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    Summary
    EudraCT Number:2020-004528-40
    Sponsor's Protocol Code Number:SY-1425-301
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-03-15
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2020-004528-40
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled Phase 3 Study of Tamibarotene Plus Azacitidine Versus Placebo Plus Azacitidine in Newly Diagnosed Adult Patients Selected for RARA-positive Higher-risk Myelodysplastic Syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to test how the investigational drug tamibarotene works in combination with azacitidine to treat higher-risk Myelodysplastic Syndrome (MDS) in patients with a certain biomarker in their blood.
    A.3.2Name or abbreviated title of the trial where available
    SELECT-MDS-1
    A.4.1Sponsor's protocol code numberSY-1425-301
    A.5.4Other Identifiers
    Name:INDNumber:129755
    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 SponsorSyros Pharmaceuticals, Inc
    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 supportSyros Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSyros Pharmaceuticals Inc.
    B.5.2Functional name of contact pointKimberley Caliri
    B.5.3 Address:
    B.5.3.1Street Address35 CambridgePark Drive, 4th floor
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02140
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 617 674 9074
    B.5.6E-mailkcaliri@syros.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 nameTamibarotene
    D.3.2Product code -
    D.3.4Pharmaceutical form 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 INNTAMIBAROTENE
    D.3.9.1CAS number 94497-51-5
    D.3.9.2Current sponsor code-
    D.3.9.4EV Substance CodeSUB10822MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 RoleComparator
    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 Yes
    D.2.1.1.1Trade name Vidaza 25 mg/ml powder for suspension for injection
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameVidaza
    D.3.2Product code -
    D.3.4Pharmaceutical form Powder for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.2Current sponsor code-
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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) 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 placeboTablet
    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
    Newly Diagnosed RARA-positive Adult Patients with Higher-risk Myelodysplastic Syndrome
    E.1.1.1Medical condition in easily understood language
    Adult patients with higher-risk Myelodysplastic syndrome (MDS) who have high levels of the RARA biomarker in their blood.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10028533
    E.1.2Term Myelodysplastic syndrome
    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
    Characterize and compare the complete remission/complete response rate of tamibarotene plus azacitidine vs. placebo plus azacitidine
    E.2.2Secondary objectives of the trial
    - Characterize and compare the overall response rate of tamibarotene plus azacitidine vs. placebo plus azacitidine;
    - Characterize and compare the Event-free survival of tamibarotene plus azacitidine vs. placebo plus azacitidine;
    - Characterize and compare the overall survival of tamibarotene plus azacitidine vs. placebo plus azacitidine;
    - Characterize the duration of complete response and duration of overall response of tamibarotene plus azacitidine or placebo plus azacitidine;
    - Characterize the time to complete remission/complete response and time to initial response of tamibarotene plus azacitidine vs. placebo plus azacitidine;
    - Characterize the safety of tamibarotene plus azacitidine vs. placebo plus azacitidine.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must be at least 18 years old at the time of signing of an informed consent.
    2. Patients must be RARA-positive based on the investigational assay.
    3. Patients must be newly diagnosed with HR-MDS as follows:
    Diagnosis of MDS according to the WHO classification (Arber 2016) and classified by the IPSS-R risk category as:
    a. Very High (risk score >6),
    b. High (risk score >4.5 to 6), OR
    c. Intermediate (risk score >3 to 4.5).
    4. Patients must have measurable disease with bone marrow blasts >5% at the Screening Visit.
    5. Patients must have ECOG Performance Status of ≤2.
    6. Patients must have adequate organ function, as defined by:
    a. total bilirubin ≤3.0 × the ULN,
    b. ALT and AST ≤3 × ULN, and
    c. creatinine clearance ≥30 mL/min based on the Cockcroft-Gault Glomerular Filtration Rate estimation.
    7. Patients must have a serum/urine pregnancy test (for females of childbearing potential) that is negative at the Screening Visit and immediately prior to initiation of treatment (first dose of study drug).
    8. Patients must be willing and able to comply with the scheduled study visits, treatment plans, laboratory tests, use of 2 methods of birth control (including a barrier method) for women of childbearing potential (WOCBP) and male patients (as described in Appendix 4), and other procedures.
    9. Patients must be capable of giving signed and dated IRB or IEC approved informed consent document.
    E.4Principal exclusion criteria
    1. Patients are suitable for and agree to undergo allogeneic HSCT at the time of screening.
    2. Patients received prior treatment for MDS with any hypomethylating agent, chemotherapy (including lenalidomide), or allogeneic HSCT, with the exception of prior treatment with growth factors or hydroxyurea. Growth factor treatment must be discontinued at least 2 weeks prior to starting study drug. Hydroxyurea treatment must be discontinued prior to starting study drug.
    3. Patients are currently receiving treatment for a malignancy (not including basal cell carcinoma, non-melanoma skin cancer, cervical carcinoma in situ, or localized prostate cancer treated with hormone therapy). Patients with history of other cancers should be free of disease for at least 2 years prior to the Screening Visit.
    4. Patients have an active, life-threatening, or clinically-significant, uncontrolled systemic infection requiring hospitalization.
    5. Patients have a known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy).
    6. Immunocompromised patients with increased risk of opportunistic infections, including known HIV-positive patients with CD4 counts ≤350 cells/mm3 or history of opportunistic infection in the last 12 months. Note: To ensure that effective ART, when used in eligible HIV-positive patients, is tolerated and that toxicities are not confused with investigational drug toxicities, patients should be on an established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to the Screening Visit.
    7. Patients have a known active or chronic hepatitis B or active HCV infection. Patients with a history of HCV infection who have completed curative therapy for HCV at least 12 weeks before the Screening Visit and have a documented undetectable viral load at the Screening Visit are eligible for enrollment.
    8. Patients have other severe acute or chronic medical conditions (and/or psychiatric conditions or laboratory abnormalities) that may increase the expected risk to the patient (i.e., the risk associated with the study participation or investigational product administration), or that may interfere with the interpretation of study results or, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    9. Patients received prior treatment with ATRA or systemic retinoid for a hematologic malignancy.
    10. Patients have not adequately recovered from a major surgery within 4 weeks of starting study drug administration.
    11. Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to the first dose of the study drug.
    12. Patients known to be refractory to platelet or packed red blood cell transfusions per Institutional Guidelines, or patients who refuse blood product support.
    13. Patients received strong inducers of CYP3A4 (see Appendix 6) within 2 weeks prior to the first tamibarotene/placebo administration.
    14. Patients received any other investigational agents within 4 weeks of the Screening Visit, or <5 half-lives since completion of previous investigational therapy have elapsed, whichever is shorter.
    15. Patients require concurrent treatment with any investigational or approved oncology agent.
    16. Patients with ≥20% blasts in peripheral blood or bone marrow or bone marrow or evidence of myeloid sarcoma (extramedullary AML).
    17. Patients with Grade ≥2 hypertriglyceridemia, defined as >300 mg/dL (CTCAE, version 5)
    18. Patients with QTc interval >480 msec based on triplicate ECG readings at the Screening Visit using QTcF, with the exception of patients with right bundle branch block or left bundle branch block
    19. Pregnant females, breastfeeding females, and males not willing to comply with contraceptive requirements or females of childbearing potential not willing to comply with contraceptive requirements.
    20. Patients who have a hypersensitivity to tamibarotene, azacitidine, or to any of their excipients.
    21. Patients for whom treatment with tamibarotene or azacitidine is contraindicated.
    E.5 End points
    E.5.1Primary end point(s)
    Complete remission/complete response rate, defined as the proportion of patients achieving complete remission/complete response as determined by the investigator per the modified IWG MDS criteria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the course of the study
    E.5.2Secondary end point(s)
    - Overall response rate, defined as the proportion of patients who achieve complete remission/complete response, partial remission/partial response, marrow complete remission/complete response, or hematologic improvement as determined by the investigator per the modified International Working Group Myelodysplastic syndrome (IWG MDS) criteria;
    - Event-free survival, defined as the time from the date of randomization to the date of transformation to Acute myeloid leukemia or death due to any cause, whichever occurs first;
    - Overall survival, defined as the duration from the date of randomization to the date of death due to any cause;
    - Transfusion independence rate, defined as the proportion of patients who achieve transfusion independence. Transfusion independence is a period of at least 56 days with no red blood cells or platelet transfusion since the date of randomization to the last dose of study drug +30 days, the initiation of post-treatment therapy, or death, whichever occurs first;
    - Duration of complete response, defined as the duration from the date of first documented evidence of complete remission/complete response to the date of documented relapse of disease as determined by the investigator per the modified IWG MDS criteria, or death due to any cause, whichever occurs first;
    - Duration of overall response defined as the duration from the date of first documented evidence of complete remission/complete response, partial remission/partial response, marrow complete remission/complete response, or hematologic improvement to the date of documented disease progression, relapse of disease as determined by the investigator per the modified IWG MDS criteria, or death due to any cause, whichever occurs first;
    - Time to complete remission/complete response, defined as the duration from the date of randomization to the date of the first documented evidence of complete remission/complete response as determined by the investigator per the modified IWG MDS criteria;
    - Time to initial response, defined as the duration from the date of randomization to the date of the first documented evidence of complete remission/complete response, partial remission/partial response, marrow complete remission/complete response, or hematologic improvement as determined by the investigator per the modified IWG MDS criteria;
    - Incidence of adverse events and changes in clinical laboratory values, electrocardiogram results, and vital sign measurements.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the course of the study
    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 No
    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) No
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    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 EEA66
    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
    Canada
    Israel
    Mexico
    United States
    Austria
    Belgium
    Czechia
    France
    Germany
    Hungary
    Italy
    Poland
    United Kingdom
    Spain
    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
    The end of the study is defined as the date of the last scheduled procedure shown in the protocol Schedule of Activities for the last patient in the study globally.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    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: 161
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 29
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 95
    F.4.2.2In the whole clinical trial 190
    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 will receive treatment until they meet study drug discontinuation criteria, as described in the Overall Design (par. 4.1 of the protocol). Patients will be followed for up to 5 years after discontinuation of study drug.
    At the time of study termination, if there are patients benefitting from treatment in the opinion of the investigator, the investigator should contact the medical monitor to discuss the possibility of treatment continuation.
    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 Decision2021-05-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-07
    P. End of Trial
    P.End of Trial StatusOngoing
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