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A Phase II Study of Fludarabine (F), Rituxan (R) and Avastin (A) Followed by RA Maintenance in Patients With Relapsed/Refractory B-cell Chronic Lymphocytic Leukemia (CLL)

Phase 2
18 Years
Not Enrolling
B-cell Chronic Lymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia

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Trial Information

A Phase II Study of Fludarabine (F), Rituxan (R) and Avastin (A) Followed by RA Maintenance in Patients With Relapsed/Refractory B-cell Chronic Lymphocytic Leukemia (CLL)


I. To estimate PFS at 2 years after FR plus Avastin (A) induction followed by Rituximab plus
Avastin (RA) maintenance therapy for relapsed/refractory CLL patients.


I. To evaluate response rates after FR-A induction and RA maintenance therapy. II. To
eliminate residual disease (documented by flow cytometry and/or PCR) in patients who have
achieved a CR after FR-A.

III. To estimate the rate of conversion of PR to CR after FR-A. IV. To determine the safety
and pharmacokinetics of FR-A and RA maintenance.


INDUCTION THERAPY: Patients receive fludarabine phosphate IV over 20-30 minutes once daily
on days 1-5 and rituximab IV once daily on days 4 or 5. Treatment repeats every 35 days for
6 courses in the absence of disease progression or unacceptable toxicity. Beginning on day
8 of course 1, patients also receive bevacizumab IV over 30 minutes. Treatment repeats every
21 days for 9 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving complete response, partial response, or nodular partial response proceed
to maintenance therapy.

MAINTENANCE THERAPY: Beginning 2 months after completion of induction treatment, patients
receive rituximab IV every 3 months and bevacizumab IV over 30 minutes every 3 weeks.
Treatment continues for 2 years in the absence of disease progression or unacceptable

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and annually thereafter.

Inclusion Criteria


- Relapse or refractory chronic Lymphocytic leukemia as defined by the WHO criteria and
exhibit active disease requiring treatment as per the NCI working group in CLL

- Disease measurable defined by a combination of lymphocytosis >= 5,000/mm^3 in
peripheral blood and lymphocytosis >= 30% in bone marrow

- Confirmed CD20 expression on malignant CLL cells

- ECOG performance status of 0-2

- Life expectancy of at least 6 months

- Documented negative serologic testing for human immunodeficiency virus (HIV),
hepatitis B (unless serologically positive due to prior vaccination), and hepatitis C
within the year prior to enrollment

- Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN)

- Total serum bilirubin < 2.5 x ULN

- Serum creatinine < 1.5 x ULN

- Hemoglobin > 8 g/dL

- Absolute neutrophil count (ANC) > 1,000 cells/mm^3

- Platelet count > 50,000/mm^3

- PT/INR and PTT < 1.5 x ULN

- Within 2 weeks prior to registration, patients must have had a urinalysis negative
for protein or a 24-hour urine collection demonstrating < 500 mg protein

- If female and of child-bearing potential, have a negative serum pregnancy test within
14 days of enrollment

- If sexually active male or sexually active female of reproductive capability, has
agreed to use a medically accepted form of contraception from time of enrollment to
completion of all follow-up study visits

- Signed an institutional review board (IRB)-approved informed consent document for
this protocol


- Patients must not require sustained support of hematopoietic cytokines or transfusion
of blood products

- Presence of acute infection or other significant systemic illness

- Central nervous system involvement by malignancy, history of CVA, or seizure

- Previously received Bevacizumab

- Received transplant or Alemtuzumab within 3 months of enrollment

- Received an investigational agent, systemic corticosteroids, chemotherapy,
immunotherapy, biologic therapy, antibody therapy (e.g., Rituximab) and/or radiation
therapy within one month of enrollment

- Radiation to > 25% of bone marrow or any radiation therapy within 4 weeks prior to
start of therapy

- Inability to comply with study and/or follow-up procedures

- Life expectancy of less than 6 months

- Fludarabine-refractory disease (no response of disease to >= 3 cycles of a
fludarabine-based regimen or relapse within 6 months of fludarabine-based regimen)

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored
bevacizumab cancer study

- Patients with prior malignancy other than lymphoma, except for adequately-treated
skin cancer (basal cell or squamous cell carcinoma), in situ cervical cancer, or
other cancer for which the patient has been disease-free for 5 years unless approved
by the PI

- Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg
and/or diastolic blood pressure > 100 mmHg)

- Prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 6 months prior to Day 1

- History of stroke or transient ischemic attack within 6 months prior to Day 1

- Known CNS disease, except for treated brain metastasis; Patients with CNS metastases
treated by neurosurgical resection or brain biopsy performed within 3 months prior to
Day 1 will be excluded

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1

- History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within 1
month prior to Day 1

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1, or anticipation of need for major surgical procedure during the
course of the study

- Core biopsy or minor surgical procedure, excluding placement of a vascular access
device, within 7 days prior to Day 1

- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1

- Serious, non-healing wound, active ulcer, or untreated bone fracture

- Proteinuria as demonstrated by a UPC ratio >= 1.0 at screening

- Known hypersensitivity to any component of bevacizumab

- Pregnancy (positive pregnancy test) or lactation; use of effective means of
contraception (men and women) in subjects of childbearing potential

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Time Frame:

At 2 years

Safety Issue:


Principal Investigator

John Pagel

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

January 2009

Completion Date:

Related Keywords:

  • B-cell Chronic Lymphocytic Leukemia
  • Refractory Chronic Lymphocytic Leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid