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    Summary
    EudraCT Number:2013-003235-30
    Sponsor's Protocol Code Number:H9H-MC-JBAV
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-11-08
    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 ConcernedGermany - BfArM
    A.2EudraCT number2013-003235-30
    A.3Full title of the trial
    Phase 2/3 Study of Monotherapy LY2157299 Monohydrate in Very Low-, Low-, and Intermediate-Risk Patients with Myelodysplastic Syndromes
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study in patients with Myelodysplastic Syndromes
    A.4.1Sponsor's protocol code numberH9H-MC-JBAV
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEli Lilly and Company
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3.4CountryUnited Kingdom
    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.3.1Product nameLY2157299 monohydrate
    D.3.2Product code LY2157299 monohydrate
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNLY2157299
    D.3.9.1CAS number 924898-09-9
    D.3.9.2Current sponsor codeLY2157299
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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.IMP: 2
    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 nameLY2157299 monohydrate
    D.3.2Product code LY2157299 monohydrate
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNLY2157299
    D.3.9.1CAS number 924898-09-9
    D.3.9.2Current sponsor codeLY2157299
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Myelodysplastic Syndromes
    E.1.1.1Medical condition in easily understood language
    Type of blood cancer.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level HLT
    E.1.2Classification code 10028536
    E.1.2Term Myelodysplastic syndromes
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 2 portion
    To estimate the distribution of best HI, based on IWG 2006 criteria in patients with very low-, low-, and intermediate-risk MDS by IPSS-R treated with LY2157299 plus best supportive care. This includes a broad range of responses (see secondary objectives).

    Phase 3 portion
    To compare the percentage of patients with very low-, low-, and intermediate-risk MDS by IPSS-R when treated with LY2157299 versus placebo, in combination with best supportive care, who are transfusion-free or have a rise of ≥1.5 g/dL Hb maintained for at least 8 weeks within the first 24 weeks of treatment.
    E.2.2Secondary objectives of the trial
    Secondary objectives of both Phase 2 and Phase 3:
    •to evaluate the safety and tolerability
    •to characterise the PK profile
    •to estimate within-treatment response (Phase 2) and between-treatment differences (Phase 3) using haematological HI parameters according to IWG criteria, such as
    - freq. of responses or progression for each of the 3 haematopoietic lineages
    - time to best HI
    - duration of best HI
    - change in transfusion requirement for platelets and red cells
    - change in blood counts
    - change in bone marrow fibrosis
    - frequency of bone marrow response (CR + PR) and cytogenetic response
    - duration of HI following discontinuation of LY2157299
    - rate of HI at 3&6 cycles
    •to evaluate PROs to assess fatigue and health status as assessed by the Brief Fatigue Inventory (Phases 2&3) and the EuroQol 5-Dimension 5-Level questionnaire (Phase 3 only)
    •to assess resource utilisation including hospitalisations and emergency room visits
    •to determine PFS and OS at 6&12 months
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    [1] have a confirmed diagnosis of MDS based on the WHO criteria. Patients with 5q deletions are allowed only if they have failed or are intolerant to lenalidomide treatment. Patients with WHO diagnosis of nonproliferative MDS/myeloproliferative neoplasms are also included.
    [2] have IPSS-R category of very low-, low-, or intermediate-risk disease as confirmed by
    • bone marrow examination during screening period (will be used also for the correlative/exploratory studies)
    •≤10% marrow blasts
    •appropriate calculation of their IPSS-R score that is not influenced by rise of haematology scores by prior infusions (eg, by reviewing the transfusion history and associated Hb levels prior to each transfusion during the 8 weeks prior to the screening period)
    [3] meet the following haematologic criteria 8 weeks prior to registration (according to the IWG criteria):
    • Phase 2: anaemia with Hb ≤10.0 g/dL (based on the average of 2 baseline measurements and untransfused for at least 1 week) with or without RBC transfusion dependence confirmed for a minimum of 8 weeks before enrolment (eg, transfusion dependency defined by at least 4 units of RBC administered within 8 weeks before baseline).
    •Phase 3: anaemia with RBC transfusion dependence confirmed within 8 weeks before enrolment (eg, transfusion dependency defined by at least 4 units of RBC administered within 8 weeks before date of enrolment).
    [4] have a performance status of ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale.
    [5] have discontinued all disease-modifying therapy for MDS, including investigational treatments, for 28 days prior to initiation of study treatment, with the exception of transfusions and the following supportive care:
    • Patients may receive prophylactic steroids (such as prednisolone, methylprednisolone, or dexamethasone) to prevent transfusion reactions.
    • Iron chelation therapy is allowed if started prior to enrolment and patients have been stable for at least 3 months.
    • Granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) is allowed in the presence of neutropaenic fever or documented neutropaenic infection.
    • Patients may have been treated with danazol or prior hypomethylating agents
    [6] have adequate hepatic function, defined as bilirubin ≤1.5 x the upper limit of normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤2.5 x ULN
    [7] have adequate renal function, defined as serum creatinine levels ≤2.0 x ULN
    [8] are at least 18 years old at the time of screening
    [9] use an approved contraceptive method (for example, intrauterine device, birth control pills, or barrier device), if appropriate (male and female patients with reproductive potential) during and for 6 months after discontinuation of study treatment
    • Women of childbearing potential must have a negative beta-human chorionic gonadotropin pregnancy test documented within 7 days prior to treatment. If condoms are used as a barrier contraceptive, a spermicidal agent should be added to ensure that pregnancy does not occur. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
    [10] have given written informed consent/assent prior to any study-specific procedures
    [11] are able to swallow tablets
    [12] are willing and able to comply with protocol procedures (including completion of diaries and health outcome measures)
    [13] have documented ferritin, folate, and B12 levels that are above the lower limit of normal as determined by the investigative site
    E.4Principal exclusion criteria
    [14] have moderate or severe cardiovascular disease:
    • have the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension.
    • have documented major ECG abnormalities (not responding to medical treatments).
    • have major abnormalities documented by ECHO with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular [LV] ejection fraction <50%, evaluation based on the institutional lower limit of normal). For additional details, refer to the attached ECHO protocol (Attachment 9).
    • have predisposing conditions that are consistent with development of aneurysms of the ascending aeorta or aeortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aeortic valve, evidence of damage to the large vessels of the heart documented by CT scan/MRI with contrast)
    [15] have previous history of AML
    [16] are women who are pregnant or lactating
    [17] have a serious concomitant systemic disorder including active infection with hepatitis B virus (positive hepatitis B surface antigen [+HBsAg]), hepatitis C virus (HCV), and human immunodeficiency virus (HIV)
    [18] have a second primary malignancy that, in the judgment of the investigator and Lilly, may affect the interpretation of results
    [19] have prior malignancies. Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low (such as basal cell carcinoma), as judged by the Lilly clinical research physician (CRP), are eligible for this study. The Lilly CRP will approve enrolment of patients with prior malignancies in remission before these patients are enrolled.
    [20] are unwilling or unable to participate in, or do not have tissue adequate for participation in, the translational research portion of the study. Patients with inadequate tissue are ineligible for this study.
    [21] are currently enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or device (other than the study drug/device used in this study) or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
    [22] have untreated hypothyroidism as determined by the investigator
    [23] have received ESAs within 28 days prior to enrolment
    [24] are receiving immunosuppressive agents (eg, cyclosporine) except for corticosteroids for transfusions
    E.5 End points
    E.5.1Primary end point(s)
    Phase 2 portion
    Distribution of best Haematological Improvement (HI) based on IWG 2006 criteria

    Phase 3 portion
    Compare % patients who are transfusion free or have Hb increase ≥1.5 g/dL maintained for at least 8 weeks in first 24 weeks
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 2 portion
    Distribution of best Haematological Improvement (HI) based on IWG 2006 criteria - Timepoint: date of start of treatment to study discontinuation any cause

    Phase 3 portion
    Compare % patients who are transfusion free or have Hb increase ≥1.5 g/dL maintained for at least 8 weeks in first 24 weeks - Timepoint: date of randomization to 24 weeks of treatment
    E.5.2Secondary end point(s)
    Phase 2 and 3 portions:
    Estimate within-treatment response (Phase 2) and between-treatment differences (Phase 3) using haematological HI parameters : frequency of responses or progression for each of the 3 haematopoietic lineages; time to and duration of best HI, change in transfusion requirements & blood counts, change in bone marrow fibrosis,frequency of bone marrow and cytogenetic response, rate of HI at 3 & 6 months. Evaluate Safety & PK, Changes in patient-reported outcomess. Progression-free & Overall survival at 6 months, 12 months.

    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase 2 and 3 portions:
    Timepoint – HI-Baseline to disease progression, Safety, PRO – Start of treatment until study discontinuation, PK Cycle 1 to end of treatment, PFS - start of treatment until documented disease progression or death from any cause
    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 Yes
    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 No
    E.6.11Pharmacogenomic No
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Phase 2 single arm unblinded; phase 3 2-arm, randomized, placebo controlled
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Germany
    Israel
    Italy
    Japan
    Spain
    United States
    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
    Each phase of the study will be considered complete when all patients in that phase have had survival assessments at 12 months and/or have completed short-term follow-up, died, withdrawn consent, or remained on treatment after 12 months of study follow-up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 115
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 55
    F.4.2.2In the whole clinical trial 140
    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)
    Patients may continue with LY2157299 treatment and best supportive care if they derive clinical benefit.
    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 Decision2014-02-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-09-24
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