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    Summary
    EudraCT Number:2015-003951-23
    Sponsor's Protocol Code Number:AG-221-AML-005
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-04-04
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2015-003951-23
    A.3Full title of the trial
    A Phase 1b/2 Open-Label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to evaluate the safety and effectiveness of a combination of either AG-120 or AG-221 tablets with azacitidine injections in patients with newly diagnosed Acute Myeloid Leukemia (AML) and who have mutations in enzymes isocitrate dehydrogenase 1 or 2 (IDH 1 or IDH2) and are not candidates to receive intensive induction chemotherapy.
    A.4.1Sponsor's protocol code numberAG-221-AML-005
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02677922
    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 SponsorCelgene Corporation
    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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol Myers Squibb International Corporation
    B.5.2Functional name of contact pointGSM-CT
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance-Avenue de Finlande, 4
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailClinical.trials@bms.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/3/16/1640
    D.3 Description of the IMP
    D.3.1Product nameenasidenib
    D.3.2Product code AG-221
    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 INNenasidenib
    D.3.9.2Current sponsor codeAG-221
    D.3.9.3Other descriptive nameenasidenib mesylate
    D.3.9.4EV Substance CodeSUB123982
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1640
    D.3 Description of the IMP
    D.3.1Product nameenasidenib
    D.3.2Product code AG-221
    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 INNenasidenib
    D.3.9.2Current sponsor codeAG-221
    D.3.9.3Other descriptive nameenasidenib mesylate
    D.3.9.4EV Substance CodeSUB123982
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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: 3
    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/3/16/1640
    D.3 Description of the IMP
    D.3.1Product nameenasidenib
    D.3.2Product code AG-221
    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 INNenasidenib
    D.3.9.2Current sponsor codeAG-221
    D.3.9.3Other descriptive nameenasidenib mesylate
    D.3.9.4EV Substance CodeSUB123982
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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: 4
    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 nameivosidenib
    D.3.2Product code AG-120
    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 INNivosidenib
    D.3.9.2Current sponsor codeAG-120
    D.3.9.3Other descriptive nameAG-120
    D.3.9.4EV Substance CodeSUB130391
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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: 5
    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 nameivosidenib
    D.3.2Product code AG-120
    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 INNivosidenib
    D.3.9.2Current sponsor codeAG-120
    D.3.9.3Other descriptive nameAG-120
    D.3.9.4EV Substance CodeSUB130391
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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: 6
    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 25mg/ml powder for suspension for injection
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/07/509
    D.3 Description of the IMP
    D.3.2Product code L01BC07
    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.3.9.4EV 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Newly diagnosed acute myeloid leukemia (AML) habouring an isocitrate dehydrogenase 1 (IDH1) or an isocitrate dehydrogenase 2 (IDH2) mutation, respectively, who are not candidates to receive intensive induction chemotherapy (IC)
    E.1.1.1Medical condition in easily understood language
    Treatment of subjects with newly diagnosed AML that have mutations in enzymes isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) and who are not candidates to receive intensive induction chemotherapy
    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 21.0
    E.1.2Level LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Ph Ib Dose Finding Stage: - To assess the safety and tolerability of the combination treatments of oral AG-120 when administered with subcutaneous (SC) azacitidine and oral AG-221 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC.
    - To establish the recommended combination dose (RCD) of oral AG-120 and oral AG-221 when administered with SC azacitidine.
    Ph Ib AG-120 Expansion Stage:- To assess the safety and tolerability of the combination treatments of oral AG-120 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 mutation who are not candidates to receive intensive IC.
    Ph II AG-221 Randomized Stage: - To assess the efficacy of oral AG-221 when administered with SC azacitidine versus SC azacitidine alone in subjects with newly diagnosed AML with an IDH2 mutation, who are not candidates to receive intensive IC.
    E.2.2Secondary objectives of the trial
    Ph Ib Dose Finding Stage: - To assess the preliminary efficacy of the combination treatments of oral AG-120 when administered with SC azacitidine and oral AG-221 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 or an IDH2 mutation, respectively, who are not candidates to receive intensive IC.
    Ph Ib AG-120 Expansion Stage: - To assess the preliminary efficacy of the combination treatments of oral AG-120 when administered with SC azacitidine in subjects with newly diagnosed AML with an IDH1 mutation, who are not candidates to receive intensive IC.
