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    Summary
    EudraCT Number:2016-003353-16
    Sponsor's Protocol Code Number:GS-US-339-1559
    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:2016-11-04
    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 number2016-003353-16
    A.3Full title of the trial
    A Phase 1b/2 Study of Entospletinib (GS-9973) Monotherapy and in Combination with Chemotherapy in Patients with Acute Myeloid Leukemia (AML)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Study of Entospletinib (GS-9973) Monotherapy and in Combination with standard of care in adult subjects with Acute Myeloid Leukemia (AML).
    A.4.1Sponsor's protocol code numberGS-US-339-1559
    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+ 44 1223897 284
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code GS-9973
    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 INNEntospletinib
    D.3.9.2Current sponsor codeENTO, GS-9973
    D.3.9.3Other descriptive nameENTOSPLETINIB
    D.3.9.4EV Substance CodeSUB182049
    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: 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.3.2Product code GS-9973
    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 INNEntospletinib
    D.3.9.2Current sponsor codeENTO, GS-9973
    D.3.9.3Other descriptive nameENTOSPLETINIB
    D.3.9.4EV Substance CodeSUB182049
    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.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
    Acute Myeloid Leukemia (AML)
    E.1.1.1Medical condition in easily understood language
    Reoccurring or resistant cancer of the white blood cells
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Groupe A
    To demonstrate the overall safety of ENTO in combination with standard dose cytarabine and daunorubicin chemotherapy (7+3) in subjects with previously untreated AML who are candidates for chemotherapy (fit subjects) and to assess the efficacy of ENTO at the recommended Phase 2 dose (RP2D)

    Groupe B
    To demonstrate the overall safety of ENTO in combination with hypomethylating agents (decitabine or azacitidine) in subjects with previously untreated AML who are not candidates for 7+3 (unfit subjects) and to assess the efficacy of ENTO at the RP2D

    Group C
    To demonstrate the overall safety of ENTO monotherapy in subjects with previously untreated AML who are not candidates for chemotherapy or in subjects with relapsed/refractory AML with or without mixed-lineage leukemia (MLL) and to assess the efficacy of ENTO at the RP2D
    E.2.2Secondary objectives of the trial
    To assess the qualitative and quantitative toxicities of ENTO monotherapy or ENTO in combination with chemotherapy in subjects with AML

    To document therapeutic response of subjects with AML treated with ENTO monotherapy or ENTO in combination with chemotherapy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Groupe A
    - Subjects age ≥ 18 with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3), who are able and should receive up to 2 cycles of induction chemotherapy with 7+3 as determined by the treating physician

    Groupe B
    - Subjects age > 70 years with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3)
    - Subjects age ≤ 70 years with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3), who refuse or are unable to receive 7+3 as determined by the treating physician

    Groupe C Phase 1b
    - Subjects age ≥ 18 years with relapsed/refractory AML by WHO criteria, excluding acute promyelocytic leukemia (M3)
    - Subjects with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3), and who would have met disease eligibility criteria for Group A or B but refuse or are unable to receive 7+3 or decitabine chemotherapy as determined by the treating physician

    Group C Phase 2 (Dose Expansion)
    - Cohort C1A: Subjects age ≥ 18 years with relapsed/refractory AML by WHO criteria, excluding acute promyelocytic leukemia (M3)
    - Cohort C2: Subjects age ≥ 18 years with relapsed/refractory AML with MLL
    - Cohort C3: Subjects with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3), and who would have met disease eligibility criteria for Group A or B but refuse or are unable to receive chemotherapy and hypomethylating agent as determined by the treating physician

    ALL patients must meet all of the following inclusion criteria to be eligible for participation in this study:
    1) Male or female ≥ 18 years of age with a diagnosis AML (M0-M7, except M3).
    2) All acute toxic effects of any prior anti-leukemia therapy resolved to Grade ≤ 1 before the start of study treatment (with the exception of alopecia [any grade permitted], or bone marrow parameters [any grade permitted] due to leukemia in the investigators opinion).
    3) ECOG performance status less than or equal to 2.
    4) Life expectancy of at least 3 months.
    5) Meet required screening laboratory criteria unless leukemia related.
    6) Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO and no clinical evidence of congestive heart failure.
    7) For female subjects of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the screening visit throughout the study treatment period and for 30 days following the last dose of ENTO or as recommended in the prescribing information for other co-administered study drugs (whichever is later).
    For male subjects of childbearing potential having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol recommended method of contraception from the start of study treatment throughout the study treatment period and for 90 days following the last dose of ENTO or as recommended in the prescribing information for other co-administered study drugs (whichever is later), and to refrain from sperm donation from the start of study treatment throughout the study treatment period and for 90 days following the last dose of ENTO or as recommended in the prescribing information for other co-administered study drugs (whichever is later).
    Note: See Appendix 4 for definition of childbearing potential and information regarding recommendations for contraception.
    8) Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions .
    9) Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
    E.4Principal exclusion criteria
    1) Patients with acute promyelocytic leukemia (M3)
    2) Known active central nervous system or leptomeningeal leukemic involvement. Note: Central nervous system testing (CSF analysis) is only required in patients with suspected involvement based on symptoms or signs.
    3) Treatment with proton pump inhibitors (PPIs) within 7 days prior to enrollment. Note: PPIs are likely to interfere with ENTO absorption, thus requiring a 7-day washout period. H2 blockers and antacids will be allowed for use during the protocol
    4) History of active non-myeloid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for > 1 year prior to start of study therapy, or any other cancer that has been in complete remission without treatment for ≥ 5 years prior to enrolment. Subjects who are on prophylaxis with long-term adjuvant hormonal therapy and are ≥ 5 years from therapy for their primary tumor are eligible for enrollment.
    5) Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection at the time of start of study treatment. Note: Patients with localized fungal infections of skin or nails are eligible.
    6) Ongoing, drug-induced liver injury, known chronic active hepatitis C Virus (HCV), chronic active hepatitis B Virus (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
    7) Ongoing (within the past 6 weeks) hepatic encephalopathy.
    8) Ongoing drug-induced pneumonitis.
    9) Ongoing inflammatory bowel disease.
    10) Ongoing alcohol or drug addiction as determined by investigator.
    11) Pregnancy or breastfeeding.
    12) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation. Note: prior allogeneic bone marrow progenitor cell or solid organ transplantation is NOT an exclusion criteria for Cohort C2 ie, MLL cohort.
    13) Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia. Patients may not have received AML-directed therapy prior to enrollment other than Hydrea or apheresis, if de-novo or for current relapse, except for patients defined as refractory disease at study enrollment. Concurrent use of methotrexate for rheumatologic conditions is permitted.
    Note: Patients may use topical, enteric, or inhaled corticosteroids as therapy for comorbid conditions and systemic steroids for autoimmune anemia and/or thrombocytopenia. Ongoing use of low dose systemic corticosteroids (<5 mg/day of methylprednisolone or equivalent) for rheumatologic conditions is permitted. During study participation, patients may receive systemic or other corticosteroids needed for treatment-emergent comorbid conditions.
    14) Concurrent participation in an investigational drug trial with therapeutic intent defined as prior study therapy within 14 days prior to study treatment.
    15) Any other prior or ongoing condition that, in the opinion of the investigator, could adversely affect the safety of the patient or impair the assessment of study results .
    16) Inability to tolerate oral medications, symptomatic disease significantly affecting gastrointestinal function manifested from resection of the stomach or small bowel or active ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
    17) Uncontrolled intercurrent illness including, but not limited to:
    a) unstable angina pectoris
    b) psychiatric illness/social situations that would limit compliance with study requirements
    c) patients with active infection are permitted to enroll provided that the infection is documented to be under control
    18) Known hypersensitivity to ENTO, decitabine, azacitidine, cytarabine and daunorubicin, the metabolites, or formulation excipient
    E.5 End points
    E.5.1Primary end point(s)
    Safety
    - Occurrence of adverse events and laboratory abnormalities defined as DLTs for Entospletinib in combination with standard dose cytarabine and daunorubicin in patients with previously untreated AML (Group A).
    - Occurrence of adverse events and laboratory abnormalities defined as DLTs for Entospletinib in combination with decitabine or azacitidine in patients with previously untreated AML who are unable to receive intensive chemotherapy (Group B).
    - Occurrence of adverse events and laboratory abnormalities defined as DLTs for Entospletinib as a single agent or in combination with mitoxantrone, etoposide and cytosine arabinoside (MEC) in patients with relapsed or refractory AML (Group C).

    Efficacy
    - Complete remission rate at induction completion: defined as the proportion of subjects who achieved morphologic complete remission (CR) at induction completion. Note: CR includes a subcategory of cytogenetic CR (CRc).
    - Composite complete remission rate at induction completion: defined as the proportion of subjects who achieved morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) at induction completion.
    - Overall response rate at induction completion: defined as the proportion of subjects who achieved CR, CRi, or partial remission (PR) at induction completion .

    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety: at laboratory clinic visits as describe in the Appendix 2 "Study procedures tables" of the protocol.

    Efficacy: at induction completion.
    E.5.2Secondary end point(s)
    Exposure
    - Drug administration and duration of exposure of study treatment.

    Safety
    - Occurrence of AEs and laboratory abnormalities not defined as DLTs.

    Efficacy
    - Event free survival (EFS) - defined for all patients and it is measured from the start of the study therapy until the date of treatment failure, AML relapse or death from any cause, whichever occurs first.
    - Overall survival (OS) – defined as the interval from the start of the study therapy to the death from any cause.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety: at laboratory clinic visits as describe in the Appendix 2 "Study procedures tables" of the protocol.

    Efficacy: at the date of treatment failure and time of death.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA1
    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 Yes
    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
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months44
    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: 57
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 133
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    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)
    After a patient has completed/terminated their study participation, long term care for the participant will remain the responsibility of their primary treating physicians.
    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 Decision2017-01-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-02-21
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