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    Summary
    EudraCT Number:2018-002141-11
    Sponsor's Protocol Code Number:Vedolizumab-3035
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-09-26
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-002141-11
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Vedolizumab in the Prophylaxis of Intestinal Acute Graft Versus Host Disease in Subjects Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial of Vedolizumab vs. placebo (dummy drug) for the prevention of intestinal Acute Graft Versus Host Disease (aGvHD), in patients undergoing allo-HSCT for a hematologic malignancy (cancers that affect the blood and/or lymphatic system).
    A.3.2Name or abbreviated title of the trial where available
    GRAPHITE
    A.4.1Sponsor's protocol code numberVedolizumab-3035
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03657160
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1216-2319
    A.5.4Other Identifiers
    Name:IND numberNumber:127,634
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/276/2019
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMillennium Pharmaceuticals, 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 supportMillennium Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda
    B.5.2Functional name of contact pointTakeda Study Registration Call Cent
    B.5.3 Address:
    B.5.3.1Street Addressunknown
    B.5.3.2Town/ cityunknown
    B.5.3.3Post codeunknown
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 877825 3327
    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 Yes
    D.2.1.1.1Trade name Entyvio
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda Pharma A/S
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameVedolizumab IV
    D.3.2Product code MLN0002
    D.3.4Pharmaceutical form Powder for 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 INNVedolizumab
    D.3.9.1CAS number 943609-66-3
    D.3.9.2Current sponsor codeMLN0002
    D.3.9.3Other descriptive nameVEDOLIZUMAB
    D.3.9.4EV Substance CodeSUB30452
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Intestinal acute graft-versus-host disease (aGvHD)
    E.1.1.1Medical condition in easily understood language
    Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10066264
    E.1.2Term Acute graft versus host disease in intestine
    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
    To evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in subjects who receive allo-HSCT as treatment for a hematologic malignancy or myeloproliferative disorder.
    E.2.2Secondary objectives of the trial
    Safety Objective:
    To evaluate the safety of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen.
    Secondary Objectives:
    • To evaluate the effect of vedolizumab compared to placebo on intestinal aGvHD free, relapse-free (free of underlying malignancy) survival by Day +180.
    • To evaluate the effect of vedolizumab compared to placebo on Grade C-D aGvHD free (any organ involvement) survival by Day +180.
    • To evaluate the effect of vedolizumab compared to placebo on NRM in subjects by Day +180.
    • To evaluate the effect of vedolizumab compared to placebo on OS by Day +180.
    • To evaluate the effect of vedolizumab compared to placebo on Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject or, when applicable, the subject’s legally acceptable representative voluntarily signs and dates a written, informed consent form (ICF) and any required privacy authorization before performance of any study-related procedures not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. As applicable, a parent/both parents or legally acceptable representative must provide signature of informed consent, and there must be documentation of age-appropriate assent by the subject.
    2. Male or female subjects ≥18 years of age and, in selected countries (where local requirements permit and based on feasibility) adolescents aged 12 years and greater and weighing ≥30 kg at time of randomization.
    3. Subjects must undergo DNA-based HLA matching and be 8 of 8 or 7 of 8 HLA-matched (single allele or antigen mismatch at HLA A, -B, and -C, and HLA-DRB1 is allowable) unrelated hematopoietic stem cell transplantation (HSCT) from either peripheral blood or bone marrow stem cells for a hematologic malignancy or myeloproliferative disorder. Subjects should follow local practice for additional HLA-match, for example, France, 9/10 or 10/10 HLA match.
    4. Subjects for whom a myeloablative conditioning or RIC is planned.
    5. Allo-HSCT eligible (meeting institutional criteria)-subjects planned medical care should include aGvHD prophylaxis with a combination of CNI (CYS or TAC) and MTX or CNI and MMF. With the exception of ATG (ATG-F or thymoglobulin), all other therapies, approved or investigational, for GvHD prophylaxis are excluded.
    6. Status of the primary disease as follows:
    a. Subjects with acute leukemia or chronic myelogenous leukemia: no circulating blasts and <5% blasts in the bone marrow.
    b. Subjects with myelodysplasia: no circulating blasts and <10% blasts in the bone marrow.
    c. Subjects with chronic lymphocytic leukemia or small lymphocytic lymphoma with chemosensitive disease at the time of transplantation (partial or complete response to last salvage therapy).
    d. Subjects with other nonHodgkin or Hodgkin lymphoma with a response to last salvage therapy or chemo-sensitive disease per institutional standards at the time of transplantation.
    e. For subjects with myelofibrosis and other myeloproliferative disorders: <5% blasts in the blood and bone marrow.
    7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 for subjects aged ≥18 years at randomization or ≥60% using the Karnofsky performance status for adolescent subjects aged 16 years at randomization or the Lansky performance status for adolescent subjects aged 12 to <16 years at randomization.
