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FCR and Bevacizumab in the Treatment of Relapsed Chronic Lymphocytic Leukemia (CLL)

Primary Purpose

Chronic Lymphocytic Leukemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Fludarabine
Cyclophosphamide
Rituximab
Bevacizumab
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring Chronic Lymphocytic Leukemia, Fludarabine, Cyclophosphamide, Rituximab, Bevacizumab, CLL

Eligibility Criteria

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

Inclusion Criteria:

  • Diagnosis of B-cell CLL
  • Relapsed, fludarabine-sensitive (duration of response > 6 months as assessed by prior treating physician) or fludarabine-naive patients
  • Rai Stage III or IV, or Rai Stage I or II if determined to have disease progression as evidenced by rapid doubling of peripheral lymphocyte count, progressive lymphadenopathy, progressive splenomegaly, or B symptoms.
  • Prestudy WHO Performance Status </= 2.
  • Signed, written Institutional Review Board (IRB)approved informed consent.
  • Men and women of reproductive potential must agree to follow accepted birth control methods during treatment and for 3 months after completion of treatment.
  • Acceptable liver function: Bilirubin </= 2.0 mg/dL (26 umol/L), AST (SGOT) and/or ALT (SGPT) </= 2 times upper limit of normal.
  • Acceptable hematologic status: Platelet count >/= 50 x 10^9/L., absolute neutrophil count (ANC) >/= 1 x 10^9/L.
  • Acceptable renal function: Serum creatinine </= 2.0 mg/dL

Exclusion Criteria:

  • Cancer radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or other investigational therapy within 4 weeks prior to Study Day 1.
  • Known infection with HIV, hepatitis B, or hepatitis C
  • Transformation to aggressive B-cell malignancy (e.g., large B-cell lymphoma, Richter's Syndrome, or prolymphocyte leukemia [PLL]).
  • Patients with secondary malignancy requiring active treatment (except hormonal therapy).
  • Active uncontrolled bacterial, viral, or fungal infections.
  • New York Heart Association Class II-IV cardiac disease or myocardial infarction within the past 6 months prior to Study Day 1.
  • Pregnant or currently breast-feeding.
  • 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.
  • Blood pressure of > 150/100 mmHg
  • Unstable angina
  • History of stroke within 6 months
  • Clinically significant peripheral vascular disease
  • Evidence of bleeding diathesis or coagulopathy
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study.
  • Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1.
  • Urine protein:creatinine ratio >/= 1.0 at screening.
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1.
  • Serious, non-healing wound, ulcer, or bone fracture.

Sites / Locations

  • University of Texas MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

FCR + Bevacizumab

Arm Description

FCR = Fludarabine 25 mg/m^2 intravenous (IV) , Cyclophosphamide 250 mg/m^2 IV daily for 3 days, Rituximab 375 mg/m^2 IV Day 1, followed by 500 mg/m^2 IV. FCR daily for 3 days. Bevacizumab 10 mg/Kg IV on Day 3, course 1.

Outcomes

Primary Outcome Measures

Progression Free Survival (PFS) Rate
Progression free survival (PFS) was defined as the time from the start of treatment to progression, which included treatment failure, relapse, or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Secondary Outcome Measures

Number of Participants With Complete or Partial Response to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated Chronic Lymphocytic Leukemia (CLL)
Response criteria for Complete response (CR) - Nodes: None; Liver/Spleen Size: Not palpable; Symptoms: None; polymorphonuclear leukocytes (PMN): >1,500/μl; Platelets >100,000/μl; Hemoglobin (untransfused): >11,0 g/dl; Lymphocytes: <4,000/μl; Bone Marrow aspirate: <30% lymphocytes; Biopsy: No lymphocyte infiltrate; and for Partial Response (PR), Nodes: >/= 50% decrease; Liver/Spleen Size: >/= 50% decrease; Symptoms: None; Platelets >100,000/μl or > 50% improvement from baseline; Hemoglobin (untransfused): >11.0 g/dl or >50% improvement from baseline; Lymphocytes: >50% decrease; Biopsy: <30% lymphocytes with residual disease on biopsy for nodular PR (NPR).
Overall Response Rate (ORR) to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated CLL
ORR defined as CR and PR response where response criteria for Complete response (CR) - Nodes: None; Liver/Spleen Size: Not palpable; Symptoms: None; polymorphonuclear leukocytes (PMN): >1,500/μl; Platelets >100,000/μl; Hemoglobin (untransfused): >11,0 g/dl; Lymphocytes: <4,000/μl; Bone Marrow aspirate: <30% lymphocytes; Biopsy: No lymphocyte infiltrate; and for Partial Response (PR), Nodes: >/= 50% decrease; Liver/Spleen Size: >/= 50% decrease; Symptoms: None; Platelets >100,000/μl or > 50% improvement from baseline; Hemoglobin (untransfused): >11.0 g/dl or >50% improvement from baseline; Lymphocytes: >50% decrease; Biopsy: <30% lymphocytes with residual disease on biopsy for nodular PR (NPR).

Full Information

First Posted
March 13, 2007
Last Updated
October 5, 2015
Sponsor
M.D. Anderson Cancer Center
Collaborators
Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00448019
Brief Title
FCR and Bevacizumab in the Treatment of Relapsed Chronic Lymphocytic Leukemia (CLL)
Official Title
Fludarabine, Cyclophosphamide, Rituximab and Bevacizumab in the Treatment of Relapsed Chronic Lymphocytic Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
October 2015
Overall Recruitment Status
Completed
Study Start Date
February 2007 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
Genentech, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The goal of this clinical research study is to learn if the combination of fludarabine, cyclophosphamide, rituximab, and bevacizumab is effective in treating chronic lymphocytic leukemia in patients who have already been treated with chemotherapy. The safety of this treatment will also be studied.
Detailed Description
During the study, you will have up to 6 "cycles" of treatment. A cycle is made up of treatment with the study drugs for 3-4 days and then about 3-1/2 weeks (25 days) of no treatment (about 4 weeks total). Treatment with the study drugs will be given for 4 days in a row on the first cycle, and 3 days in a row on Cycles 2-6. On Day 1 of each cycle, you will receive rituximab through a needle in a vein. On Cycle 1, since it is your first exposure to rituximab, it must be given slowly, so it may take 6-8 hours to complete. On the cycles after that, it can be given more rapidly, over 3-4 hours. Cyclophosphamide and fludarabine will be given separately through a needle in a vein on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2-6. Cyclophosphamide and fludarabine will each be given over 30 minutes. Bevacizumab will be given through a needle in a vein over 90 minutes on Day 3 of Cycle 1. If it is well tolerated, the next dose of Bevacizumab will be given over 60 minutes on Day 2 of Cycle 2. If the Cycle 2 dose is well tolerated, the next doses of Bevacizumab will be given over 30 minutes on Day 2 of Cycles 2-6. In addition to the study drugs, you may also be given fluids by vein to help flush the kidneys, to help prevent possible kidney damage. You may receive up to 6 cycles of treatment. Treatment will be given on an outpatient basis. The injections for each daily treatment visit should take less than 6 hours. Up to 66 patients will take part in the study. All will be enrolled at M.D. Anderson.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia
Keywords
Chronic Lymphocytic Leukemia, Fludarabine, Cyclophosphamide, Rituximab, Bevacizumab, CLL

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
FCR + Bevacizumab
Arm Type
Experimental
Arm Description
FCR = Fludarabine 25 mg/m^2 intravenous (IV) , Cyclophosphamide 250 mg/m^2 IV daily for 3 days, Rituximab 375 mg/m^2 IV Day 1, followed by 500 mg/m^2 IV. FCR daily for 3 days. Bevacizumab 10 mg/Kg IV on Day 3, course 1.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara, Fludarabine Phosphate
Intervention Description
25 mg/m^2 IV over 30 minutes daily for 3 days
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan, Neosar
Intervention Description
250 mg/m^2 IV over 30 minutes daily for 3 days
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
375 mg/m^2 IV on Day 1 by prolonged infusion. All subsequent doses 500 mg/m^2 IV 30-minute infusion.
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin, Anti-VEGF monoclonal antibody, rhuMAb-VEGF
Intervention Description
10 mg/Kg IV on Day 3, course 1 over 30-90 minutes
Primary Outcome Measure Information:
Title
Progression Free Survival (PFS) Rate
Description
Progression free survival (PFS) was defined as the time from the start of treatment to progression, which included treatment failure, relapse, or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame
Baseline up to 5 years
Secondary Outcome Measure Information:
Title
Number of Participants With Complete or Partial Response to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated Chronic Lymphocytic Leukemia (CLL)
Description
Response criteria for Complete response (CR) - Nodes: None; Liver/Spleen Size: Not palpable; Symptoms: None; polymorphonuclear leukocytes (PMN): >1,500/μl; Platelets >100,000/μl; Hemoglobin (untransfused): >11,0 g/dl; Lymphocytes: <4,000/μl; Bone Marrow aspirate: <30% lymphocytes; Biopsy: No lymphocyte infiltrate; and for Partial Response (PR), Nodes: >/= 50% decrease; Liver/Spleen Size: >/= 50% decrease; Symptoms: None; Platelets >100,000/μl or > 50% improvement from baseline; Hemoglobin (untransfused): >11.0 g/dl or >50% improvement from baseline; Lymphocytes: >50% decrease; Biopsy: <30% lymphocytes with residual disease on biopsy for nodular PR (NPR).
Time Frame
Response assessed after three 4-week courses and after six courses, up to 24 weeks
Title
Overall Response Rate (ORR) to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated CLL
Description
ORR defined as CR and PR response where response criteria for Complete response (CR) - Nodes: None; Liver/Spleen Size: Not palpable; Symptoms: None; polymorphonuclear leukocytes (PMN): >1,500/μl; Platelets >100,000/μl; Hemoglobin (untransfused): >11,0 g/dl; Lymphocytes: <4,000/μl; Bone Marrow aspirate: <30% lymphocytes; Biopsy: No lymphocyte infiltrate; and for Partial Response (PR), Nodes: >/= 50% decrease; Liver/Spleen Size: >/= 50% decrease; Symptoms: None; Platelets >100,000/μl or > 50% improvement from baseline; Hemoglobin (untransfused): >11.0 g/dl or >50% improvement from baseline; Lymphocytes: >50% decrease; Biopsy: <30% lymphocytes with residual disease on biopsy for nodular PR (NPR).
Time Frame
Response assessed after three 4-week courses and after six courses, up to 24 weeks

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of B-cell CLL Relapsed, fludarabine-sensitive (duration of response > 6 months as assessed by prior treating physician) or fludarabine-naive patients Rai Stage III or IV, or Rai Stage I or II if determined to have disease progression as evidenced by rapid doubling of peripheral lymphocyte count, progressive lymphadenopathy, progressive splenomegaly, or B symptoms. Prestudy WHO Performance Status </= 2. Signed, written Institutional Review Board (IRB)approved informed consent. Men and women of reproductive potential must agree to follow accepted birth control methods during treatment and for 3 months after completion of treatment. Acceptable liver function: Bilirubin </= 2.0 mg/dL (26 umol/L), AST (SGOT) and/or ALT (SGPT) </= 2 times upper limit of normal. Acceptable hematologic status: Platelet count >/= 50 x 10^9/L., absolute neutrophil count (ANC) >/= 1 x 10^9/L. Acceptable renal function: Serum creatinine </= 2.0 mg/dL Exclusion Criteria: Cancer radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or other investigational therapy within 4 weeks prior to Study Day 1. Known infection with HIV, hepatitis B, or hepatitis C Transformation to aggressive B-cell malignancy (e.g., large B-cell lymphoma, Richter's Syndrome, or prolymphocyte leukemia [PLL]). Patients with secondary malignancy requiring active treatment (except hormonal therapy). Active uncontrolled bacterial, viral, or fungal infections. New York Heart Association Class II-IV cardiac disease or myocardial infarction within the past 6 months prior to Study Day 1. Pregnant or currently breast-feeding. 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. Blood pressure of > 150/100 mmHg Unstable angina History of stroke within 6 months Clinically significant peripheral vascular disease Evidence of bleeding diathesis or coagulopathy Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study. Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 1. Urine protein:creatinine ratio >/= 1.0 at screening. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1. Serious, non-healing wound, ulcer, or bone fracture.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Susan O'Brien, MD
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
25043749
Citation
Jain P, Lee HJ, Qiao W, Wierda W, Benjamini O, Burger J, Ferrajoli A, Estrov Z, Kantarjian H, Keating M, O'Brien S. FCR and bevacizumab treatment in patients with relapsed chronic lymphocytic leukemia. Cancer. 2014 Nov 15;120(22):3494-501. doi: 10.1002/cncr.28910. Epub 2014 Jul 15.
Results Reference
result
Links:
URL
http://www.mdanderson.org
Description
University of Texas MD Anderson Cancer Center Website

Learn more about this trial

FCR and Bevacizumab in the Treatment of Relapsed Chronic Lymphocytic Leukemia (CLL)

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