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    Summary
    EudraCT Number:2016-002985-30
    Sponsor's Protocol Code Number:Vedolizumab-2004
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-01-20
    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 ConcernedFrance - ANSM
    A.2EudraCT number2016-002985-30
    A.3Full title of the trial
    An Open-Label, Dose-Finding Study of Vedolizumab IV for Treatment of Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD) in Patients who Have Undergone Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Vedolizumab for Treatment of Graft-Versus-Host Disease (GvHD) that has not responded to steroid treatment in patients who have had stem cell transplantation.
    A.4.1Sponsor's protocol code numberVedolizumab-2004
    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 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 organisationDohmen Life Science Services
    B.5.2Functional name of contact pointMedical Information Call Centre
    B.5.3 Address:
    B.5.3.1Street Address190 N Milwaukee Street
    B.5.3.2Town/ cityMilwaukee
    B.5.3.3Post codeWI 53202
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1510740-1273
    B.5.6E-mailGlobalOncologyMedinfo@takeda.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 Yes
    D.2.1.1.1Trade name Vedolizumab IV (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, MLN02, LDP-02, MLN0002 IV
    D.3.9.3Other descriptive nameENTIVYO
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD)
    E.1.1.1Medical condition in easily understood language
    Acute Intestinal Graft-Versus-Host Disease (GvHD), a complication of bone marrow transplantation, that has not responded to steroid treatment.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to describe the initial activity, tolerability, and safety and to identify a recommended dose and regimen of vedolizumab IV administered for treatment of steroid-refractory acute intestinal GvHD in patients who have undergone allo-HSCT.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:

    To evaluate overall response to vedolizumab treatment at Day 28.

    To determine the nonrelapse mortality at 6 months after treatment with vedolizumab.

    To evaluate overall survival (OS).

    To determine the GvHD-free, relapse-free survival at 6 and 12 months after treatment with vedolizumab.

    To characterize the PK in patients treated with vedolizumab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients aged 18 years or older.

    2. Recipient of 1 allo-HSCT but not more than 1 allo-HSCT.

    3. Patients with primary steroid-refractory GvHD as defined in the protocol.

    4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 as per Appendix E of the protocol.

    5. Acute GvHD with intestinal disease involvement with a severity index of B, C, or D using the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)-modified International Bone Marrow Transplant Registry Database (IBMTR) index (See Appendix F of the protocol).

    6. Evidence of myeloid engraftment defined by absolute neutrophil count ≥0.5×109/L on 3 consecutive days.

    7. Creatinine clearance based on the Cockcroft-Gault estimate of ≥60 mL/minute/1.73 m2 for patients with serum creatinine concentrations above institutional limits.

    8. Sufficient cognitive ability to reliably complete the RAMP questionnaire at Baseline.

    9. Female patients who:
    Are postmenopausal for at least 1 year before the Screening visit, OR
    Are surgically sterile, OR
    If they are of childbearing potential, agree to practice one highly effective method of contraception and one additional effective (barrier) method at the same time, from the time of signing the informed consent 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 patients, even if surgically sterilized (ie, status postvasectomy), who:
    Agree to practice effective barrier 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. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

    11. Suitable venous access for the study-required blood sampling, including PK and biomarker sampling.
    E.4Principal exclusion criteria
    1. Presence of chronic GvHD at Screening (including acute-chronic overlap syndrome).

    2. Relapsed disease after allo-HSCT.

    3. Patients with hyperacute GvHD defined as onset of GvHD within the first 15 days following hematopoietic stem cell infusion.

    4. Received systemic agents other than corticosteroids for treatment of acute GvHD. GvHD prophylaxis agents (eg, calcineurin inhibitors) may be continued.

    5. Acute steroid-resistant GvHD beyond 28 days from primary treatment.

    6. Patients with a positive PML subjective checklist must be evaluated by a neurologist for possible PML before enrollment. Patients will be excluded if PML cannot be ruled out.

    7. Evidence of encephalopathy at Screening.

    8. Evidence of severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome.

    9. Life expectancy of <3 weeks.

    10. History of any major neurological disorders, including multiple sclerosis or neurodegenerative disease. Patients with a history of stroke or brain tumor within the past 3 years are also excluded.

    11. Patients with active cytomegalovirus (CMV) colitis.

    12. The patient has chronic hepatitis B (HBV) or hepatitis C (HCV) infection indicated by testing for positive HBV surface antigen, and/or HCV RNA.

    13. Any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).

    14. Positive Clostridium difficile toxin test on a stool sample or evidence of other intestinal pathogens (eg, adenovirus) during Screening.

    15. Evidence of uncontrolled active systemic infection.

    16. Any serious medical or psychiatric condition that could, in the investigator’s or medical monitor’s opinion, potentially interfere with the completion of treatment according to this protocol.

    17. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurologic, or other medical disorder that, in the opinion of the investigator or medical monitor, would confound the study results or compromise patient safety.

    18. History of hypersensitivity or allergies to vedolizumab or its components.

    19. If female, the patient is pregnant or lactating 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. If male, the patient intends to donate sperm during the course of this study or for 18 weeks thereafter.
    E.5 End points
    E.5.1Primary end point(s)
    1. The proportion of subjects with overall response (partial response [PR]+very good partial response [VGPR]+CR) at Day 28.

    2. The number and percentage of patients who experience SAEs from administration of the first dose of vedolizumab IV through Day 28.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. evaluated at Day 28
    2. evaluated from administration of the first dose of vedolizumab IV
    through Day 28
    E.5.2Secondary end point(s)
    1. The proportion of subjects who have died in the absence of primary malignancy relapse after allo-HSCT at 6 months.

    2. The proportion of subjects with CR at Day 28.

    3. The proportion of subjects with intestinal overall response at Day 28.

    4. OS at 6 and 12 months.

    5. The proportion of subjects alive without GvHD or relapse of primary malignancy at 6 and 12 months.

    6. The number and percentage of patients who experience TEAEs from administration of the first dose of vedolizumab IV through 18 weeks after administration of the last dose of vedolizumab IV.

    7. The number and percentage of patients who experience SAEs from administration of the first dose of vedolizumab IV through 18 weeks after administration of the last dose of vedolizumab IV.

    8. Mean serum concentrations of vedolizumab before dosing (Ctrough) on Day 99.

    9. The total dose of steroids administered (mg/kg/day of methylprednisolone or equivalent) from the start of the first IV infusion of vedolizumab through both 6 and 12 months.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. evaluated at 6 months
    2. & 3. evaluated at Day 28
    4. & 5. evaluated at 6 and 12 months
    6. & 7. evaluated from administration of the first dose of vedolizumab IV
    through 18 weeks after administration of the last dose of vedolizumab
    IV
    8. evaluated at Day 99
    9. evaluated from the start of the first IV infusion of vedolizumab
    through both 6 and 12 months
    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 No
    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) 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 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Comparison between different doses of vedolizumab
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Norway
    Sweden
    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 years0
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months36
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    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 18
    F.4.2.2In the whole clinical trial 38
    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)
    Patients who respond and tolerate vedolizumab and who develop recurrent symptoms of intestinal GvHD following discontinuation of therapy (i.e. after the 5th dose) may enter an extension phase where they may receive 300 mg vedolizumab IV every 2 wks for 2 doses followed by Q4W for up to 1 yr from the first dose of study drug. Patients may continue to receive drug beyond 1 yr if, the patient is benefitting from treatment.
    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 Decision2017-01-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-06-04
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