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    Summary
    EudraCT Number:2017-002715-34
    Sponsor's Protocol Code Number:ADN014
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-01-03
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-002715-34
    A.3Full title of the trial
    A Phase I/II, open label, dose escalation study to investigate the pharmacokinetics, pharmacodynamics, safety and clinical activity of begelomab as an initial treatment of acute Graft-versus-Host Disease in combination with standard steroid therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    -
    A.4.1Sponsor's protocol code numberADN014
    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 SponsorADIENNE SA
    B.1.3.4CountrySwitzerland
    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 supportADIENNE SA
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationADIENNE SA
    B.5.2Functional name of contact pointChief Scientific Officer
    B.5.3 Address:
    B.5.3.1Street Addressvia Zurigo, 46
    B.5.3.2Town/ cityLugano
    B.5.3.3Post code6900
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41912104726
    B.5.5Fax number+41919211978
    B.5.6E-mailgiovanni.amabile@adienne.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 number(EU/3/10/808)
    D.3 Description of the IMP
    D.3.1Product nameBEGEDINA 2.0 mg/ml concentrate for solution for infusion
    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 INN-
    D.3.9.1CAS number 1403744-56-8
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameBEGELOMAB
    D.3.9.4EV Substance CodeSUB174332
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20.0
    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 Yes
    D.3.11.13.1Other medicinal product typemonoclonal antibody
    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 graft versus host disease after allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion
    E.1.1.1Medical condition in easily understood language
    Acute Graft versus Host Disease
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10066260
    E.1.2Term Acute graft versus host disease
    E.1.2System Organ Class 10021428 - Immune system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objectives of the trial will be:
    •to establish the optimal biological dose (OBD) of intravenously infused begelomab in terms of modulation of CD26/CD3 lymphocyte activity;
    •to investigate the pharmacokinetics and pharmacodynamics of begelomab following escalating multiple doses of begelomab;
    •to investigate efficacy endpoints;
    •to investigate the safety and tolerability of multiple doses of begelomab in patients with acute Graft-versus-Host Disease.

    E.2.2Secondary objectives of the trial
    •Cumulative overall response at Day 28, Day 56, Day 100 and Day 180
    •Duration of overall response
    •Overall response of grade II-IV visceral acute GvHD at Day 28, Day 56, Day 100 and Day 180
    •Incidence and severity of systemic infections
    •Overall Survival at Day 28, Day 56, Day 100 and Day 180
    •GvHD relapse-free survival at Day 100 and Day 180
    •Transplant-related mortality at Days 28, 56, 100 and 180
    •Cumulative dose of steroid treatment
    •Percentage reduction of the steroid dose compared with respect to initial dosing
    •Incidence of steroid-resistant acute GvHD at Day 28, Day 56, Day 100 and Day 180
    •Incidence of chronic GvHD at Day 100 and Day 180
    Pharmacokinetics of begelomab
    •Incidence and titre time-course of HAMA
    •Time course of circulating CD26+
    •AE and AE)incidence
    •Proportion of participants who have a TRAE after infusion of begelomab




    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Age ≥12 and ≤70 years old.
    Subject must be willing and able to comply with study requirements, remain at the clinic, and return to the clinic for the follow-up evaluation, as specified in this protocol during the study period.
    Subject must be able and willing to provide signed informed consent. For patients aged <18 years, informed consent will be obtained from their parents or legal guardians.
    Patients receiving all types of allogeneic transplantation except patients transplanted with ex vivo T-cell-depleted grafts.
    Patients with acute GvHD Grade II, III and IV diagnosed after allogeneic hematopoietic transplant using either bone marrow (BM), peripheral blood stem cells (PBSC) or cord blood (CB), or after donor lymphocyte infusion (DLI).
    A confirmatory biopsy is required, if clinically feasible, to confirm diagnosis of skin and gastrointestinal GvHD, and is recommended when feasible in case of isolated liver involvement. Reasons for any omission of biopsy will be documented in the CRF.
    De novo acute GvHD requiring systemic therapy. GvHD is defined as the presence of skin rash and/or persistent nausea, vomiting, and/or diarrhea and/or cholestasis presenting in a context in which acute GvHD is likely to occur and where other aetiologies such as drug rash, enteric infection, or hepatotoxic syndromes are unlikely or have been ruled out.
    A confirmatory biopsy is required, if clinically feasible, to confirm diagnosis of skin and gastrointestinal GvHD, and is recommended when feasible in case of isolated liver involvement. Reasons for any omission of biopsy will be documented in the CRF.
    The patient must have had no previous systemic immune suppressive therapy for treatment of acute GvHD except for a maximum 24 hours of prior corticosteroid therapy at ≤2.0 mg/kg methylprednisolone or equivalent after the onset of acute GvHD.
    Evidence of myeloid engraftment (absolute neutrophil count (ANC) ≥ 500/µL).
    The disease for which the patient underwent to HSCT must be in remission.
    Patients with adequate renal reserve as defined by serum creatinine ≤ 3× upper limit of normal (ULN) or calculated creatinine clearance (CLcr) ≥30 mL/min using the Cockroft-Gault equation (1976).
    Respiratory function: forced vital capacity (FVC) or forced expiratory volume in one second (FEV1) ≥ 50% of predicted.
    Cardiac ejection fraction > 40%.
    Lansky performance score ≥ 70% for patients aged <16 years or Karnofsky performance score ≥50% for patients aged ≥ 16 years).
    Life expectancy of greater than 1 month.
    Women of child-bearing potential and men must agree to take adequate contraceptive measures in order to avoid any pregnancies of their sexual partners during the course of the study (or for at least 3 months following the last dose of study drug, whichever is longer). Acceptable methods of birth control include oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device IUD) or intrauterine system (IUS), barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/ film/ cream/suppository. Abstinence is only considered an acceptable form of contraception when it is the usual life style of an individual.
    Women must have a negative pregnancy test at Screening and at Baseline and must not be breastfeeding.
    E.4Principal exclusion criteria
    Patients transplanted with ex vivo T-cell-depleted grafts.
    Patients with signs of steroid-resistance.
    Participants with manifestations of chronic GvHD.
    Participants with acute/chronic GvHD overlap syndrome.
    Patient with evidence of relapsed/persistent malignancy.
    Patients with adequate renal reserve as defined by serum creatinine ≥ 3× ULN or calculated creatinine clearance (CLcr) ≤ 30 mL/min using the Cockroft-Gault equation.
    Lansky performance score ≤70 for patients aged <16 years or Karnofsky performance score ≤50% for patients aged ≥ 16 years).
    Severe organ dysfunction unrelated to underlying GVHD, including:
    -Cholestatic disorders or unresolved veno-occlusive disease (VOD) of the liver.
    -Clinically significant or uncontrolled cardiac disease.
    -Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen.
    Patients with severe hepatic veno-occlusive disease or sinusoidal obstruction syndrome who in the judgement of the treating physician are not expected to have normalized bilirubin by Day 56 after enrollment
    Any underlying or current medical or psychiatric condition that, in the opinion of the investigator, would interfere with the evaluation of the subject including, but not limited to symptomatic congestive heart failure (New York Heart Association [NYHA] Class III to IV), unstable angina pectoris or cardiac arrhythmia. Any other serious medical condition, as judged by the investigator, which places the subject at an unacceptable risk if he or she were to participate in the study or confounds the ability to interpret data from the study.
    Patients with known central nervous system (CNS) involvement.
    Pleural effusion or ascites > 1 liter
    Patients with uncontrolled bacterial, viral or fungal infections
    Uncontrolled diabetes at the time of cytoreduction.
    Evidence of HIV seropositivity and/or positive PCR assay, HTLV1 / HTLV2 seropositivity.
    Evidence of seropositivity for hepatitis B virus surface antigen (HBsAg) and/or anti-hepatitis C virus (anti-HCV) antibodies.
    Serologic positivity in the absence of detectable HBV or HCV DNA/RNA will not be exclusion criteria.
    Evidence of a clinically relevant CMV-viremia.
    Clinically relevant CMV-viremia is defined as detection of viral load ≥5000 copies/mL in whole blood, as measured by quantitative PCR.
    A history of prolonged QTc syndrome.
    Administration of any other investigational agents (not approved by the United States Food and Drug Administration Agency [FDA] or European Medicines Agency [EMA] for any indication) within 4 weeks prior to enrolment. Participation in any clinical trial for prevention of acute GvHD or within 5 half-lives of the study treatment (whichever is longer) within 4 weeks of the screening visit.
    Known hypersensitivity to murine proteins.
    Women who are pregnant, breastfeeding or at risk to become pregnant during study participation; female patients of childbearing potential who have not been started on an anti-ovulatory regimen prior to initiation of chemo-inductive regimen must test negative for pregnancy (serum) at the Baseline Visit.
    Unwillingness to use effective contraceptive measures up to 3 months after the end of study drug administration (females and males). Acceptable methods of birth control include oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device IUD) or intrauterine system (IUS), barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/ film/ cream/suppository. Abstinence is only considered an acceptable form of contraception when it is the usual life style of an individual.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study will be the dose of begelomab leading to a maximum receptor occupancy within the tested dose range 4.0 – 25.0 mg/m2/day, as determined with flow cytometry.
    E.5.1.1Timepoint(s) of evaluation of this end point
    throughout treatment period
    E.5.2Secondary end point(s)
    •Cumulative overall response at Day 28, Day 56, Day 100 and Day 180
    •Duration of overall response
    •Overall response of grade II-IV visceral acute GvHD at Day 28, Day 56, Day 100 and Day 180
    •Incidence and severity of systemic infections
    •Overall Survival at Day 28, Day 56, Day 100 and Day 180
    •GvHD relapse-free survival at Day 100 and Day 180
    •Transplant-related mortality at Days 28, 56, 100 and 180
    •Cumulative dose of steroid treatment
    •Percentage reduction of the steroid dose compared with respect to initial dosing
    •Incidence of steroid-resistant acute GvHD at Day 28, Day 56, Day 100 and Day 180
    •Incidence of chronic GvHD at Day 100 and Day 180
    • Pharmacokinetics of begelomab as determined by the Cmax, tmax, AUC0-t, CL, t1/2z, and the accumulation ratios for Cmax and AUC
    • Incidence and titre time-course of human anti-murine antibody (HAMA) and its neutralizing ability
    •Time course of circulating CD26+
    • Adverse Event (AE) and Serious Adverse Event (SAE) incidence
    • Proportion of participants who have a treatment-related AE (TRAE) after infusion of begelomab
    •Exploratory endpoints: will be exploratory biomarkers

    E.5.2.1Timepoint(s) of evaluation of this end point
    Cumulative OR, OR of grade II-IV visceral acute GvHD at Day 28, 56,100,180
    Duration of OR from baseline to Day 180
    Incidence and severity of systemic infections Day 28,100,180
    GvHD relapse-free survival at Day 100,180
    Transplant-related mortality at Days 28,56,100,180
    Cumulative dose of steroid treatment Day 7,15,8,56,100,180
    Percentage reduction of the steroid dose compared to initial dosing Day 28, 56,100,180
    Incidence of steroid-resistant acute GvHD at Day 28,56,100,180
    chronic GvHD at Day 100,180
    Pharmacokinetics of begelomab from Day 1 to 31
    Incidence and titre time-course of HAMA
    Time course of circulating CD26(-1 to Day 180)
    AE/SAE from baseline to Days 28,100,180
    TRAE after infusion from baseline to Days 28,100,180
    Exploratory biomarkers: from baseline to Day 180
    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 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 I/II
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned7
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    the end of study is defined as any one of the following, whichever occurs first:
    •the date of the last scheduled visit for the last subject;
    •the date of death of the last subject;
    •the date of withdrawal of the last subject.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days15
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state50
    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 will be treated as deemed appropriate by the investigator following the end of 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 Decision2018-01-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-09
    P. End of Trial
    P.End of Trial StatusOngoing
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