Bevacizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
Bevacizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
This phase II trial is studying how well bevacizumab works in treating patients with relapsed
 or refractory B-cell chronic lymphocytic leukemia. Monoclonal antibodies, such as
 bevacizumab, can block cancer growth in different ways. Some block the ability of cancer
 cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing
 substances to them. Bevacizumab may also stop the growth of cancer cells by blocking blood
 flow to the cancer.
PRIMARY OBJECTIVES:

 I. Assess the treatment success rate of Bevacizumab in patients with relapsed or refractory
 B-cell chronic lymphocytic leukemia (CLL).

 II. Assess the toxicity associated with this regimen in patients with relapsed or refractory
 CLL

 SECONDARY OBJECTIVES:

 I. Assess sensitivity to apoptosis/cell death of residual B-cell clone during therapy (e.g.
 is treatment selecting out a resistant clone).

 II. Evaluate if the risk stratification parameters (ie immunoglobulin mutational, ZAP-70,
 FISH defects and /or CD38 status) corresponds to both baseline apoptosis/cell death and the
 rates of apoptosis of CLL B-cells when cultured with Bevacizumab.

 III. Examine if Bevacizumab can be synergistic with other chemotherapeutic drugs such as
 chlorambucil or fludarabine.

 IV. Assess if marrow vascularity is increased at entry to study and if it is modulated
 following therapy with Bevacizumab.

 V. Examine the association of VEGF plasma levels at baseline with clinical responses to
 Bevacizumab.

 VI. Examine the levels of VCAM at entry to the study and during treatment with Bevacizumab.

 OUTLINE: This is a multicenter study. Patients receive bevacizumab IV over 30-90 minutes on
 days 1 and 15.

 Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
 After completion of study treatment, patients are followed periodically for up to 5 years.
Inclusion Criteria:

 -  Diagnosis of B-cell chronic lymphocytic leukemia (CLL)*, as defined by the following
 phenotypic characteristics:

 -  Predominant population of cells share both B-cell antigens (CD19, CD20, or CD23)
 as well as the T-cell antigen (CD-5), in the absence of other pan-T-cell markers
 (CD-3, CD-2, etc.)

 -  Mantle cell lymphoma must be excluded by demonstrating the absence of the
 t(11;14) by fluorescent in situ hybridization (FISH)

 -  Dim surface immunoglobulin expression

 -  Exclusively kappa and lambda light chains

 -  Peripheral blood absolute lymphocyte count > 5,000/mm^3

 -  Lymphocytosis must consist of small to moderate size lymphocytes, with ≤ 55%
 prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically

 -  Requires chemotherapy, as indicated by any of the following:

 -  Disease related symptoms, including the following:

 -  Weight loss ≥ 10% within the previous 6 months

 -  Extreme fatigue

 -  Fevers > 100.5°F for 2 weeks without evidence of infection

 -  Night sweats without evidence of infection

 -  Evidence of progressive marrow failure, as manifested by the development of or
 worsening anemia (hemoglobin ≤ 10 g/dL) and/or thrombocytopenia (platelet count ≤
 100,000/mm^3)

 -  Massive (i.e., > 6 cm below left costal margin) or progressive splenomegaly

 -  Measurable and progressive lymphadenopathy

 -  Measurable (i.e., > 5,000/mm^3) and progressive lymphocytosis

 -  Progressive disease or relapsed after or refractory to 1 course of an alkylating
 agent-based or purine nucleoside-based (e.g., fludarabine) regimen

 -  No marrow function attributable to dysplasia related to prior therapy

 -  ECOG performance status 0, 1, or 2

 -  Serum creatinine < 2 mg/dL

 -  If serum creatinine > 1.5 mg/dL but < 2 mg/dL, creatinine clearance must be ≥ 30
 mL/min

 -  Platelet count > 30,000/mm^3

 -  Direct bilirubin ≤ 2 mg/dL

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  No other second malignancy within the past 2 years except squamous cell or basal cell
 carcinoma of the skin or in situ carcinoma of the cervix

 -  No New York Heart Association class III or IV heart failure

 -  No blood pressure > 150/90 mm Hg

 -  No unstable angina

 -  No myocardial infarction or stroke within the past 6 months

 -  No clinically significant peripheral vascular disease

 -  No evidence of bleeding diathesis or coagulopathy

 -  No significant traumatic injury within the past 28 days

 -  Urine protein:creatinine (UPC) ratio ≤ 1.0

 -  Patients with a UPC ratio > 1.0 must undergo a 23-hour urine collection and must
 demonstrate < 1 gram of protein per day

 -  No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
 the past 6 months

 -  No serious, non-healing wound, ulcer, or bone fracture

 -  No active infections requiring oral or intravenous antibiotics

 -  No active bleeding or pathological conditions that carry a high risk of bleeding
 (e.g., known varices)

 -  No thrombocytopenia requiring transfusion

 -  See Disease Characteristics

 -  More than 4 weeks since prior participation in an experimental drug study

 -  At least 8 weeks since prior rituximab

 -  At least 6 weeks since prior chemotherapy

 -  More than 28 days since prior major surgery or open biopsy

 -  More than 7 days since prior minor surgery, fine needle aspirations, or core biopsies

 -  No concurrent major surgery

 -  No concurrent participation in another experimental drug study

 -  Concurrent full-dose warfarin or low molecular weight heparin allowed provided patient
 is on a stable dose AND INR is in range