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    Summary
    EudraCT Number:2008-000280-42
    Sponsor's Protocol Code Number:CPKC412D2201
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-07-28
    Trial results View results
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2008-000280-42
    A.3Full title of the trial
    A Single Arm, Phase II, Open-Label Study to Determine the Efficacy of 100mg Twice Daily Oral Dosing of Midostaurin Administered to Patients with Aggressive Systemic Mastocytosis or Mast Cell Leukemia +/- an Associated Hematological Clonal Non-Mast Cell Lineage Disease.
    A.3.2Name or abbreviated title of the trial where available
    ND
    A.4.1Sponsor's protocol code numberCPKC412D2201
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberND
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNOVARTIS FARMA
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMidostaurina
    D.3.2Product code PKC412
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 120685-11-2
    D.3.9.2Current sponsor codePKC412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Aggressive Systemic Mastocytosis or Mast Cell Leukemia +/- an Associated Hematological Clonal Non-Mast Cell Lineage Disease
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10056453
    E.1.2Term Aggressive systemic mastocytosis
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of midostaurin in patients with ASM or MCL with or without an AHNMD when administered orally at a dose of 100 mg b.i.d. continuously for 6 cycles (of 4 weeks each) as measured by overall response rate
    E.2.2Secondary objectives of the trial
    To evaluate the duration of response To evaluate the time to response To evaluate overall survival To evaluate the safety and tolerability of midostaurin in patients with aggressive systemic mastocytosis or mast cell leukemia (+/- an AHNMD) To characterize the KIT mutational status at baseline and after 6 cycles of therapy and evaluate potential associations with efficacy outcomes. Exploratory To explore the pharmacokinetic (PK) profile of midostaurin in patients with ASM or MCL (+/- an AHNMD) To explore potential correlations between improvements in quality of life and observed response rates To explore the clinical benefit as defined as the sum of all responses (MR and PR) plus stable disease (SD) To explore changes in all C-Findings combined, including non-measurable ones.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Aged >18 and &#8804; 70 years of age Patient must give written informed consent ECOG performance status of 0-3 Life expectancy > 12 weeks ECG QTc interval &#8804; 450 ms Meeting the following laboratory values: AST and ALT &#8804; 2.5 x Upper Limit of Normal (ULN), if caused by ASM/MCL &#8804; 5 x ULN Serum Bilirubin &#8804; 1.5 x ULN, if related to ASM/MCL &#8804; 3 x ULN Serum Creatinine &#8804; 2.0 mg/dL Diagnosed with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) according to the WHO criteria for SM plus the established criteria for ASM or MCL documented by: Diagnosis of SM will be based: either on the presence of one major plus at least one minor criterion, or of at least 3 minor criteria: Major criterion: Multifocal dense infiltrates of mast cells (>15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s). Minor criteria: >25% of all mast cells are atypical cells (type I or type II) on bone marrow smears or are spindle-shaped in mast cell infiltrates detected on sections of visceral organs c-kit point mutation at codon 816 in the bone marrow or another extracutaneous organ Mast cells in bone marrow or blood or another extracutaneous organ express CD2 or/and CD25 Baseline serum tryptase concentration > 20 ng/ml (in the case of an associated myeloid neoplasm, is not valid as an SM criterion) Additionally, patients with ASM and MCL also have to present with one or more of the following measurable C-Findings*: ANC<1.0 x 109/L or Hgb < 10g/L or platelets <100 x109/L Hepatomegaly with impaired liver function - i.e. elevated transaminases and/or bilirubin levels and/or hypoalbuminemia (with or without ascites or portal hypertension) Palpable splenomegaly with hypersplenism (e.g. as documented by thrombocytopenia i.e. platelets < 100,000/ &#956;L) Malabsorption with hypoalbuminemia and/or significant weight loss defined as >10% weight loss over the last 6 months *Note: Patients presenting with only non-evaluable C-Findings such as skeletal lesions or hepatomegaly only with ascites or portal hypertension, are not permitted to be included into the study. CFindings need to be documented to result from local aggressive mast cell infiltrates i.e., any other cause/disease must be ruled out For patients with MCL the following criterion has to be met (in addition to the SM and ASM criteria as mentioned above): Bone marrow aspirate smears show 20% or more immature mast cells Typically, there is also an elevated percentage of mast cells in the blood.
    E.4Principal exclusion criteria
    Patients unwilling or unable to comply with the protocol. Any other concurrent severe known disease (except carcinoma in-situ) concurrent severe and/or uncontrolled medical condition (e.g.uncontrolled diabetes, cardiovascular disease including congestive heart failure, myocardial infarction within previous 6 months and poorly controlled hypertension, chronic renal disease, or active uncontrolled infection) which could compromise participation in the study. Confirmed diagnosis of HIV infection or active viral hepatitis. Female patients who are pregnant or breast-feeding or adults of reproductive potential not employing an effective method of birth control. Barrier contraceptives must be used throughout the study in both sexes for fertile patients. Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of midostaurin. Women considered not of childbearing potential include any of the following: no menses for at least 2 years or menses within 2 years but amenorrheic for at least 6 months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal postmenopausal range (according to definition of postmenopausal for laboratory used) or bilateral oophorectomy or radiation castration and amenorrheic for at least 6 months. Patients who have demonstrated relapse to more than two prior regimen of SM treatment - regardless of treatment regimen for supportive care (e.g. symptom limiting therapies). Patients who have received any investigational agent, chemotherapy, interferon-&#945;, or 2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to Day 1. Patients who have aggressive systemic mastocytosis with eosinophilia and known positivity for the FIP1L1-PDGFR&#945; fusion unless they have demonstrated relapse or disease progression on prior imatinib therapy. Patients on imatinib and known to be KIT D816V negative unless they have demonstrated relapse, resistance or intolerance to imatinib. Patients who have received any treatment of midostaurin prior to study entry. Patients who have received hematopoietic growth factor support within 14 days of Day 1 of midostaurin treatment. Patients who have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1. Patients with any pulmonary infiltrate including those suspected to be of infectious origin. In particular, patients with resolution of clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on chest x-ray are not eligible until pulmonary infiltrates have completely resolved. Exception: Patients with ASM/MCL +/- AHNMD related pleural effusion as confirmed by the investigator are permitted to enter the study
    E.5 End points
    E.5.1Primary end point(s)
    overall response rate (ORR)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 60
    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 Decision2008-07-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-07-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-08-24
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