Identifying Prognostic Factors in Frontline FCR for Patients With Chronic Lymphocytic Leukemia (CLL)

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00759798
• Collaborator: (none)
• Enrollment: 289
• Location: 1
• Arm: 1
• Actual Duration (Months): 143.3
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn more about the characteristics of CLL, including genes and chromosome abnormalities and proteins expressed by the leukemia cells, which may help doctors predict if patients who receive standard treatment (fludarabine, cyclophosphamide, and rituximab) for the first time will experience a complete remission.

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

Detailed Description

The Study Drugs:

Fludarabine is designed to make cancer cells less able to repair damaged DNA (the genetic material of cells). This may increase the likelihood of the cells dying.

Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

Rituximab is designed to attach to lymphoma cells, which may cause them to die.

Study Drug Administration:

Each cycle is 4-6 weeks.

If you are found to be eligible to take part in this study, on Day 1 of each cycle, you will receive rituximab through a needle into your vein over 6-8 hours.

On Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond, you will receive fludarabine by vein over 30 minutes. You will also receive cyclophosphamide by vein over 30 minutes.

You will receive drugs (such as Tylenol, Benadryl, Zofran, allopurinol, and Valtrex) to help prevent side effects. If you have side effects while receiving rituximab, you may be monitored by the study staff for 2 hours after each dose.

Study Visits:

Once a week, blood (about 1 tablespoon) will be drawn for routine tests.

After 3 months (3 cycles of treatment), the following tests and procedures will be performed:

• You will have a physical exam.

• Blood (about 2 tablespoons) will be drawn for routine tests.

• You will have a bone marrow aspirate and biopsy to check the status of the disease.

Length of Study:

You will be on treatment for about 6 months. You will be taken off treatment early if you have intolerable side effects or the disease gets worse.

End-of-Treatment Visit:

After you are off treatment, you will have an end-of-treatment visit for doctors to learn your overall response to the treatment. The following tests and procedures will be performed:

• You will have a physical exam.

• Blood (about 2 tablespoons) will be drawn for routine tests.

• You will have a bone marrow aspirate and biopsy to check the status of the disease.

Long-Term Follow-up:

At 6 months after you have finished treatment and then every year from then on, you will have follow-up visits. The following tests and procedures will be performed:

• You will have a physical exam.

• Blood (about 2 tablespoons) will be drawn for routine tests.

• If your doctor thinks it is needed, you will have a bone marrow biopsy and aspirate to check the status of the disease.

This is an investigational study. Fludarabine, cyclophosphamide, and rituximab are FDA approved and commercially available for the treatment of CLL. The correlation with response to treatment and the characteristics of the leukemia cells is investigational.

Up to 300 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 289 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective Identification of Significant Prognostic Factors in Patients Treated With Fludarabine, Cyclophosphamide, and Rituximab (FCR) as Initial Therapy for Chronic Lymphocytic Leukemia.
• Actual Study Start Date: Aug 13, 2008
• Actual Primary Completion Date: Jul 22, 2020
• Actual Study Completion Date: Jul 22, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Fludarabine, Cyclophosphamide, Rituximab Fludarabine 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21)

Drug: Fludarabine; 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond.; Other Names: Fludara® ; Drug: Cyclophosphamide; 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond.; Other Names: Cytoxan® Neosar® ; Drug: Rituximab; 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21); Other Names: Rituxan®

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Complete Remission (CR) [After 6 months]

   Complete Response defined by NCI Working Group / International Working Group for CLL criteria as no evidence of disease on physical examination (no adenopathy or organomegaly) or microscopic examination of blood (ALC <4,000/L) and bone marrow (<30% lymphocytes, no lymphoid nodules), and recovery of hemoglobin, neutrophil, and platelet counts.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients will have a diagnosis of CLL, Small Lymphocytic Lymphoma (SLL), or CD20 positive low-grade lymphoproliferative disorder.

2. All patients with untreated Rai stage III-IV are eligible for this protocol. Prior treatment with single-agent rituximab permitted. OR Patients with untreated Rai stage 0-II who meet one or more criteria for active disease as defined by the International Working Group for CLL (IWCLL). Prior treatment with single-agent rituximab permitted.

3. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

4. Patients must have adequate renal and hepatic function (creatinine <2mg%, bilirubin <2mg%). Patients with renal or liver dysfunction due to organ infiltration by lymphocytes may be eligible after discussion with the study chairman.

5. Patients may not receive other concurrent chemotherapy, radiotherapy, or immunotherapy. Localized radiotherapy to an area not compromising bone marrow function does not apply.

