Summary
EudraCT Number:2006-005520-16
Sponsor's Protocol Code Number:BO20603
National Competent Authority:France - ANSM
Clinical Trial Type:EEA CTA
Trial Status:Ongoing
Date on which this record was first entered in the EudraCT database:2007-03-27
Trial results View results
A. Protocol Information
A.1Member State ConcernedFrance - ANSM
A.2EudraCT number2006-005520-16
A.3Full title of the trial
A multi-center, randomized, double-blind, placebo-controlled phase III trial comparing the efficacy of bevacizumab in combination with rituximab and CHOP (RA-CHOP) versus rituximab and CHOP (R-CHOP) in previously untreated patients with CD20-positive diffuse large B-cell lymphoma (DLBCL)
A.3.2Name or abbreviated title of the trial where available
MAIN
A.4.1Sponsor's protocol code numberBO20603
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 Ltd
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 Yes
D.2.1.1.1Trade name Avastin
D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
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.3.4Pharmaceutical 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 INNbevacizumab
D.3.9.1CAS number 216974-75-3
D.3.9.2Current sponsor codeRO4876646
D.3.10 Strength
D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
D.3.10.2Concentration typeequal
D.3.10.3Concentration number100 mg/4 ml
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 typeRecombinant humanised monoclonal antibody
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.2.1.1.1Trade name Avastin
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.3.4Pharmaceutical 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 INNbevacizumab
D.3.9.1CAS number 216974-75-3
D.3.9.2Current sponsor codeRO4876646
D.3.10 Strength
D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
D.3.10.2Concentration typeequal
D.3.10.3Concentration number400mg/16mL
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 typeRecombinant humanised monoclonal antibody
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 placeboConcentrate for solution for infusion
D.8.4Route of administration of the placeboIntravenous use
D.8 Placebo: 2
D.8.1Is a Placebo used in this Trial?Yes
D.8.3Pharmaceutical form of the placeboConcentrate for solution 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
Previously untreated CD20-positive Diffuse Large B-Cell Lymphoma (DLBCL) patients
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 8.1
E.1.2Level LLT
E.1.2Classification code 10012818
E.1.2Term Diffuse large B-cell 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 demonstrate superior clinical efficacy as measured by progression free survival (PFS) of bevacizumab in combination with rituximab and CHOP (RA-CHOP) versus R-CHOP alone for the treatment of previously untreated patients with diffuse large B cell lymphoma (DLBCL) with at least low-intermediate risk disease according to the IPI or bulky disease regardless of IPI risk category.
E.2.2Secondary objectives of the trial
• To compare the overall survival (OS) between both treatment groups.
• To compare event-free survival (EFS) between both treatment groups.
• To compare disease-free survival (DFS) between both treatment groups
• To compare the safety profile of both treatment arms.
• To compare the overall response rate (ORR) between both treatment groups.
• To compare the complete response rate (CR) between both treatment groups.
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
• Written informed consent
• Age ≥ 18 years
• CD20-positive diffuse large B-cell lymphoma (DLBCL) or histologic variants under the WHO classification
• Low-intermediate, high-intermediate, or high risk disease according to the IPI score and/or bulky disease (largest diameter > 7.5 cm) regardless of IPI score
• Bi-dimensionally measurable disease
• Performance status (ECOG) 0-2
• Cardiac ejection fraction ≥ 50 % as measured by MUGA or 2D-ECHO without clinically significant abnormalities
• Adequate hematological function: hemoglobin ≥ 9g/dL absolute neutrophil count ≥ 1,500/µL and platelet count ≥ 100,000/µL, unless abnormalities are due to bone marrow involvement by lymphoma
• Adequate renal function as documented by:
• a serum creatinine level < 2 mg/dL (177 µmol/L)
• urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24-hrs urine collection must demonstrate ≤ 1 g protein secretion in 24 hours
• Adequate hepatic function (total bilirubin < 1.5 x ULN, transaminases < 2.5 x ULN [or < 5 x ULN in the presence of DLBCL involvement of the liver])
• The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR, or other monitoring test as appropriate, is within therapeutic limits and the patient has been on a stable dose of anticoagulants for at least 2 weeks at the time of randomization. Patients not receiving anticoagulant medication must have an INR ≤ 1.5 and a PTT ≤ 1.5 x ULN within 7 days of randomization.
• Life expectancy > 6 months
• A negative serum pregnancy test one week prior to treatment must be available both for pre-menopausal women and for women who are < 2 years after the onset of menopause, or within 14 days with a confirmatory urine pregnancy test within 1 week prior to study treatment start
E.4Principal exclusion criteria
• Transformed NHL or types of NHL other than DLBCL and its subtypes according to WHO classification
• Prior therapy for DLBCL
• CNS involvement by lymphoma or any evidence of spinal cord compression. Brain
CT/MRI is only mandatory (within 4 weeks prior to randomization) in case of clinical
suspicion of CNS involvement by lymphoma.
• CT-scan based evidence of tumor invading major blood vessels (putting patients at risk for bleeding during study treatment)
• Gastrointestinal tract involvement by lymphoma. Note that endoscopy is not a
mandated pre-study procedure for all patients.
• Seropositivity for Hepatitis B unless clearly due to vaccination (Hepatitis B testing is not mandatory, but highly recommended)
• Known HIV infection (HIV testing is not mandatory in this study)
• Active viral, bacterial or fungal infection
• History of solid organ transplantation
• Pregnant or nursing females
• Men and women of childbearing potential
(< 2 years after last menstruation) not using effective means of contraception (oral
contraceptives, intrauterine contraceptive device, barrier method of contraception in
conjunction with spermicidal jelly, or surgically sterile)
• Prior malignancy (except adequately treated basal cell carcinoma of the skin, in situ
cervical cancer, or any other cancer for which the patient has been in remission for at least 5 years)
• Known hypersensitivity to any of the study drugs or its ingredients (i.e., hypersensitivity to Polysorbate 20, CHO cell products, or recombinant human antibodies)
• Uncontrolled seizures requiring permanent anticonvulsant therapy
• Severe chronic obstructive pulmonary disease with hypoxemia
• Uncontrolled diabetes mellitus
• Uncontrolled hypertension, CVA/stroke (≤ 6 months prior to randomization),
myocardial infarction (≤ 6 months prior to randomization), unstable angina
(≥ NYHA Grade IV), thrombosis within 6 months before enrolment, NYHA ≥ Grade II
CHF, or serious cardiac arrhythmia requiring ongoing medication
• Clinically significant, active peripheral vascular disease, serious non-healing
wound/ulcer, bone fracture, bleeding diathesis (history or evidence of inherited bleeding diathesis) or coagulopathy
• Major surgery, open biopsy or trauma within 28 days before enrolment (lymph node
biopsies are not considered major surgery), or the need for major surgery during the course of study treatment
• History of active ulcer (within 1 year prior to randomization), abdominal fistula,
gastrointestinal perforation, or intra-abdominal abscess or concurrent therapy for
treatment/prevention of ulcer
• Current or recent (within the 30 days prior to starting study treatment) treatment with another investigational drug or participation in another investigational therapeutic study
• Evidence of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates use of an investigational drug, or patient at high risk from treatment
complications
• Any co-existing medical or psychological condition that would compromise ability to
give informed consent
E.5 End points
E.5.1Primary end point(s)
• Progression free survival (PFS)
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 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 Yes
E.6.13.1Other scope of the trial description
biomarker study
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) No
E.7.1.1First administration to humans Information not present in EudraCT
E.7.1.2Bioequivalence study Information not present in EudraCT
E.7.1.3Other Information not present in EudraCT
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 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 Yes
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 concerned19
E.8.5The trial involves multiple Member States Yes
E.8.5.1Number of sites anticipated in the EEA30
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
NA
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years7
E.8.9.1In the Member State concerned months5
E.8.9.1In the Member State concerned days
E.8.9.2In all countries concerned by the trial years7
E.8.9.2In all countries concerned by the trial months6
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 state120
F.4.2 For a multinational trial
F.4.2.1In the EEA 730
F.4.2.2In the whole clinical trial 1060
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)
All patients will be followed-up every 3 months until the end of year 2 and every 6 months until 5 years and then at least annually until the end of the study. At each visit until 5 years (or disease progression if it occurs before 5 years). After 5 years, patients will only be followed for survival. After disease progression, patients will be followed for survival only.
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 Decision2007-05-09
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2007-03-28
P. End of Trial
P.End of Trial StatusOngoing