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Feasibility Study of R-CHOP Plus Bevacizumab in Patients With Diffuse Large B Cell Lymphoma (DLBCL)

Phase 2
18 Years
Not Enrolling
Non-Hodgkin's Lymphoma, B-cell Lymphoma

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Trial Information

Feasibility Study of R-CHOP Plus Bevacizumab in Patients With Diffuse Large B Cell Lymphoma (DLBCL)

Non-Hodgkin's lymphoma is increasing in incidence with more than 287,000 cases world-wide
and 9000 cases in UK diagnosed each year. DLBCL is the most frequently occurring NHL,
constituting approximately 31% of all non-Hodgkin's lymphomas.

Rituximab-CHOP chemotherapy has shown clinical efficacy and is regarded as standard
treatment in patients with DLBCL. NICE has recently approved the use of rituzimab in
combination with CHOP for all newly diagnosed patients with DLBCL stage II-IV.

Angiogenesis plays an important role in the pathophysiology of both solid tumours and
hematologic malignancies. Vascular endothelial growth factor (VEGF) is the most important
pro-angiogenic factor involved in normal and pathologic angiogenesis and studies have also
implicated VEGF in lymphomagenesis. Elevated VEGF gene expression correlates with diffuse
large B cell lymphoma subtypes of poor prognosis on microarray analysis. In patients with
lymphoma, high circulating serum VEGF levels have been strongly associated with poor
clinical outcomes independent of other predictive factors.

Bevacizumab is a humanized monoclonal antibody that binds to VEGF thus preventing binding to
its receptors thus inhibiting the downstream pathways dependent on receptor stimulation.
Bevacizamab has shown activity in solid tumours (colorectal, renal, breast and non-small
cell lung cancer) and early results suggest that the combination of R-CHOP plus bevacizamab
is feasible in patients with non Hodgkin's lymphoma.

Patients will be treated with a minimum of 6 cycles of treatment. A further 2 cycles, to a
total of 8 cycles, may be administered if continuing response to treatment has been
documented but residual disease is still detectable on restaging after 6 cycles. Each cycle
of treatment is 21 days.

Follow up - a) Clinic visit with physical examination at 3, 6, 9, 12, 18 and 24 months after
completion of R-CHOP-B, then annually.

b) CT scan of chest, abdomen and pelvis at 3 months and 1 year after finishing treatment.

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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary endpoint of this study is cardiac and bevacizumab-specific toxicity. Toxicities will be evaluated according to the NCI Common Toxicity Criteria for Adverse Events v3.0

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

David Cunningham

Investigator Role:

Principal Investigator

Investigator Affiliation:

Royal Marsden NHS Foundation Trust


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:

CCR 2719



Start Date:

May 2008

Completion Date:

September 2012

Related Keywords:

  • Non-Hodgkin's Lymphoma
  • B-Cell Lymphoma
  • diffused large B cell lymphoma, DLBCL, R-Chop, bevacizumab
  • Diffuse large B-cell non-Hodgkin's lymphoma.
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse