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    Summary
    EudraCT Number:2020-004287-26
    Sponsor's Protocol Code Number:5F9009
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-03-05
    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 ConcernedIreland - HPRA
    A.2EudraCT number2020-004287-26
    A.3Full title of the trial
    ENHANCE: A Randomized, Double-blind, Multicenter Study Comparing Magrolimab in Combination with Azacitidine versus Azacitidine Plus Placebo in Treatment-naïve Patients with Higher Risk Myelodysplastic Syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing efficacy of Magrolimab in combination with Azacitidine versus Azacitidine Plus Placebo in previously untreated patients with higher risk Myelodysplastic Syndrome
    A.4.1Sponsor's protocol code number5F9009
    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 SponsorGilead Sciences, 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 supportGilead Sciences, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGilead Sciences International Ltd.
    B.5.2Functional name of contact pointClinical Trials Mailbox
    B.5.3 Address:
    B.5.3.1Street AddressFlowers Building, Granta Park
    B.5.3.2Town/ cityAbington, Cambridge
    B.5.3.3Post codeCB21 6GT
    B.5.3.4CountryUnited Kingdom
    B.5.5Fax number+441223897284
    B.5.6E-mailclinical.trials@gilead.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/20/2288
    D.3 Description of the IMP
    D.3.1Product nameMagrolimab
    D.3.2Product code GS-4721
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMagrolimab
    D.3.9.2Current sponsor codeGS-4721
    D.3.9.3Other descriptive nameHu5F9-G4
    D.3.9.4EV Substance CodeSUB194348
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Intermediate/high/very high risk myelodysplastic syndrome (MDS)
    E.1.1.1Medical condition in easily understood language
    Myelodysplastic syndrome (MDS)
    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 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
    To evaluate the efficacy and survival benefit of magrolimab + azacitidine compared to azacitidine + placebo in previously untreated patients with intermediate/high/very high risk MDS by IPSS-R prognostic risk categories.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy, safety, PK, immunogenicity and health-related quality of life, of magrolimab + azacitidine compared to azacitidine + placebo in previously untreated patients with intermediate/high/very high risk MDS by IPSS-R prognostic risk categories.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Participants with MDS defined according to WHO classification, with
    an IPSS-R prognostic risk category of intermediate, high, or very high
    risk. Note: participants who require AML-like therapy are not eligible.
    2. White blood cell (WBC) count ≤ 20 × 10^3/μL prior to randomization.
    If the participant's WBC is > 20 × 10^3/μL prior to randomization, the
    participant can be randomized, assuming all other eligibility criteria are met. Of note, while this does not impact eligibility, please ensure that the WBC is ≤ 20 × 103/μL prior to the first dose of study treatment and prior to each magrolimab/placebo dose for priming doses of magrolimab. Patients can be treated with hydroxyurea (up to 4 g/day) throughout the study or prior to randomization to reduce the WBC to ≤ 20 × 10^3/μL to enable eligibility and magrolimab dosing. Oral etoposide (up to 200 mg orally per day) may be given as an alternative to hydroxyurea for patients who are intolerant to hydroxyurea or cannot achieve sufficient WBC lowering on hydroxyurea.
    3. Participant has provided informed consent.
    4. Participant is willing and able to comply with clinic visits and
    procedures outlined in the study protocol.
    5. Male or female, age ≥ 18 years.
    6. Eastern Cooperative Oncology Group (ECOG) performance score of 0
    to 2.
    7. Willing to undergo blood transfusions as deemed clinically necessary.
    8.Pretreatment blood cross-match including ABO (any of the 4 blood
    groups A, B, AB, and O comprising the ABO system)/Rh (Rhesus factor),
    DAT (direct antiglobulin test), and
    phenotyping or genotyping completed.
    9. Biochemical indices within the ranges shown below:
    a. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic
    transaminase and alanine aminotransferase (ALT)/serum glutamic
    pyruvic transaminase ≤ 3× upper limit of normal (ULN)
    b. Total bilirubin ≤ 1.5 × ULN or 3.0 × ULN and primarily unconjugated if participant has a documented history of Gilbert's syndrome or genetic equivalent
    c. Serum creatinine ≤ 1.5 × ULN or calculated glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2
    10. All participants must have a documented hemoglobin =9.0 g/dL
    within 24 hours prior to the first two doses of magrolimab/placebo
    infusion. Participants who do not meet these criteria must be transfused
    and have their hemoglobin rechecked to meet the minimum hemoglobin
    threshold prior to administering each of the first 2 doses of
    magrolimab/placebo. Transfusions are allowed in order to meet
    hemoglobin eligibility.
    11. Female participants of childbearing potential must not be nursing or planning to be pregnant and must have a negative urine or serum
    pregnancy test within 30 days before randomization and within 72 hours before the first administration of study treatment.
    12. Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix H of
    protocol.
    13. Willing to consent to mandatory pretreatment and on-treatment
    bone marrow biopsies (trephines), unless not feasible as determined vestigator and discussed with the Sponsor.
    E.4Principal exclusion criteria
    1. Prior treatment with CD47 or SIRPα-targeting agents.
    2. Prior therapy for the treatment of MDS with an IPSS-R prognostic risk
    category of intermediate, high or very high risk (excluding hydroxyurea
    or oral etoposide), prior treatment with hypomethylating agents and/or
    low dose cytarabine. NOTE: Localized noncentral nervous system (CNS)
    radiotherapy, erythroid and/or myeloid growth factors, previous
    hormonal therapy with luteinizing hormone-releasing hormone (LHRH)
    agonists for prostate cancer, and treatment with bisphosphonates and
    receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors
    are not criteria for exclusion. Prior lenalidomide is also not exclusionary.
    3. Immediately eligible for an allogeneic SCT, as determined by the
    investigator, with an available donor.
    4. Contraindications to azacitidine, including advanced malignant hepatic
    tumors or known hypersensitivity to azacitidine or mannitol.
    5. Known inherited or acquired bleeding disorders.
    6. Previous SCT within 6 months prior to randomization, active graftversus-
    host disease, or requiring transplant-related immunosuppression.
    7. Clinical suspicion of active CNS involvement by MDS.
    8. Significant medical diseases or conditions, as assessed by the
    Investigators and Sponsor, that would substantially increase the risk
    benefit ratio of participating in the study. This includes, but is not limited
    to, acute myocardial infarction within the last 6 months, unstable
    angina, uncontrolled diabetes mellitus, significant active infections, and
    congestive heart failure New York Heart Association Class III-IV.
    9. Second malignancy, except treated basal cell or localized squamous
    skin carcinomas, localized prostate cancer, or other malignancies for
    which participants are not on active anticancer therapies and have had
    no evidence of active malignancy for at least ≥ 1 year.
    10. History of psychiatric illness or substance abuse likely to interfere
    with the ability to comply with protocol requirements or give informed
    consent.
    11. Pregnancy or active breastfeeding.
    12. Known active or chronic hepatitis B or C infection or HIV infection in
    medical history.
    13) Active hepatitis B virus (HBV) and/or active hepatitis C virus (HCV),
    and/or HIV following testing at screening:
    a) Participants who test positive for hepatitis B surface antigen (HBsAg).
    Participants who test positive for hepatitis B core antibody (anti-HBc)
    will require HBV DNA by quantitative polymerase chain reaction (PCR)
    for confirmation of active disease.
    b) Participants who test positive for HCV antibody. These participants
    will require HCV RNA by quantitative PCR for confirmation of active
    disease.
    c) Participants who test positive for HIV antibody.
    d) Participants not currently on antiviral therapy and who have an
    undetectable viral load in the prior 3 months may be eligible for the
    study.
    E.5 End points
    E.5.1Primary end point(s)
    - Complete Remission (CR) rate as assessed by investigators
    - Overall Survival (OS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Response assessments will be done in conjunction with bone marrow assessments, according to the Schedule of Assessments (refer to protocol). Accompanying laboratory results ± 2 weeks from the protocol-specified bone marrow efficacy assessment can be used to support an efficacy assessment of CR. Response assessments are scheduled on Day 1 of Cycles 3, 5, and 7 and then every 3 cycles thereafter during study treatment.

    The length of OS is measured from randomization to the date of death from any cause. Those who are not observed to die during the study will be censored at their last known alive date.
    E.5.2Secondary end point(s)
    - Duration of complete remission (CR)
    - Objective Response rate (ORR) and Duration of Response (DOR)
    - Red Blood Cell (RBC) transfusion independence rate
    - Progression-free survival (PFS)
    - Event-free survival (EFS)
    - Minimum Residual Disease (MRD) - negative response rate
    - Time to transformation to Acute Myeloid Leukaemia (AML)
    - Measurement of Adverse Events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0
    - Magrolimab concentration versus time
    - Antidrug antibody (ADA) to magrolimab
    - Functional Assessment of Cancer Therapy (FACT) -Anemia response rate
    E.5.2.1Timepoint(s) of evaluation of this end point
    Response assessments of efficacy endpoints are scheduled on Day 1 of Cycles 3, 5, and 7 and then every 3 cycles thereafter during study treatment.
    All AEs that occur after the first dose of study treatment through 30 days after the last dose of study treatment are assessed.
    Pharmacokinetic measurements are collected at Day 1 and 8 of Cycle 1 and Day 1 of Cycles 2, 3, 5, 7, 10, and 13 and EOT.
    Measurements of Antidrug antibody (ADA) to magrolimab, are collected on Day 1 of Cycles 1, 2, 3, 5, 7, 10, and 13 and EOT.
    Patients-reported outcome assessments are scheduled for Day 1 of Cycles 1-3.
    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) 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA110
    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
    Hong Kong
    Mexico
    New Zealand
    United States
    Austria
    Finland
    France
    Poland
    Netherlands
    Spain
    Switzerland
    Czechia
    Germany
    Italy
    Belgium
    Hungary
    Ireland
    Norway
    Portugal
    Turkey
    United Kingdom
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 340
    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 state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 520
    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)
    None
    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 Decision2021-03-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-12
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-07-18
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