18 februari 2011

Originele protocol

Randomized phase III study on the effect of early intensification of rituximab in combination with 2-weekly CHOP chemotherapy followed by rituximab maintenance in patients with diffuse large B-cell lymphoma

Inclusion criteria

  • Patients with a confirmed histologic diagnosis of diffuse large B-cell lymphoma (DLBCL) based upon a representative histology specimen according to the WHO classification (see appendix A)
  • DLBCL must be CD20 positive
  • Ann Arbor stages II-IV (see appendix C)
  • Age 18-65 (inclusive) years and aa-IPI 1-3 (see appendix G)
    OR Age 66-80 (inclusive) years and aa-IPI 0-3 (see appendix G)
  • WHO performance status 0 – 2 (see appendix E)
  • Written informed consent
    Eligibility criteria for second randomization: Patients achieving a CR (or FDG-PET negative PR/CRu) after 6 cycles (elderly patients) or 8 cycles (young patients) of R-CHOP14 will be randomized to maintenance treatment with rituximab or no further treatment.
  • Patients in complete remission or FDG-PET negative partial remission/unconfirmed complete remission at least 4 weeks after the last cycle of R-CHOP14 (including last rituximab administration)
  • Time interval since last cycle of R-CHOP14 (including last rituximab administration) between 4 and 8 weeks
  • No rituximab-related adverse event necessitating stopping of rituximab administration
  • No active infection
  • Written informed consent

Exclusion criteria

  • Age 18-65 (inclusive) years and aa-IPI 0 (no risk factors, see appendix G)
  • Intolerance of exogenous protein administration
  • Severe cardiac dysfunction (NYHA classification III-IV, see appendix F) or LVEF < 45% Congestive heart failure or symptomatic coronary artery disease or cardiac arrhythmias not well controlled with medication. Myocardial infarction during the last 6 months
  • Severe pulmonary dysfunction (vital capacity or diffusion capacity < 50% of predicted value) unless clearly related to NHL involvement
  • Patients with uncontrolled asthma or allergy, requiring systemic steroid treatment
  • Significant hepatic dysfunction (total bilirubin ≥ 30µmol/l or transaminases ≥ 2.5 x upper normal limit), unless related to NHL
  • Significant renal dysfunction (serum creatinine ≥ 150 umol/l or clearance ≤ 60 ml/min), unless related to NHL
  • Clinical signs of severe cerebral dysfunction
  • Suspected or documented Central Nervous System involvement by NHL
  • Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs
  • Testicular DLBCL
  • Primary mediastinal B cell lymphoma
  • Transformed indolent lymphoma
  • (EBV) post-transplant lymphoproliferative disorder
  • Secondary lymphoma after previous chemotherapy or radiotherapy
  • Major surgery, other than diagnostic surgery, within the last 4 weeks
  • Patients with active uncontrolled infections
  • Patients known to be HIV-positive
  • Active chronic hepatitis B or C infection
  • Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease)
  • Life expectancy < 6 months
  • Prior treatment with chemotherapy, radiotherapy or immunotherapy for this lymphoma, except a short course of prednisone (< 1 week) and/or cyclophosphamide (< 1 week and not in excess of 900 mg/m2 cumulative) or local radiotherapy in order to control life threatening tumor related symptoms
  • History of active cancer during the past 5 years, except basal carcinoma of the skin or stage 0 cervical carcinoma