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    Summary
    EudraCT Number:2017-000763-33
    Sponsor's Protocol Code Number:20160283
    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:2017-09-18
    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 number2017-000763-33
    A.3Full title of the trial
    A Phase 1b/2 Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 592 in Adult Subjects with Steroid Refractory Chronic Graft versus Host Disease.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and Efficacy of AMG 592 in Subjects With Steroid Refractory Chronic Graft versus Host Disease
    A.4.1Sponsor's protocol code number20160283
    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 SponsorAmgen, 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 supportAmgen, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen NV
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressTelecomlaan 5-7
    B.5.3.2Town/ cityDiegem
    B.5.3.3Post code1831
    B.5.3.4CountryBelgium
    B.5.4Telephone number+322755 27 10
    B.5.6E-mailmedinfo-belux@amgen.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 AMG592
    D.3.4Pharmaceutical form Solution 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.3.9.2Current sponsor codeAMG 592
    D.3.9.3Other descriptive nameRECOMBINANT FACTOR FC FUSION PROTEIN
    D.3.9.4EV Substance CodeSUB181656
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 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
    Steroid Refractory Chronic Graft versus Host Disease
    E.1.1.1Medical condition in easily understood language
    Chronic Graft versus Host Disease
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • (Phase 1b) To evaluate the safety and tolerability of multiple ascending doses of AMG 592 in subjects with steroid refractory cGVHD in order to estimate the MTD and establish the RP2D
    • (Phase 2) To evaluate the efficacy of AMG 592 in subjects with steroid refractory cGVHD as measured by the best overall response rate (ORR) during the study according to the 2014 cGVHD National Institutes of Health (NIH) Consensus Criteria
    E.2.2Secondary objectives of the trial
    • (Phase 1b)To evaluate the immunologic effects of AMG 592 including fold change from baseline in regulatory T cell (Treg), conventional T cell (Tcon), and NK cell numbers (cells/μL) and the Treg/Tcon ratio .
    • (Phase 1b) To characterize the pharmacokinetic (PK) profile following multiple ascending subcutaneous dose administrations of AMG 592.
    • (Phase 1b) To evaluate the incidence of anti AMG 592 antibody formation and cross reactivity to native human IL 2.
    • (Phase 2) To evaluate the safety and tolerability of AMG 592 as measured by the occurrence of treatment emergent adverse events
    • (Phase 2) To evaluate ORR, as defined by cGVHD NIH Consensus Criteria at various timepoints in AMG 592-treated subjects
    • (Phase 2) To evaluate failure free survival (FFS), defined as absence of relapse, death, or need for additional systemic immunosuppressant cGVHD therapy
    • (Phase 2)To evaluate changes in steroid use over time
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subject or legally acceptable representative has provided informed consent prior to initiation of any study specific activities/procedures.
    Subject is an adult (≥ 18 years old at the time of signing the informed consent).
    Subject is a recipient of an allogeneic hematopoietic stem cell transplant (HSCT).
    Subject has moderate to severe steroid-refractory cGVHD as defined by all of
    the following criteria:
    • Diagnosed with cGVHD per the 2014 cGVHD NIH Consensus Criteria
    (Jagasia, 2015; Appendix 8) within the past 2 years prior to screening.
    • Steroid refractory cGVHD, defined as having persistent signs and symptoms
    of cGVHD despite ≥ 4 weeks of prednisone (or equivalent) dosed at
    ≥ 0.25 mg/kg/day (or ≥ 0.5 mg/kg every other day) within the 12 months prior
    to screening.
    • Moderate to severe cGVHD (in accordance with 2014 cGVHD NIH
    Consensus Criteria [Jagasia, 2015; Appendix 9]) at screening with
    involvement of at least one of the following organs at the screening and
    baseline visits: skin, mouth, eyes, gastrointestinal (GI) tract, liver,
    lungs, and joint and fascia.
    Subject has received no more than 3 previous treatments for cGVHD, excluding topical agents.
    • Treatment with corticosteroids is considered a treatment for cGVHD and should be included in determining the number of previous treatments.
    - Lines of therapy consisting of concurrent medications or interventions
    (eg, tacrolimus and corticosteroids; ECP and corticosteroids) count as 2 separate treatments.
    • If cGVHD has worsened during a taper of immunosuppressive agents, restoring the agents to therapeutic level is permitted and does not count as an additional treatment.
    Subject may be receiving corticosteroid therapy provided that the dose is
    ≤ 1 mg/kg/day of systemic prednisone or equivalent and has been stable for at
    least 2 weeks prior to first dose of AMG 592.
    Subject may be receiving other non-corticosteroid immunosuppressive
    therapies provided that the immunosuppressant dose is stable for at least
    2 weeks prior to first dose of AMG 592. Adjustments to dose of calcineurin
    inhibitor or sirolimus are allowed only to maintain drug levels within therapeutic
    range.
    Subject has a Karnofsky performance status score ≥ 50%.
    Subject has an estimated life expectancy of > 3 months.
    Subjects must have adequate hepatic function:
    • total bilirubin < 2.0 mg/dL (34.2 µmol/L) - exception permitted in participants with Gilbert's Syndrome
    • aspartate transaminase [AST; SGOT]/Alanine transaminase [ALT; SGPT] ≤ 2x upper limit of normal (ULN), unless hepatic dysfunction is a manifestation of presumed cGVHD.
    • abnormal LFTs in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the abnormal LFTs as being consistent with hepatic cGVHD. If LFT abnormalities are deemed consistent with hepatic cGVHD by the investigator, a liver biopsy will not be mandated.
    Subjects must have adequate pulmonary function defined as: forced expiratory volume in 1 second (FEV1) ≥ 50% or hemoglobin-adjusted diffusion capacity for carbon monoxide (DLCO Hb) ≥ 40% of predicted, unless pulmonary dysfunction is deemed to be due to cGVHD.
    Subjects must have adequate renal function defined as: a calculated glomerular filtration rate of > 50 mL/min/1.73 m2 using the MDRD formula.
    Subjects must have adequate cardiac function defined as:: no history within 6 months prior to screening of myocardial infarction, unstable angina, New York Heart Associate Class III or IV heart failure, or stroke. No findings on the screening electrocardiogram (ECG) that in the opinion of the investigator requires further cardiovascular evaluation, including severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Any ECG abnormality at screening must be documented by the investigator as not clinically significant prior to enrollment into the study.
    Subjects must have adequate bone marrow function indicated by ANC > 1.00 x 109/L and platelets > 50 x 109/L without growth factors or transfusions within the 4 weeks prior to starting AMG 592.
    E.4Principal exclusion criteria
    Subject is concurrently receiving treatment with calcineurin-inhibitor plus sirolimus
    Subject has received ibrutinib, imatinib, bortezomib, entospletinib, ruxolitinib or
    other JAK inhibitor, or treatment with any investigational drug or device within
    4 weeks prior to starting AMG 592.
    Subject has received the following therapies considered investigational for treament of cGVHD: imatinib, ibrutinib, bortezomib, ruxolitnib, entospletinib, within 4 weeks prior to enrollment or is currently receiving treatment in another investigational drug or device study.
    Subject has received treatment with T-cell depleting, B-cell depleting or IL-2 signaling targeted medication (within 12 weeks prior to starting AMG 592.
    Subject has received treatment with T regulatory cell expanding therapies (ie ECP, PUVA, UVB, adoptively transferred T regulatory cells) within 4 weeks prior to starting AMG 592.
    Subject has received a donor lymphocyte infusion within 12 weeks prior to starting AMG 592.
    Subject with active morphologic relapse/progression of hematologic malignancy post transplantation. Persistent CLL early after transplantation that subsequently entered remission will not be excluded.
    Subject has a history of malignancy, other than the indication for hematopoietic cell transplantation, with the following exceptions:
    • adequately treated nonmelanoma skin cancers without current evidence of disease
    • adequately treated cervical carcinoma in situ without current evidence of disease
    • adequately treated breast ductal cancer in situ without current evidence of disease
    • any malignancy treated with curative intent and with no evidence of active disease present for more than 5 years prior to screening and felt to be at low risk for recurrence by the treating physician.
    Subject has a history of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura.
    Subject has an active infection requiring treatment with IV antibiotics or has been hospitalized for treatment of an active infection in the 4 weeks prior to starting AMG 592.
    Subject has known history of active tuberculosis.
    Subject has a positive test for tuberculosis during screening defined as either:
    • positive purified derivative (PPD) (≥ 5 mm of induration at 48 to 72 hours after test is placed)
    OR
    • positive Quantiferon or T-SPOT test
    • subjects with a positive PPD and a history of Bacillus Calmette-Guérin vaccination are allowed with a negative Quantiferon test and negative chest x ray
    • subjects with a positive PPD test (without a history of Bacillus Calmette-Guérin vaccination) or subjects with a positive or indeterminate Quantiferon test are allowed if they have ALL of the following at screening:
    o no symptoms per tuberculosis worksheet provided by Amgen
    o document history of a completed course of adequate prophylaxis (completed treatment for latent tuberculosis [TB] per local standard of care prior to the start of investigational product
    o no known exposure to a case of active tuberculosis after most recent prophylaxis
    o negative chest X-ray

    Subject is positive for hepatitis B surface antigen, hepatitis B core antibody (confirmed by hepatitis B deoxyribonucleic acid [DNA] polymerase chain reaction [PCR] test) or detectable hepatitis C virus ribonucleic acid (RNA) by PCR (screening is generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive). Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed.
    Subject has positive test results for Human Immunodeficiency Virus (HIV) or known to be HIV positive.
    Phase 1b subject has a drug or alcohol urine test positive for illicit drugs at the screening visit. Prescription medications detected by the drug test are
    allowed if they are being taken under the direction of a physician.
    Phase 1b subjects can not be a current smoker, nor have used any nicotine or tobacco containing products within the last 6 months prior to screening.
    Phase 1b subject is unable to avoid alcohol or tobacco consumption for the duration of the study.
    Subject has known sensitivity to AMG 592 or its excipients to be administered during dosing.
    Subject likely to be unable to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge.
    History or evidence of any other clinically significant disorder, condition, or disease
    Females who are pregnant or breastfeeding, or planning to become pregnant or breastfeed during treatment and for an additional 6 weeks after the last dose of AMG 592.
    Females of child bearing potential with a positive pregnancy test
    Females of childbearing potential who are unwilling to use 1 highly effective method of contraception during treatment and for an additional 6 weeks after receiving the last dose of AMG 592.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b
    Incidence of dose limiting toxicities (DLTs) at first 4 weeks

    Incidence of dose limiting toxicities (DLTs) at first 4 weeks
    • Incidence of all treatment related and treatment emergent adverse events and serious adverse events

    Phase 2

    • Best ORR defined as the proportion of subjects achieving a Complete
    Response (CR) or Partial Response (PR) during the study according to the 2014 cGVHD NIH Consensus Criteria
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout study
    E.5.2Secondary end point(s)
    Phase 1b

    Fold changes from baseline of Treg absolute cell counts (cells/μL), after AMG 592 administration.
    • Fold changes from baseline of Tcon and NK absolute cell counts (cells/μL), after AMG 592 administration.

    • AMG 592 serum concentration and PK parameters including, but not
    limited to, maximum observed concentration (Cmax), the time of maximum observed concentration (Tmax), and the area under the concentration-time curve over a dosing interval (AUCtau) after the first and week 16 doses
    • Subject incidence of anti AMG 592 binding antibodies and cross reactivity to IL 2
    • Subject incidence of anti AMG 592 and anti IL 2 neutralizing antibodies

    Phase 2

    • Treatment-emergent and treatment-related adverse events and serious adverse events throughout the study
    • ORR at 8, 16, 24, 36, and 52 weeks
    • Time to first response
    • Duration of response
    • FFS at 52 weeks
    • Steroid use over time as compared to baseline
    • Changes in Lee Symptom Score over time
    • Changes in SF36v over time
    • Changes in Karnofsky performance status over time
    • AMG 592 plasma concentration and PK parameters including, but not limited to, maximum observed concentration (Cmax), the time of maximum observed concentration (Tmax), and AUCtau after the first and last doses and AUC from time 0 to the time of the last quantifiable sample (AUClast).
    • Subject incidence of anti AMG 592 binding antobidies and cross-reactivity to IL 2
    • Subject incidence of anti AMG 592 and anti IL 2 neutralizing antibodies
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout 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 No
    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 No
    E.6.11Pharmacogenomic No
    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
    Phase 1b/2
    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.8.2.4Number of treatment arms in the trial4
    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 EEA40
    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
    Belgium
    France
    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 years4
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    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: 83
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 41
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 124
    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)
    36 month long term follow-up period
    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 Decision2017-11-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-01
    P. End of Trial
    P.End of Trial StatusOngoing
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