R-CHOP-B Bevacizumab for Diffuse Large B Cell Lymphoma

Inclusion Criteria:

* Age \> 18 years.
* Histological proven diffuse large B cell non-Hodgkin's lymphoma (DLBCL) according to the World Health Organization classification including morphological variants. The B cell nature of the proliferation must be verified by the positivity with an anti-CD20 antibody. All histology will be reveiwed by a central Lymphoma Trials Office pathology panel.
* No previous chemotherapy, radiotherapy or other investigational drug for this indication.
* Stage II, III and IV disease.
* WHO performance status 0\<2.
* Adequate bone marrow function with platelets \> 100x109/l: neutrophils \> 1.5x109/l at the time of study entry unless attributed to bone marrow infiltration by lymphoma.
* Serum creatinine \< 150μmol/l , serum bilirubin \< 35μmol/l and transaminases \< 2.5 x upper limit of institutional normal range unless attributed to lymphoma.
* Normal MUGA or echocardiogram without any areas of abnormal contractility. Patients must have an acceptable left ventricular ejection fraction (LVEF) \> 50%.
* No current uncontrolled medical condition.
* No active malignant disease other than basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix in the last 10 years.
* Adequate contraceptive precautions for all patients of childbearing potential.
* Written, informed consent.

Exclusion Criteria:

* T-cell lymphoma or transformed follicular lymphoma.
* Previous history of treated or non-treated indolent lymphoma. However, patients not previously diagnosed who have a large B-cell lymphoma with some small cell infiltration in bone marrow or lymph node may be included.
* Past history of heart failure or uncontrolled angina pectoris.
* Central nervous system, meningeal involvement or cord compresssion by the lymphoma
* Cardiac contra-indication to doxorubicin (abnormal contractility on echocardiography or nuclear medicine examination\[MUGA\])
* Neurological contra-indication to vincristine (e.g pre-existing diabetic neuropathy).
* Any other serious active disease
* General status that does not allow the administration of 8 courses of CHOP according to the investigator
* Positive serology for HIV, Hepatitis B or Hepatitis C
* Medical or psychiatric conditions that compromise the patient's ability to give informed consent
* Bevacuzumab related criteria:

  * No major surgery, major trauma or open biopsy within 28 days prior to study entry. Patients requiring insertion of central venous access for treatment (e.g due to poor venous access) should have the procedure performed at least 2 days before starting treatment.
  * No serious, non-healing would, ulcer or bone fracture.
  * Absence of obvious risk of requiring emergency surgery after commencement of study treatmene, such as impending bowel obstruction.
  * Absense of clinically significant (i.e active) cardiovascular disease e.g. cerebrovascular accidents (\<6 months prior to randomisation), myocardial infarction (\< 1 year prior to randomisation), uncontrolled hypertension while receiving chronic medication, unstable angina, New York Hearth Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhymia requiring medication.
  * No recent history of any active gastrointestinal inflammatory condition such a peptic ulcer disease, diverticulitis or inflammatory bowel disease. If patients have a known diagnosis of any of the above, evidence of disease control is required by negative endoscopy within the last 28 days.
  * No evidence of bleeding disthesis or coagulopathy.
  * No recent commencement of full oral anticoagulation (warfarin), unless stable and within therapeutic range for at least 10 days. No thrombolytic therapy within 10 days prior to commencement of study treatment.
  * No chronic, daily treatment with high-dose aspirin (\> 325mg/day) or nonsteroidal anti-inflammatory medications (those known to inhibit platelet function at doses used to treat chronic inflammatory diseases).
  * No chronic treatment with corticosteriods (dose of . 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
  * No known allergy to Chinese hamster ovary cell proteins or other recombinant human or humanized antibodies or to any other excipients of bevacizumab formulation, platinum compounds or to any other components of the study drugs.
  * No proteinuria at baseline as defined by\>1g of protein/24 hr by 24-hour urine collection.