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    Summary
    EudraCT Number:2009-015968-34
    Sponsor's Protocol Code Number:FHCRC1840
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-02-16
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2009-015968-34
    A.3Full title of the trial
    Nonmyeloablative Conditioning with Pre- and Post-Transplant Rituximab followed by Related or Unrelated Donor Hematopoietic Cell Transplantation for Patients with Advanced Chronic Lymphocytic Leukemia: A Multi-Center Trial
    A.3.2Name or abbreviated title of the trial where available
    FHCRC protocol 1840 for CLL
    A.4.1Sponsor's protocol code numberFHCRC1840
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    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.2.1.1.1Trade name Rituximab
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameRituximab
    D.3.2Product code EU/1/98/067/001
    D.3.4Pharmaceutical form Intravenous infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.3Other descriptive nameanti-CD20 antibodies
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    Chronic lymphocytic leukemia (CLL) is a malignant disease. CLL is the most common form of leukemia in western countries. Median age at diagnosis is 70 years, and only 10-15% of patients are younger than 50 years. Despite some therapeutic progress, standard treatment is not curative for CLL
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.0
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. Determine whether nonmyeloablative conditioning and allogeneic HCT improves survival at 18 months for patients with fludarabine-refractory, FCR-failed, or del 17p CLL over that of historical controls (45% at 18 months) given CAMPATH-1H.[14]
    E.2.2Secondary objectives of the trial
    1. Estimate the overall response rate (CR + PR) by standard morphologic, flow cytometric, and molecular techniques.
    2. Assess the rate of relapse/progression.
    3. Define incidences of RRT and infections within the first 200 days and the incidence of TRM within the first year.
    4. Estimate incidences of grade II-III and III-IV acute GVHD and chronic GVHD.
    5. Assess the impacts of Rituximab
    6. Graft-versus-leukemia analysis
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    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.
    2. Patients with B-Cell CLL or PLL who:
    a. Failed to meet NCI Working Group criteria2 (Appendix I) for complete or partial response after therapy with regimens containing fludarabine (or another nucleoside analog, e.g. 2-CDA, pentostatin) or with disease relapse within 12 months after completing therapy with fludarabine (or another nucleoside analog) containing regimen.
    b. Failed FCR or PCR combination chemotherapy at any time point.
    c. Patients with novo or acquired “17p deletion” cytogenetic abnormality. Patients should have received induction chemotherapy but could be transplanted in 1st CR.
    3. Patients who have suitable HLA-matched related or unrelated donors willing to receive G-CSF, undergo leukopharesis to collect PBMC, and to donate stem cells
    E.4Principal exclusion criteria
    1. Infection with HIV.
    2. Active diagnosis of CNS involvement with CLL. For LP requirement, see Appendix O.
    3. Patients unwilling to use contraceptive techniques before and for 12 months after HCT
    4. Pregnant women or females who are breastfeeding.
    5. The addition of cytotoxic agents for “cytoreduction” with the exception of tyrosine kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning.
    6. Active bacterial or fungal infections unresponsive to medical therapy.
    7. Performance status:
    a. Karnofsky score < 60 (see Appendix B) for adult patients
    b. Lansky Play-Performance Score < 40 (Appendix C) for pediatric patients.
    8. Severe organ dysfunction:
    a. Cardiovascular:
    i. Cardiac ejection fraction < 40%. Ejection fraction is required if age > 50 years or there is a history of prior transplant, anthracycline exposure or history of cardiac disease.

    ii. Poorly controlled hypertension despite multiple antihypertensives.

    b. Pulmonary:
    i. DLCO < 40%, TLC <40%, FEV1 <40% and/or requiring continuous supplementary oxygen, or severe deficits in pulmonary function testing as defined by pulmonary consultant service.

    ii. The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules.

    c. Hepatic:
    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. Patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, hepatic damage with bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin >3 mg/dl, or symptomatic biliary disease.

    9. Patients with active non-hematologic malignancies (except non-melanoma skin cancers).

    10. Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a >20% risk of disease recurrence
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this protocol is to estimate survival using allogeneic HCT from related or unrelated donors after nonmyeloablative conditioning and peri-transplant Rituximab in patients with advanced CLL, and to gain a preliminary indication as to whether survival is improved compared to treatment with conventional salvage therapies. The primary endpoint will be survival at 18 months. The 18 months time point is chosen because prior experience with HCT indicates that survival reaches a relative plateau by that time, and thus offers an endpoint that can be evaluated somewhat more rapidly than 2 year survival. The estimated 18 months survival with standard treatment (Campath-1H) from historical patients is approximately 0.45. This treatment approach will be deemed promising for further study if we can achieve reasonable confidence that survival exceeds 0.45. Reasonable confidence will be taken to mean that the lower limit of a one-sided 80% confidence interval for the true survival fraction at 18 months is greater than 0.45.
    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 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) 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.8.3 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 No
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    Criteria for Termination of Study
    This will be a single stage trial of a single cohort of 40 patients. However, safety stopping rules will be imposed for acute grade IV GHVD, and transplant-related mortality at 200 days.
    These rules will be evaluated after every fifth patient is evaluable for the endpoint in question.
    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 Yes
    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.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 80
    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)
    Not different from the expected normal 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 Decision2010-02-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-03-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-07-28
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