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    Summary
    EudraCT Number:2008-003460-19
    Sponsor's Protocol Code Number:BO21003
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-04-14
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2008-003460-19
    A.3Full title of the trial
    An open-label, multi-centre, dose escalating, phase I/randomized phase II study to investigate the safety and tolerability of RO5072759 given as monotherapy in patients with CD20+ malignant disease.
    A.4.1Sponsor's protocol code numberBO21003
    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 SponsorF.Hoffmann-La Roche
    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 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 No
    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 nameRO5072759
    D.3.2Product code RO5072759/F01
    D.3.4Pharmaceutical form Powder for solution for 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.3.9.1CAS number 949142-50-1
    D.3.9.2Current sponsor codeRO5072759
    D.3.9.3Other descriptive nameGA101
    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) No
    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 Yes
    D.3.11.13.1Other medicinal product typeRO5072759 is a humanized and glycoengineered monoclonal antibody (mAB)
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 MabThera 100mg concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    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 nameMabThera (Rituximab)
    D.3.4Pharmaceutical form Concentrate for solution for 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.3.9.2Current sponsor codeRO 045-2294/V01
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100 to 10
    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) No
    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 Yes
    D.3.11.13.1Other medicinal product typemouse/human monoclonal antibody
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 MabThera 500mg concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd.
    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 nameMabThera (Rituximab)
    D.3.4Pharmaceutical form Concentrate for solution for 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.3.9.2Current sponsor codeRO45-2294/V02
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500 to 50
    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) No
    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 Yes
    D.3.11.13.1Other medicinal product typemouse/human monoclonal 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
    Patients with relapsed CD20+ indolent NHL will be enrolled (Relapsed defined as; relapsed indolent lymphoma with documented history of response [CR, CRu, or PR) of≥6 months in duration from the completion of last rituximab containing regimen at some point in a patients treatment history).
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10029547
    E.1.2Term Non-Hodgkin's lymphoma
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the overall response rate and safety data of RO5072759 (1000mg flat dose) given as monotherapy in patients with relapsed CD20+ indolent NHL compared with rituximab (375mg/m2) monotherapy.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are:
    • To characterize the pharmacokinetics of RO5072759.
    • To investigate if a shorter RO5072759 duration of infusion schedule is feasible (Phase II part of the study only).
    • To investigate peripheral blood B-cell depletion and repletion with increasing doses of RO5072759.
    • To obtain preliminary data on the anti-tumor efficacy of RO5072759 monotherapy compared with rituximab (375mg/m2) monotherapy (including the maintenance extended treatment regimen period) in patients with relapsed CD20+ indolent NHL by evaluating:
    – overall response rate (ORR)
    – progression- free survival (PFS)
    – event-free survival (EFS)
    • To investigate pharmacogenetic parameters (FcyRIIa and FcyRIIIa polymorphisms at baseline) and pharmacodynamic parameters (including but not limited to bcl-2 rearrangements, at baseline, during and after treatment) in relation to efficacy.
    • To evaluate the feasibility of extended therapy with RO5072759.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients in the phase II (including those in the SDI) part of the study must meet the following criteria:
    1. Have history of histologically confirmed CD20+, indolent B-cell NHL (any grade). This includes small lymphocytic lymphoma and marginal zone lymphoma but exclude B-CLL. For each patient, a prior biopsy demonstrating CD20 positivity of tumor cells must be available locally at the investigator site (review performed according to local standard procedures), prior to dosing, and will be further confirmed following central pathology review after dosing. A biopsy must be performed if transformation is suspected.
    2. Have a clinical indication for treatment as determined by the investigator.
    3. Relapsed disease with documented history of response (CR, CRu, or PR) of ≥6 months in duration from completion of last rituximab containing regimen. A rituximab-containing regimen is defined as rituximab as a single agent during induction and/or maintenance, or in combination with other agents during induction and/or maintenance.
    4. All patients must have at least one bi-dimensionally measurable lesion (>1.5 cm in its largest dimension by computerized tomography [CT] scan). Note that all measurable and evaluable disease must be assessed and documented prior to initiation of RO5072759/rituximab treatment. Tumor response will be based on the status of all areas of disease.
    5. ECOG performance status: of 0-2

    All patients (Phase I and II) must also meet the following criteria to be eligible for study entry:
    6. Able and willing to provide written informed consent and to comply with the study protocol
    7. Age ≥18 years
    8. Life expectancy of ≥12 weeks.
    E.4Principal exclusion criteria
    Patients who meet any of the following criteria will be excluded from the study:
    1. Prior use of any investigational monoclonal antibody within 6 months of study start.
    2. Prior administration of rituximab within 56 days of study entry or 3 months for any radioimmunotherapy.
    3. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products.
    4. Central nervous system lymphoma or histological evidence of transformation to high grade or diffuse large B-cell lymphoma (if transformation is clinically suspected a re-biopsy is mandatory).
    5. History of other malignancy which could affect compliance with the protocol or interpretation of results. Patients with a history of malignancy that has been treated, but not with curative intent, will also be excluded, unless the malignancy has been in remission without treatment for ≥2 years prior to enrollment.
    6. Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of symptomatic bronchospasm).
    7. Known active bacterial, viral (including human immunodeficiency virus [HIV], ( HCV, HBV, HTLV I), fungal, mycobacterial, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (relating to the completion of the course of antibiotics) within 4 weeks of 1st dose of RO5072759 or rituximab.
    8. Recent major surgery (within 4 weeks prior to screening), other than for diagnosis.
    9. Unless clearly due to lymphoma any of the following abnormal laboratory values (Note 5% window allowed for inter-laboratory variation per protocol):
    • Renal – Calculated creatinine clearance by Cockcroft-Gault formula ≤50 mL/min
    • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal.
    • Platelet count <75 × 109/L.
    • Neutrophils <1.5 × 109/L
    • Hemoglobin <10g/dL
    10. Presence of positive test results for any of the following: all of the first 5 tests should be done for all patients
    • Human immunodeficiency virus (HIV)
    • Hepatitis B (HB virus [B DNA], HB surface antigen [HBsAg], total HB core antibody [anti HB c])
    • Hepatitis C [Hepatitis C virus [HCV] antibody serology testing.
    • Human T-lymphotropic virus 1 [HTLV I] (in endemic countries only)
    11. Women who are pregnant or lactating.
    12. Fertile men or women of childbearing potential unless (1) surgically sterile or (2) using an adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly. Effective contraception is required throughout the study and (because of the long half-life of humanized monoclonal antibodies and the potential for prolonged lymphopenia) for at least 12 months after the last dose of RO5072759 or rituximab.
    13. Ongoing corticosteroid use, with the exception of corticosteroid use for other indications, is permitted only up to a maximum dose of 30 mg/day prednisone or equivalent.
    14. Treatment with an investigational agent or participation a clinical study 30 days prior to study day 1.
    NOTE: Patients with cell counts below the thresholds listed above may be considered eligible if in the investigators opinion, the reason is believed to be due to bone marrow infiltration. Likewise patients may be considered for the study if liver or kidney function is impaired and this is believed to be due to lymphoma. The investigator will discuss the eligibility of such patients with the Sponsor and only upon approval (confirmed in writing) by the Sponsor will a patient be enrolled in the study.
    Patients eligible for the exploratory SDI part of the study, must meet the entry criteria for Phase II (Please refer to Appendix 9 for more information).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint for the phase II part of the study will be overall response rate. Overall response rate will be analyzed in frequency tables including 95% Pearson Clopper confidence intervals by dose group for the phase I part of the study and by treatment group for the phase II part of the study. (This is a secondary endpoint for the phase I part of the study.)
    For the phase II part of the study, the hypothesis of no difference in overall response rate versus a larger overall response rate in RO5072759 over rituximab will be tested in the two randomized treatment arms using a one sided y2-test at an alpha level of 0.2 restricted to follicular NHL patients only.
    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 Information not present in EudraCT
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Exploration of a Shorter RO5072759 Duration of Infusion (SDI).
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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.8.6 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 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
    2.5 years after the last patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 state
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 220
    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 Decision2009-04-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-05-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-03-14
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