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    Summary
    EudraCT Number:2011-001012-56
    Sponsor's Protocol Code Number:I3X-MC-JHTB(a)
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-06-27
    Trial 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 ConcernedAustria - BASG
    A.2EudraCT number2011-001012-56
    A.3Full title of the trial
    A Phase 2 Study of LY2784544 in Patients with Myeloproliferative Neoplasms
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of LY2784544 in patients with blood cancer
    A.3.2Name or abbreviated title of the trial where available
    JHTB
    A.4.1Sponsor's protocol code numberI3X-MC-JHTB(a)
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01594723
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEli Lilly and Company
    B.1.3.4CountryUnited States
    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 supportnot applicable
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEli Lilly
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street AddressChemin des Coquelicots, 16
    B.5.3.2Town/ cityVernier/Geneva
    B.5.3.3Post code1214
    B.5.3.4CountrySwitzerland
    B.5.6E-mailEU_Lilly_Clinical_Trials@lilly.com
    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.3.2Product code LY2784544
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNn/a
    D.3.9.1CAS number n/a
    D.3.9.2Current sponsor codeLY2784544
    D.3.9.3Other descriptive nameImidazo[1,2-b]pyridazin-6-amine,3-[(4-chloro-2-flurophenyl)methyl]-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(4-morpholinylmethyl)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 200
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    Myeloproliferative neoplasms (MPNs), myelofibrosis, essential thrombocythemia, and polycythemia vera
    E.1.1.1Medical condition in easily understood language
    MPNs are a group of diseases of the bone marrow which result in the production of excess cells. They are related to and may evolve into leukemia.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10036061
    E.1.2Term Polycythemia vera
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10028537
    E.1.2Term Myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10015493
    E.1.2Term Essential thrombocythaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to assess the activity of LY2784544 therapy administered once daily, as measured by objective response rate, in patients with the myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF).
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are:
    To characterise the toxicity profile
    To assess response criteria
    To assess efficacy
    To characterise PD-PHK.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    [1] Have a diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or myelofibrosis (MF) as defined by the World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (Swerdlow et al. 2008) and meet the following additional subtype specific criteria:
    A. PV:
    i. have failed or is intolerant of standard therapies or refuses to take standard medications.
    B. ET:
    i. have failed or is intolerant of standard therapies or refuses to take standard medications.
    C. MF (patients with MF must meet at least 1 of the following):
    i. have intermediate 1, intermediate 2, or high-risk MF according to the Dynamic International Prognostic Scoring System (DIPPS Plus) for Primary Myelofibrosis (Gangat et al. 2011); or
    ii. have symptomatic MF with spleen greater than 10 cm below left costal margin; or
    iii. have post-polycythemic MF; or
    iv. have post-ET MF
    All PV, ET, and MF patients must meet the following criteria:
    [2] Have a quantifiable JAK2 V617F mutation. For patients in Dose Level 3, this inclusion criterion will not apply to the subset of patients in Cohorts 10 and 11 that are required to be negative for the JAK2 V617F mutation. This subset of patients must be negative for the mutation with unquantifiable levels of JAK2 V617F.
    [3] Are 18 years of age.
    [4] Have given written informed consent prior to any study-specific procedures.
    [5] Have adequate organ function, including:
    Hepatic: Bilirubin 1.5 times upper limits of normal (ULN), alanine transaminase (ALT), and aspartate transaminase (AST) 2.5 times ULN.
    Renal: Serum creatinine 1.5 times ULN.
    Bone Marrow Reserve: Absolute neutrophil count (ANC) ≥1000/mcL, platelets ≥50,000 /mcL for patients with ET or PV and ≥25,000 /mcL for patients with MF.
    [6] Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale (refer to Attachment 4).
    [7] Have discontinued all previous approved therapies for MPNs, including any chemotherapy, immunomodulating therapy (for example, thalidomide, interferon-alpha), immunosuppressive therapy (for example, corticosteroids >10 mg/day prednisone or equivalent), radiotherapy, and erythropoietin, thrombopoietin, or granulocyte colony stimulating factor for at least 14 days and recovered from the acute effects of therapy. Hydroxyurea used to control blood cell counts is permitted at study entry if the subject has been maintained on a stable dose for at least 4 weeks. Low-dose acetylsalicylic acid (aspirin) is permitted as well.
    [8] Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.
    [9] Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the study and for 3 months following the last dose of study drug.
    [10] Females with child-bearing potential must have had a negative urine pregnancy test 7 days before the first dose of study drug and must also not be breastfeeding.
    [11] Are able to swallow capsules.
    [12] For patients who have undergone recent major surgery, at least 28 days must have elapsed between surgery and study participation and the subject must have achieved, in the opinion of the treating physician, at least a good recovery from the surgical procedure
    E.4Principal exclusion criteria
    [13] Are currently enrolled in, or discontinued within the last 14 days from a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
    [14] Have a corrected QT (QTc) interval >470 msec using Bazett's formula.
    [15] Have serious preexisting medical conditions that, in the opinion of the investigator would preclude participation in the study (for example a gastrointestinal disorder causing clinically significant symptoms such as nausea, vomiting, and diarrhea, or malabsorption syndrome).
