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    Summary
    EudraCT Number:2011-000088-28
    Sponsor's Protocol Code Number:FHCRH2448
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-07-27
    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 number2011-000088-28
    A.3Full title of the trial
    A Randomized Phase III Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD after Unrelated Donor Hematopoietic Cell Transplantation using Nonmyeloablative Conditioning for Patients with Hematologic Malignancies A Multi-Center Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized Phase III Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute GVHD after Unrelated Donor Hematopoietic Cell Transplantation using Nonmyeloablative Conditioning for Patients with Hematologic Malignancies A Multi-Center Trial
    A.4.1Sponsor's protocol code numberFHCRH2448
    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 SponsorFred Hutchinson Cancer Research Center
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form
    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 INNSirolimus
    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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form
    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 INNMycophenolate mofetil
    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: 3
    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.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCiclosporine
    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
    Graft versus host disease
    E.1.1.1Medical condition in easily understood language
    Graft versus host disease is a process where donor cells may react against cells of your body causing inflammation that can involve the skin, liver and gastrointestinal system.
    E.1.1.2Therapeutic area Not possible to specify
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10053239
    E.1.2Term Prophylaxis against graft versus host disease
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the effectiveness of 2GVHD prophylaxis regimens in preventing acute grades II-IV GVHD.
    E.2.2Secondary objectives of the trial
    1. Compare non-relapse mortality in the two arms.
    2. Compare survival and progression-free survival in the two arms.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Ages >50 years with hematologic malignancies treatable by unrelated HCT.

    Ages <= 50 years of age with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a high dose transplant (>40% risk of TRM).

    Ages <= 50 years of age with chronic lymphocytic leukemia (CLL) (these patients do not require patient review committee approvals).

    Ages <= 50 years of age with hematologic diseases treatable by allogeneic HCT who refuse a high-dose HCT.

    The following diseases will be permitted:
    1) Aggressive nonHodgkin lymphomas (NHL) and Other Histologies Such as Diffuse large B cell NHL– not eligible for autologous HCT, not eligible for high-dose allogeneic HCT, or after failed autologous HCT.
    2) Mantle Cell NHL -may be treated in first CR.
    3) Low grade NHL– with < 6 month duration of CR between courses of conventional therapy
    4) CLL – must have either 1) failed to meet NCI Working Group criteria for complete or partial response after therapy with a regimen containing FLU (or another nucleoside analog, e.g. 2-CDA, pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog); 2) failed FLU-CY-Rituximab (FCR) combination chemotherapy at any time point; or 3) have “17p deletion” cytogenetic abnormality. Patients should have received induction chemotherapy but could be transplanted in 1st CR; or 4) Patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL.
    5) Hodgkin Lymphoma – must have received and failed frontline therapy.
    6) Multiple Myeloma – must have received prior chemotherapy. Consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted.
    7) Acute Myeloid Leukemia (AML)– must have < 5% marrow blasts at the time of transplant.
    8) Acute Lymphocytic Leukemia (ALL) – must have <5% marrow blasts at the time of transplant.
    9) Chronic Myeloid Leukemia (CML) – Patients will be accepted if they are beyond P1 and if they have received previous myelosuppressive chemotherapy or HCT, and have <5% marrow blasts at time of transplant.
    10) Myelodysplasia(MDS)/Myeloproliferative Syndrome (MPS) – Patients must have <5% marrow blasts at time of transplant.
    11) Waldenstrom’s Macroglobulinemia – must have failed 2 courses of therapy.
    E.4Principal exclusion criteria
    1) Patients with rapidly progressive intermediate or high grade NHL.
    2) Patients with a diagnosis of CMML.
    3) Patients with RAEB who have not received myelosuppressive chemotherapy i.e. induction chemotherapy.
    4) CNS involvement with disease refractory to intrathecal chemotherapy.
    5) Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, MDS, ALL or CML.
    6) Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment.
    7) Females who are pregnant or breast-feeding.
    8) Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years.
    9) Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month.
    10) Organ dysfunction.
    a. Cardiac ejection fraction < 35%. Ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease.
    b. Pulmonary:
    i) DLCO < 40%, TLC <40%, FEV1 <40% and/or receiving supplementary continuous oxygen.
    ii) The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules.
    c. Liver function abnormalities: Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension.
    11) Karnofsky scores < 60 or Lansky Score <50
    12) Patient has poorly controlled hypertension and on multiple antihypertensives
    13) HIV positive patients.
    14) Active bacterial or fungal infections unresponsive to medical therapy.
    15) All patients receiving antifungal therapy voriconazole, posaconazole, or fluconazole and who are then randomized to ARM2 or ARM 3 must have sirolimus reduced.
    16) The addition of cytotoxic agents for “cytoreduction” with the exception of tyrosine kinase inhibitors (such as imatinib), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint for this trial will be the rate of acute grade II-IV GHVD at day 100 post-transplant, exclusive of GVHD that occurs as a result of alterations to immunosuppressive therapy in response to relapse or progression.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 150 patients have been randomized and evaluated for 100 days post-transplant, an interim analysis for futility will be conducted. This analysis will estimate the conditional power of the study, given the data available at that time and assuming that going forward the rates of GVHD will differ by 15% between arms, with the rates for each arm centered around the pooled estimate of the rate from the combined arms. The conditional power will be estimated by Monte Carlo simulation. If the estimated conditional power is <33.3% then the trial will be stopped, otherwise the trial will continue to completion.
    E.5.2Secondary end point(s)
    Secondary endpoints that will be analyzed include grade III-IV acute GVHD, chronic extensive GVHD, non-relapse mortality, relapse, and overall survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 150 patients have been randomized and evaluated for 100 days post-transplant, an interim analysis for futility will be conducted. This analysis will estimate the conditional power of the study, given the data available at that time and assuming that going forward the rates of GVHD will differ by 15% between arms, with the rates for each arm centered around the pooled estimate of the rate from the combined arms. The conditional power will be estimated by Monte Carlo simulation. If the estimated conditional power is <33.3% then the trial will be stopped, otherwise the trial will continue to completion
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    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 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) 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 No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Randomized Phase III
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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
    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
    After 150 patients have been randomized and evaluated for 100 days post-transplant, an interim analysis for futility will be conducted. If the estimated conditional power is <33.3% then the trial will be stopped, otherwise the trial will continue to completion.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 5
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 20
    F.4.2.2In the whole clinical trial 300
    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 the subject has ended the participation in the trial he will be treated according the local standard of care of each site.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Medizinische Universitätsklinik II. Hematology/Oncology
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-24
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-07-27
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