    Ph II AG-221 Randomized Stage: - To evaluate the safety of oral AG-221 when administered with SC azacitidine.
    - To characterize the PK of oral AG-221 when administered with SC azacitidine.
    - To evaluate the effect of oral AG-221 when administered with SC azacitidine versus SC azacitidine alone on health-related quality-of-life (HRQoL) outcomes.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Extension Phase:
    During the Extension Phase, the subjects will continue to be treated with
    AG-120/AG-221 + SC azacitidine or single agent AG-120, AG-221, or
    azacitidine if in the investigator's assessment the subject continues to
    show clinical benefit and all protocol-specified criteria for continuing
    study treatment are met.
    Objective
    • To allow all Phase 1b and Phase 2 subjects still on treatment to have
    continued access to the study treatment to assess the long-term efficacy
    and safety of the study treatment and to follow the subjects for survival.
    During the Extension Phase, the subjects will continue to be assessed for
    efficacy until EOT and safety on an ongoing basis and as clinically
    indicated until 28 days after the last study drug dose and as outlined in
    Table 5. After the End of Treatment visit, the subjects will be followed
    for survival until death, lost to follow-up, withdrawal of consent, or the
    End of Trial, whichever occurs first.
    The Extension Phase applies to all Phase 1b and Phase 2 subjects that
    are still on study treatment or in long-term Follow-up after the primary
    analysis CSR and after the 24-month follow-up update for DMC. Once
    Amendment 3.0 is approved by regulatory authorities and ethics
    committees and subjects sign informed consent, they may continue to
    receive study treatment until disease progression, development of
    unacceptable toxicity, or as per investigator discretion. During the
    Extension Phase, all subjects will be required to complete study visits
    and assessments as outlined in Table 5: Extension Phase - Table of
    Events. Subjects will be assessed for safety (AEs, SAEs and concomitant
    medications and procedures) on an ongoing basis and as clinically
    indicated until 28 days after the last study drug dose. Safety
    assessments including laboratory tests will be performed locally and as
    clinically indicated. Disease response assessments will be performed
    locally per modified IWG AML response criteria and according to
    standard of care (SoC) and as clinically indicated. Subjects who
    discontinue from the study treatment for any reason should undergo an
    End of Treatment (EOT) visit and should be assessed for safety and
    efficacy at this visit. After the Extension Phase - End of Treatment visit,
    subjects will be followed for survival until death, lost to follow-up,
    withdrawal of consent, or the End of Trial, whichever occurs first. No
    central lab samples will be collected nor samples for exploratory analysis
    (pharmacodynamics, correlative studies, MRD, Buccal swabs) will be
    collected during the Extension Phase.
    E.3Principal inclusion criteria
    1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
    2. Subject must understand and voluntarily sign an ICF prior to any study-related
    assessments/procedures being conducted.
    3. Subject is willing and able to adhere to the study visit schedule and other protocol
    requirements.
    4. Subject has newly diagnosed, primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms [MPN], or therapy-related) AML according to the
    WHO classification (Appendix B) with ≥ 20% leukemic blasts in the bone marrow:
    a. Have an IDH1 or IDH2 gene mutation (R132, R140, or R172)
    - IDH mutational status will be assessed locally; for sites without local testing capabilities, a referral lab will be identified.
    b. By the investigator’s assessment who are not candidates to receive intensive IC.
    5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1
    or 2 (Appendix D).
    6. Subject has adequate organ function defined as:
    - Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless
    considered due to leukemic organ involvement.
    - Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, ≤3 times the upper limit of normal for Gilbert’s syndrome (eg, a gene mutation in
    UGT1A1), or leukemic organ involvement.
    - Serum creatinine < 2 x ULN or creatinine clearance > 30 mL/min based on the Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR):
    GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)
    7. Agree to serial bone marrow aspirate/biopsies.
    8. Females of childbearing potential (FCBP)* may participate, providing they meet the
    following conditions:
    - Agree to practice true abstinence ** from sexual intercourse or to use highly effective contraceptive methods (eg, combined [containing estrogen and progestogen] or progestogen only associated with inhibition of ovulation, oral, injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization [note that a vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant and that a vasectomized partner has received medical assessment of the surgical success]) at screening and throughout the study, and for at least 4 months following the last study treatment; and
    - Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG)
    pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
    - Have a negative serum or urine (investigator’s discretion under local regulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment in the Treatment Period (note that the screening serum pregnancy test can be used as the test prior to the start of study treatment in the Treatment Period if it is performed within the 72-hour timeframe).