    [16] Are currently being treated with agents that are metabolized by CYP3A4 with a narrow therapeutic margin (for example, alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) or CYP2B6 (for example, cyclophosphamide, ifosfamide, tamoxifen, efavirenz, propofol, methadone, and bupropion).
    [17] Are currently being treated with warfarin or 1 of its derivatives which is known to alter levels of protein C or protein S. An exception to this criterion will be allowed for patients with a prior history of Budd-Chiari Syndrome who are being treated with warfarin or 1 of its derivatives.
    [18] Have received a hematopoietic stem cell transplant.
    [19] Have a second primary malignancy that in the judgment of the Investigator and Sponsor may affect the interpretation of results.
    [20] Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis (screening is not required).
    [21] Have a history of congestive heart failure with New York Heart Association Class >2 (NYHA Class 1 and 2 are eligible), unstable angina, recent myocardial infarction (within 6 months prior to administration of study drug), or documented history of ventricular arrhythmia.
    E.5 End points
    E.5.1Primary end point(s)
    This study is designed to assess evidence of efficacy of LY2784544 and at least 1 out of 10 patients in each cohort must demonstrate objective response in order for the regimen to be considered for further study.
    The primary efficacy measure is objective response as defined by the European LeukemiaNet Response Criteria for ET and PV and the International Working Group Consensus Criteria for Treatment Response in MF. A responder in patients with ET or PV is defined as any patient who exhibits a complete response or partial response for molecular, clinicohematologic, or histologic assessments. A treatment response in patients with MF is defined as any patient who exhibits a complete remission, partial remission, or clinical improvement according to the IWG criteria. Molecular and histologic responses for patients with MF will be assessed in the same way as defined for patients with ET and PV.
    Best response is determined from the sequence of responses assessed.
    The Sponsor or designee will collect and store all bone marrow biopsies and spleen images on all enrolled patients throughout the study. A central review of bone marrow histology including fibrosis grading and reticulin staining will be performed by a blinded, independent panel of pathologists. An independent review of spleen images may be performed if a response to LY2784544 is observed.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Bone Marrow Core Biopsy and Aspirate with karyotype evaluation, as well as physician assessment of response will be done in Cycle 6 and every 6th cycle thereafter (i.e., Cycle 12, 18, 24, etc) or if evidence of molecular remission.
    CT or MRI of Spleen and Liver (may include contrast), as well as physician assessment of response will be collected only in Cycles 3, 6, 9, 12 and then every 6th cycle.
    E.5.2Secondary end point(s)
    Secondary Efficacy Measures
    Molecular response rate: JAK2 V617F mutant clone burden will be used to determine molecular response. Also called mutant allele burden.
    Hematological improvement rate: To determine clinicohematologic response based on complete blood count in conjunction with spleen size and disease related symptoms (preexisting conditions and adverse events).
    Decrease in spleen size: To determine change in spleen size based on physical exam and imaging. Measurements will be used conjunction with blood counts and disease related symptoms for clinicohematologic response.
    Bone marrow biopsy histology: To determine histological response. Bone marrow fibrosis grade will be recorded and standard bone marrow histology will be evaluated.
    Number of thrombotic or hemorrhagic events: To determine if the number of these events is decreased as compared to an individual’s historical records.
    Coagulation factor status: Measured by the following analytes: prothrombin time/international normalized ratio, activated partial thromboplastin time, free protein S, total protein S, Factor II and V functional assay, C4b binding protein.
    Frequency of phlebotomies and transfusions: To determine if the need for and frequency of these procedures is decreased as compared to an individual’s historical records and to determine the effect on the rate of dependence on these procedures.
    Duration of response: (Relapse-free survival for patients who achieve CR). From the time response was achieved to disease progression or death.
    Time to best response: Time from study enrollment to best response (including partial response).
    Health outcome measurements: To assess ability of study treatment to modify health outcome measures using the 6-item physician assessment and patient-reported data from the MPN-SAF, ADL/IADL, and EQ-5D questionnaires.
    IPSS, DIPSS, and DIPSS Plus: To determine the effect of study treatment on DIPSS, DIPSS Plus, and disease risk modification.
    Time to treatment failure: Time from study enrollment to the first observation of objective progression or death from any reason or early , discontinuation of study therapy.
    Time to disease progression: Time from the date of study enrollment to the date of first observation of objective progression.
    Progression-free survival: Time from the date of study enrollment to the date of first observation of objective progression or death from any cause.
    Abbreviations: CR = complete response/remission; DIPSS = Dynamic International Prognostic Scoring System; EQ-5D = EuroQol – 5 dimensions; IPSS = International Prognosis Scoring System; MPN SAF = Myeloproliferative Neoplasm Symptom Assessment Form
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be evaluated throughout the study according to timepoints in the study schedule of events.
    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 Yes
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    United Kingdom
    United States
    Austria
    France
    Germany
    Italy
    Netherlands
    Spain
    Sweden
    E.8.7Trial has a data monitoring committee No
    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
    The end of the trial is the completion of the last visit of the last patient undergoing treatment on the study.
    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 months5
    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 months9
    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.1.2.1Number of subjects for this age range: 138
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 118
    F.4.2.2In the whole clinical trial 188
    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)
    as in protocol
    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 Decision2012-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-10
    P. End of Trial
    P.End of Trial StatusOngoing
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