    8. Sufficient cognitive ability to reliably complete the PML checklist at baseline.
    9. Female subjects who are:
    • Postmenopausal for at least 1 year before signing of the informed consent, OR
    • Surgically sterile, OR
    • If they are aged 12 years and greater and not postmenopausal or surgically sterilized, must use a highly effective method of contraception during the study and through 18 weeks after the last dose of study drug, OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    Male subjects, even if surgically sterilized (ie, status postvasectomy), who:
    • Agree to practice an acceptable effective barrier method of contraception during the entire study treatment period and through 18 weeks after the last dose of study drug, OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    10. Suitable venous access for the study-required blood sampling, including PK sampling.
    E.4Principal exclusion criteria
    1. Prior allo-HSCT.
    2. Planned umbilical cord blood transplant or planned to receive posttransplant cyclophosphamide, in vivo or ex vivo T-cell depleted hematopoietic stem cells (HSCs) with the exception of ATG (ATG-F or thymoglobulin).
    3. Planned allo-HSCT for nonmalignant hematological disorders (eg, aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia or immunodeficiency).
    4. Known active cerebral/meningeal disease (including central nervous system involvement of the primary disease), or signs or symptoms of PML, any history of PML, or a positive PML subjective checklist before the administration of study drug on Day -1.
    5. Evidence of encephalopathy at screening.
    6. History of any major neurological disorder, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.
    7. Prior or current therapy with α4 and/or β7 integrin inhibitors (including, but not limited to natalizumab, etrolizumab, AMG-181), MAdCAM-1-antibodies, anti-CD11a mAb (eg, efalizumab) within 60 days or 5 half-lives, whichever is longer from randomization.
    8. Prior known exposure of the transplant recipient to vedolizumab.
    9. Any serious medical or psychiatric condition that could, in the investigator or medical monitor’s opinion, potentially interfere with the completion of treatment according to this protocol.
    10. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, coagulation, immunological, endocrine/metabolic, neurologic or other medical disorder not related to the subject’s primary disease that, in the opinion of the investigator, would confound the study results or compromise subject safety.
    11. Clinically active systemic infection during screening.
    12. Clinically active cytomegalovirus (CMV) colitis during screening.
    13. Clinically active Clostridium difficile infection or other intestinal pathogen during screening.
    14. Active or latent tubercolosis (TB), regardless of treatment history, as evidenced by any of the following: history of TB, OR positive QuantiFERON test OR T-Spot or 2 successive indeterminate QuantiFERON tests, OR T-Spot tests OR a tuberculin skin test reaction ≥10 mm (≥5 mm in subjects receiving the equivalent of >15 mg/day prednisone).
    15. Chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive [HBsAg+]), or hepatitis C infection (evident by active viral replication by polymerase chain reaction [PCR] if hepatitis C virus antibody positive). Hepatitis B core antibody (HBcAb) positive (HBcAb+) and negative for hepatitis B surface antigen (HBsAg-) may be enrolled if viral DNA is undetectable.
    16. History of human immunodeficiency virus (HIV) positive test.
    17. Treatment with anti-T-cells antibody such as alemtuzumab (anti-CD52), excluding ATG (ATG-F or thymoglobulin), within 4 months before the first dose of study drug on Day -1.
    18. Treatment with any live vaccinations within 30 days before randomization.
    19. If female, the subject is pregnant, lactating or breastfeeding, or intending to become pregnant before, during or within 18 weeks after participating in this study, or intending to donate ova during such time period.
    20. Diagnosed or treated for another malignancy within 2 years before the first dose of study drug or previously diagnosed with another malignancy and have any evidence of residual disease. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is intestinal aGvHD-free survival by Day +180 after allo HSCT. Intestinal aGvHD is defined as Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day +180
    E.5.2Secondary end point(s)
    • Intestinal aGvHD-free and relapse-free (of the underlying malignancy) survival by Day +180.
    • Grade C-D aGvHD-free (any organ involvement) survival by Day +180.
    • NRM by Day +180.
    • OS by Day +180.
    • Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day +180
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Canada
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Japan
    Korea, Republic of
    Norway
    Poland
    Portugal
    Romania
    Russian Federation
    Singapore
    Spain
    Sweden
    Switzerland
    Taiwan
    Turkey
    United Kingdom
    United States
    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 global study will end after the last subject has completed the final visit 12 months after allo-HSCT, or the subject has died, withdrawn consent, or been lost to follow-up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days17
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days23
    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: 380
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 158
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 334
    F.4.2.2In the whole clinical trial 558
    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)
    The ET visit will be conducted on Day +180 after allo-HSCT. All subjects will participate in posttreatment follow-up, that will begin after the Day +180 visit or after ET, will include a Day +280 final safety visit (or 18 weeks after the last dose of study drug), and will conclude 12 months after allo-HSCT. In addition, upon completion or ET, all subjects or their parents/legal representative will be administered by telephone the LTFU questionnaire 6 months after their last dose of study drug.
    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 Decision2018-11-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-28
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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