6. Patients must be 16 years of age or older.

7. Patients must sign informed consent indicating that they are aware of the investigational nature of this study according to the policies of the MD Anderson Cancer Center Institutional Review Board (MDACC IRB).

Exclusion Criteria:

N/A

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

Investigators

• Principal Investigator: William Wierda, M.D., M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 22, 2019

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: NCT00759798
• Other Study ID Numbers: 2008-0431; NCI-2012-01663; 246915
• First Posted: Sep 25, 2008
• Last Update Posted: Sep 5, 2021
• Last Verified: Aug 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Chronic Lymphocytic Leukemia; Leukemia; FCR; Fludarabine; Cyclophosphamide; Rituximab
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Fludarabine

Study Results

Participant Flow

Recruitment Details	Recruitment Period: August 2008 to April 2016

Arm/Group Title	Fludarabine, Cyclophosphamide, Rituximab
Arm/Group Description	Fludarabine 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21) Fludarabine: 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide: 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab: 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21)
Period Title: Overall Study
STARTED	289
COMPLETED	289
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Fludarabine, Cyclophosphamide, Rituximab
Arm/Group Description	Fludarabine 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21) Fludarabine: 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide: 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab: 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21)
Overall Participants	289
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	237 82%
>=65 years	52 18%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	106 36.7%
Male	183 63.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 0.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	19 6.6%
White	256 88.6%
More than one race	0 0%
Unknown or Not Reported	12 4.2%
Region of Enrollment (participants) [Number]
United States	289 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Complete Remission (CR)
Description	Complete Response defined by NCI Working Group / International Working Group for CLL criteria as no evidence of disease on physical examination (no adenopathy or organomegaly) or microscopic examination of blood (ALC <4,000/L) and bone marrow (<30% lymphocytes, no lymphoid nodules), and recovery of hemoglobin, neutrophil, and platelet counts.
Time Frame	After 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fludarabine, Cyclophosphamide, Rituximab
Arm/Group Description	Fludarabine 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21) Fludarabine: 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide: 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab: 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21)
Measure Participants	289
Count of Participants [Participants]	185 64%

Adverse Events

Time Frame	Up to 7 years, 8 months
Arm/Group Title	Fludarabine, Cyclophosphamide, Rituximab
Arm/Group Description	Fludarabine 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21) Fludarabine: 25 mg/m^2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Cyclophosphamide: 250 mg/m2 given intravenously on Days 2-4 of Cycle 1 and Days 1-3 of Cycles 2 and beyond. Rituximab: 375 mg/m2 given intravenously on Day 1 of Course 1 All subsequent Courses: 500 mg/m2 given intravenously on Day 1 (Weeks 5,9,13,17,21)
All Cause Mortality
	Fludarabine, Cyclophosphamide, Rituximab
	Affected / at Risk (%)	# Events
Total	20/289 (6.9%)
Serious Adverse Events
	Fludarabine, Cyclophosphamide, Rituximab
	Affected / at Risk (%)	# Events
Total	65/289 (22.5%)
Blood and lymphatic system disorders
Neutropenic Fever	22/289 (7.6%)	23
Gastrointestinal disorders
Nausea/Vomiting	1/289 (0.3%)	1
General disorders
Fever	15/289 (5.2%)	18
Abdominal Pain	3/289 (1%)	3
Pain Lower Extremity	1/289 (0.3%)	1
Flu Like Symptoms	1/289 (0.3%)	1
Pain	1/289 (0.3%)	1
Infections and infestations
Infection	3/289 (1%)	3
Upper Respiratory Infection	1/289 (0.3%)	1
Pneumonia	8/289 (2.8%)	12
Bronchitis	1/289 (0.3%)	1
Cellulitis	1/289 (0.3%)	1
staphylococcus Infection Leg	1/289 (0.3%)	1
Opportunistic Infection	2/289 (0.7%)	2
Injury, poisoning and procedural complications
Hip Fracture	1/289 (0.3%)	1
Tibia Fracture	1/289 (0.3%)	1
Fall	1/289 (0.3%)	1
Investigations
Hyperbilirubinemia	1/289 (0.3%)	2
Metabolism and nutrition disorders
Tumor Lysis Syndrome	1/289 (0.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy	3/289 (1%)	3
Renal and urinary disorders
Acute Renal Failure	1/289 (0.3%)	1
Reproductive system and breast disorders
Perineal Abcess	1/289 (0.3%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/289 (0.7%)	2
Pleural Effusion	1/289 (0.3%)	1
Pneumonitis	1/289 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Fludarabine, Cyclophosphamide, Rituximab
	Affected / at Risk (%)	# Events
Total	0/289 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.