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

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00448019
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 64
• Location: 1
• Arm: 1
• Duration (Months): 92
• Patients Per Site Per Month: 0.7

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Rituximab; Drug: Bevacizumab	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Fludarabine, Cyclophosphamide, Rituximab and Bevacizumab in the Treatment of Relapsed Chronic Lymphocytic Leukemia
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: FCR + Bevacizumab 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.

Drug: Fludarabine; 25 mg/m^2 IV over 30 minutes daily for 3 days; Other Names: Fludara Fludarabine Phosphate ; Drug: Cyclophosphamide; 250 mg/m^2 IV over 30 minutes daily for 3 days; Other Names: Cytoxan Neosar ; Drug: Rituximab; 375 mg/m^2 IV on Day 1 by prolonged infusion. All subsequent doses 500 mg/m^2 IV 30-minute infusion.; Other Names: Rituxan ; Drug: Bevacizumab; 10 mg/Kg IV on Day 3, course 1 over 30-90 minutes; Other Names: Avastin Anti-VEGF monoclonal antibody rhuMAb-VEGF

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) Rate [Baseline up to 5 years]

   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

1. Number of Participants With Complete or Partial Response to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated Chronic Lymphocytic Leukemia (CLL) [Response assessed after three 4-week courses and after six courses, up to 24 weeks]

   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).

2. Overall Response Rate (ORR) to Fludarabine, Cyclophosphamide, Rituximab, and Bevacizumab Therapy in Previously Treated CLL [Response assessed after three 4-week courses and after six courses, up to 24 weeks]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Genentech, Inc.

Investigators

• Principal Investigator: Susan O'Brien, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00448019
• Other Study ID Numbers: MDACC-2005-0992; NCI-2010-00591
• First Posted: Mar 15, 2007
• Last Update Posted: Nov 1, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by M.D. Anderson Cancer Center: Chronic Lymphocytic Leukemia; Fludarabine; Cyclophosphamide; Rituximab; Bevacizumab; CLL
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Vidarabine; Cyclophosphamide; Bevacizumab; Rituximab; Fludarabine; Fludarabine phosphate

Study Results

Participant Flow

Recruitment Details	Recruitment Period: February 23, 2007 to November 17, 2010. All recruitment done at The University of Texas MD Anderson Cancer Center.

Arm/Group Title	FCR + Bevacizumab
Arm/Group 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.
Period Title: Overall Study
STARTED	64
COMPLETED	57
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	FCR + Bevacizumab
Arm/Group 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.
Overall Participants	64
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	13 20.3%
Male	51 79.7%
Region of Enrollment (participants) [Number]
United States	64 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Five participants of the 62 treated participants were not evaluable for response.

Arm/Group Title	FCR + Bevacizumab
Arm/Group 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.
Measure Participants	57
Median (Full Range) [Months]	13.5

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Five participants of the 62 treated participants were not evaluable for response.

Arm/Group Title	FCR + Bevacizumab
Arm/Group 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.
Measure Participants	57
Complete Response (CR)	13 20.3%
Partial Response (PR)	24 37.5%
Nodular Partial Response (NPR)	8 12.5%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Five participants of the 62 treated participants were not evaluable for response.

Arm/Group Title	FCR + Bevacizumab
Arm/Group 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.
Measure Participants	57
Number [percentage of participants]	79 123.4%

Adverse Events

Time Frame	Participants evaluated for adverse events at each study visit for study duration, up to six courses of 4 weeks. Overall collection period: May 2011 to September 2014.
Arm/Group Title	FCR + Bevacizumab
Arm/Group 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.
All Cause Mortality
	FCR + Bevacizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	FCR + Bevacizumab
	Affected / at Risk (%)	# Events
Total	33/62 (53.2%)
Blood and lymphatic system disorders
Anemia	1/62 (1.6%)
Gastrointestinal hemorrhage	1/62 (1.6%)
Gastrointestinal disorders
Dehydration	1/62 (1.6%)
Diarrhea	1/62 (1.6%)
Esophagitis	1/62 (1.6%)
Nausea	1/62 (1.6%)
Vomiting	1/62 (1.6%)
General disorders
Death	4/62 (6.5%)
Fatigue	1/62 (1.6%)
Fever	2/62 (3.2%)
Pain	1/62 (1.6%)
Tumor lysis Syndrome	1/62 (1.6%)
Infections and infestations
Herpes simplex II	1/62 (1.6%)
Infection	3/62 (4.8%)
Neutropenic Fever	10/62 (16.1%)
pneumonia	6/62 (9.7%)
Metabolism and nutrition disorders
Hypocalcemia	1/62 (1.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy	9/62 (14.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/62 (3.2%)
Shortness of Breath	1/62 (1.6%)
Other (Not Including Serious) Adverse Events
	FCR + Bevacizumab
	Affected / at Risk (%)	# Events
Total	62/62 (100%)
Blood and lymphatic system disorders
Neutropenia	41/62 (66.1%)
Thrombocytopenia	18/62 (29%)
Anemia	9/62 (14.5%)
Gastrointestinal Hemorrhage	2/62 (3.2%)
Cardiac disorders
Hypertension	1/62 (1.6%)
Eye disorders
Blurred vision	2/62 (3.2%)
Gastrointestinal disorders
Nausea and vomiting	22/62 (35.5%)
General disorders
Fatigue	16/62 (25.8%)
Infections and infestations
Infection	30/62 (48.4%)
Nervous system disorders
Syncope	1/62 (1.6%)
Skin and subcutaneous tissue disorders
Rash	2/62 (3.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.