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Bevacizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

Primary Purpose

B-cell Chronic Lymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
bevacizumab
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-cell Chronic Lymphocytic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Mayo Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (monoclonal antibody therapy)

Arm Description

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.

Outcomes

Primary Outcome Measures

Number of Patients With Confirmed Objective Status of Complete Response (CR), Complete Clinical Response (CCR), Nodular Partial Response (nPR), or Partial Response (PR).
The NCI Working Group criteria will be used to assess response to therapy. A confirmed response is defined as a response documented on 2 consecutive evaluations at least 4 weeks apart. Complete Response: No lymphadenopathy No hepatomegaly or splenomegaly Absense of constitutional symptoms Polymorphonuclear leukocytes ≥ 1500/ul Platelets > 100,000/ul Hemoglobin > 11.0 gm/dl Peripheral blood lymphocytes ≤ 4000/uL. Confirmation by Marrow Aspirate and biopsy. Complete Clinical Response: -CR without bone marrow biopsy confirmation. Nodular Partial Response: -CR with the presence of residual clonal nodules. Partial Response requires: ≥ 50% decrease in peripheral blood lymphocyte count ≥ 50% reduction in lymphadenopathy ≥ 50% reduction in size of liver and/or spleen 1 or more of the following: Polymorphonuclear leukocytes ≥ 1500/ul Platelets >100,000/ul Hemoglobin >11.0 gm/dl

Secondary Outcome Measures

Toxicity Associated With This Regimen in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).
As per NCI Common Toxicity Criteria for Adverse Effects (CTCAE) Version 3.0, the term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. The number of participants experiencing grade 3 or higher toxicity will be reported here.
Overall Survival
The Kaplan-Meier method will be used to estimate distributions in the B-CLL population.
Time to Progression
Progression is defined as one of the following: A ≥50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive determinations 2 weeks apart (at least one node must be ≥2 cm) or the appearance of new palpable lymph nodes, or A ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or the appearance of hepatomegaly or splenomegaly which was not previously present, or The transformation to a more aggressive histology (e.g. Richter's transformation), or A ≥ 50% increase in the absolute number of circulating lymphocytes. The Kaplan-Meier method will be used to estimate time to progression.

Full Information

First Posted
February 9, 2006
Last Updated
April 21, 2014
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00290810
Brief Title
Bevacizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
Official Title
A Phase II Trial of Bevacizumab to Prevent or Delay Disease Progression in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2012
Overall Recruitment Status
Completed
Study Start Date
December 2005 (undefined)
Primary Completion Date
October 2008 (Actual)
Study Completion Date
August 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-cell Chronic Lymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (monoclonal antibody therapy)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
bevacizumab
Other Intervention Name(s)
anti-VEGF humanized monoclonal antibody, anti-VEGF monoclonal antibody, Avastin, rhuMAb VEGF
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Number of Patients With Confirmed Objective Status of Complete Response (CR), Complete Clinical Response (CCR), Nodular Partial Response (nPR), or Partial Response (PR).
Description
The NCI Working Group criteria will be used to assess response to therapy. A confirmed response is defined as a response documented on 2 consecutive evaluations at least 4 weeks apart. Complete Response: No lymphadenopathy No hepatomegaly or splenomegaly Absense of constitutional symptoms Polymorphonuclear leukocytes ≥ 1500/ul Platelets > 100,000/ul Hemoglobin > 11.0 gm/dl Peripheral blood lymphocytes ≤ 4000/uL. Confirmation by Marrow Aspirate and biopsy. Complete Clinical Response: -CR without bone marrow biopsy confirmation. Nodular Partial Response: -CR with the presence of residual clonal nodules. Partial Response requires: ≥ 50% decrease in peripheral blood lymphocyte count ≥ 50% reduction in lymphadenopathy ≥ 50% reduction in size of liver and/or spleen 1 or more of the following: Polymorphonuclear leukocytes ≥ 1500/ul Platelets >100,000/ul Hemoglobin >11.0 gm/dl
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Toxicity Associated With This Regimen in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).
Description
As per NCI Common Toxicity Criteria for Adverse Effects (CTCAE) Version 3.0, the term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. The number of participants experiencing grade 3 or higher toxicity will be reported here.
Time Frame
From the date of registration to the to the date of last treatment evaluation, median number of days on treatment was 56 days.
Title
Overall Survival
Description
The Kaplan-Meier method will be used to estimate distributions in the B-CLL population.
Time Frame
From the date of registration to the date of the event (i.e., death or the date of last follow-up), up to 5 years.
Title
Time to Progression
Description
Progression is defined as one of the following: A ≥50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive determinations 2 weeks apart (at least one node must be ≥2 cm) or the appearance of new palpable lymph nodes, or A ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or the appearance of hepatomegaly or splenomegaly which was not previously present, or The transformation to a more aggressive histology (e.g. Richter's transformation), or A ≥ 50% increase in the absolute number of circulating lymphocytes. The Kaplan-Meier method will be used to estimate time to progression.
Time Frame
From the date of registration to the date of the event (i.e., death or disease progression) or the date of last follow-up, up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tait Shanafelt
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

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Bevacizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

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