    9. Male subjects must agree to practice true abstinence from sexual intercourse or agree to the use of highly effective contraceptive methods (as described above) with non-pregnant female partners of child bearing potential at screening and throughout the course of the study and should avoid conception with their partners during the course of the study and for at least 4 months following the last study treatment (6 months following last dose of azacitidine in Canada).
    Furthermore, the male subject must agree to use a condom while treated with azacitidine and for at least 4 months following the last azacitidine dose.
    E.4Principal exclusion criteria
    1. Subject is suspected or proven to have acute promyelocytic leukemia based on
    morphology, immunophenotype, molecular assay, or karyotype (Appendix B).
    2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C).
    3. Subject has received a targeted agent against an IDH1 or IDH2 mutation.
    4. Subject has received prior systemic anticancer therapy, HSCT, or radiotherapy for AML. Note: Hydroxyurea is allowed prior to enrollment for the control of peripheral leukemic blasts in subjects with leukocytosis. (however, hydroxyurea should not be given within 72 hours prior to and after administration of azacitidine). For subjects with secondary AML (eg, MDS or MPN) treatment for prior cancer is not exclusionary; full treatment information will be collected within the CRF. The use of all trans retinoic acid (ATRA) for suspected APL is not exclusionary provided it is discontinued prior to initiation of treatment in the protocol.
    5. Subject has received more than 1 cycle of prior treatment with azacitidine, or subject has received any prior treatment with decitabine for MDS.
    6. Subject has or is suspected of having central nervous system (CNS) leukemia.
    Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
    suspected during screening.
    7. Subject has immediate life-threatening, severe complications of leukemia such as
    uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
    intravascular coagulation.
    8. Subject has significant active cardiac disease within 6 months prior to the start of study
    treatment, including New York Heart Association (NYHA) class III or IV congestive
    heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke; or left
    ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
    acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment.
    9. Subject has prior history of malignancy, other than MDS, MPN, or AML, unless the
    subject has been free of the disease for ≥ 1 year prior to the start of study treatment.
    However, subjects with the following history/concurrent conditions are allowed:
    -Basal or squamous cell carcinoma of the skin
    -Carcinoma in situ of the cervix
    -Carcinoma in situ of the breast
    -Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node,
    metastasis clinical staging system)
    10. Subject is known seropositive for or has active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
    11. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
    conditions that limit the ingestion or gastrointestinal absorption of drugs administered
    orally
    12. Subject has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
    diastolic BP > 100 mmHg)
    13. Subject is taking the following sensitive CYP substrate medications that have a narrow
    therapeutic range are excluded from the study unless the subject can be transferred to
    other medications at least 5 half-lives prior to the start of study treatment: phenytoin
    (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
    tizanidine (CYP1A2) (Appendix K).
    14. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive
    substrate rosuvastatin; subject should be excluded from the study unless he/she can be
    transferred to other medications at least 5 half-lives prior to the start of study treatment
    (Appendix L).
    15. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as
    ongoing signs/symptoms related to the infection without improvement despite
    appropriate antibiotics, antiviral therapy, and/or other treatment).
    16. Subject has known or suspected hypersensitivity to any of the components of study
    therapy.
    17. Subject is taking medications that are known to prolong the QT interval (Appendix M)
    unless he/she can be transferred to other medications within ≥ 5 half-lives prior to the start of study treatment. (If equivalent medication is not available, QTc will be closely monitored as defined in Section 8.1.)
    18. Subject has QTc interval (ie, Fridericia’s correction [QTcF]) ≥ 450 ms or other factors
    that increase the risk of QT prolongation or arrhythmic events (eg, heart failure,
    hypokalemia, family history of long QT interval syndrome) at screening.
    19. Female subject who is pregnant or lactating.
    20. Subject has any significant medical condition, laboratory abnormality, or psychiatric
    illness that would prevent the subject from participating in the study.
    21. Subject has any condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk if he/she were to participate in the study.
    22. Subject has any condition that confounds the ability to interpret data from the study.
    E.5 End points
    E.5.1Primary end point(s)
    Ph Ib Dose Finding and AG-120 Expansion:
    1. Recommended Combination Dose - Review of dose-limiting toxicities (DLTs), safety, PK / pharmacodynamic, biomarker, and preliminary efficacy data by DRT.
    2. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
    Ph II:
    3. Overall Response Rate (as assessed by the investigator)- Rate of CR + CRi + CRp + MLFS + PR according to modified IWG AML response criteria (Appendix F).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Ph Ib Dose Finding and AG-120 Expansion:
    1. Recommended Combination Dose - Approximately 8 months
    2. Safety / tolerability - Approximately 13 months
    Ph II:
    3. Overall Response Rate (as assessed by the investigator- Approximately 30 months
    E.5.2Secondary end point(s)
    Ph Ib Dose Finding and AG-120 Expansion:
    1. Overall Response Rate (as assessed by the investigator) - Rate of CR + CRi + CRp + MLFS + PR according to modified IWG AML response criteria (Appendix F).
    2. Sponsor Derived CR and CRh - Rate of CR/ CRh and CR + CRh based on laboratory data
    3. Pharmacodynamics (Exploratory) - To evaluate the pharmacodynamics of oral AG-120 + SC azacitidine and oral AG-221 + SC azacitidine when administered in combination in this population.
    Ph II:
    4. Event-Free Survival - Time from randomization to documented morphologic relapse, progression according to modified IWG AML response criteria (Appendix F), or death from any cause, whichever occurs first.
    5. Safety / tolerability - Type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment.
    6. Complete remission rate - Rate of CR according to modified IWG AML response criteria (Appendix F).
    7. Sponsor Derived CR - Rate of CR based on laboratory data
    8. Sponsor Derived CR and CRh - Rate of CR +CRh based on laboratory data
    9. Hematologic improvement rate - Rate of HI-N + HI-P + HI-E according to IWG MDS HI criteria (Appendix G).
    10. Duration of Response - Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, progression according to modified IWG AML response criteria (Appendix F), or death due to any cause, whichever occurs first
    11. Time to response - Time from first dose of study drug to first documented CR/CRi/CRp/MLFS/PR according to modified IWG AML response criteria (Appendix F)
    12. Time to sponsored assessed CR and CRh - Time from first dose of study drug to first documented CR / CRh
    13. Duration of sponsor assessed CR and CRh - Time from the first documented CR/CRh to documented morphologic relapse, progression
    14. Overall Survival - Time from randomization to death due to any cause.
    15. One-year survival - The probability of survival at 1 year from randomization
    16. PK parameters - Plasma concentrations and pharmacokinetic parameters of AG-120 or AG-221.
    17. HRQoL outcomes - European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) (Appendix N) and EuroQoL Group EQ-5D-5L instrument (Appendix O)
    18. Healthcare resource utilization (Exploratory) - Information about all resource use
    (eg, hospitalization)
    19. Days alive and out of hospital (Exploratory)- Measurement of days without hospitalization
    20. Pharmacodynamics (Exploratory) - Evaluation of 2-HG and α-KG levels in plasma and/or bone marrow.
    Evaluate methylation in PB and/or transcription in BM.
    21. Correlative studies (Exploratory) - Evaluation of molecular, cellular and metabolic markers which may be predictive of antitumor activity and/or resistance.
    Evaluation of minimal residual disease (MRD) by flow cytometry and by IDH2 variant allele fraction (VAF) in blood and bone marrow cells.
    Evaluation of changes in cellular differentiation and changes in histone and deoxyribonucleic acid (DNA) methylation profiles of IDH2 mutated leukemic cells.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Ph Ib Dose Finding and AG-120 Expansion: All secondary and Exploratory objectives - Approximately 13 months
    Ph II: All secondary and Exploratory objectives - Approximately 30 months

    The full length of the study is expected to be approximately 96 months
    including recruitment, screening, treatment, and follow up for Phase 1b
    Phase 2 and the Extension Phase. For a single subject, the expected
    duration of the study is approximately 30 months, including a screening
    period for up to 28 days, inclusive of overall survival.
    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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 No
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Korea, Republic of
    United States
    France
    Germany
    Italy
    Netherlands
    Portugal
    Spain
    Switzerland
    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
    The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date.
    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 years6
    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: 41
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 97
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 78
    F.4.2.2In the whole clinical trial 138
    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)
    Subjects can continue to receive study treatment if they continue to
    show clinical benefit per investigator’s assessment until they
    discontinue the study.
    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 Decision2016-06-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-11
    P. End of Trial
    P.End of Trial StatusCompleted
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