of subjects for this age range: 0 F Adolescents (12-17 years) F Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) Yes F Number of subjects for this age range: 29 F.1.3 Elderly (>=65 years) Yes F Number of subjects for this age range: 115 F.2 Gender F.2.1 Female Yes F.2.2 Male Yes F.3 Group of trial subjects F.3.1 Healthy volunteers F.3.2 Patients Yes F.3.3 Specific vulnerable populations F Women of childbearing potential not using contraception Information not present in EudraCT F Women of child-bearing potential using contraception Information not present in EudraCT F Pregnant women Information not present in EudraCT F Nursing women Information not present in EudraCT F Emergency situation Information not present in EudraCT F Subjects incapable of giving consent personally Information not present in EudraCT F Others F.4 Planned number of subjects to be included F.4.1 In the member state 124 F.4.2 For a multinational trial F In the EEA 144 F In the whole clinical trial 144

6 6 von :00 F. Population of Trial Subjects F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition) After finishing all study relevant procedures, therapy and follow-up period, the patient will be followed in terms of routine aftercare and treated if necessary by the primary responsible hematologic-oncologic center. G. Investigator Networks to be involved in the Trial N. Review by the Competent Authority or Ethics Committee in the country concerned N. Competent Authority Decision Authorised N. Date of Competent Authority Decision N. Ethics Committee Opinion of the trial application Favourable N. Ethics Committee Opinion: Reason(s) for unfavourable opinion N. Date of Ethics Committee Opinion P. End of Trial P. End of Trial Status Ongoing Legal tice EU Clinical Trials Register Service Desk: euctr@ema.europa.eu European Medicines Agency Westferry Circus, Canary Wharf, London E14 4HB