E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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.1.2 | Version | 8.1 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10012818 | E.1.2 | Term | Diffuse large B-cell lymphoma | |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.4 | Principal 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.5.1 | Primary end point(s) | • Progression free survival (PFS) | |
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description | |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
E.8.7 | Trial 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 | |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |