FCR Versus FC Alone in the Treatment of Chronic Lymphocytic Leukemia (CLL) in Relapsed Patients

Study Overview
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Brief Summary
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The purpose of this study is to provide treatment for patients who have chronic lymphocytic leukemia (CLL), and to compare the use of rituximab added to fludarabine+cyclophosphamide (FC) with FC alone, to determine if rituximab lengthens the time a patient remains free of leukemia symptoms.

Official Title
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Open-label, Multicenter, Randomized, Comparative, Phase III Study to Evaluate the Efficacy and Safety of FCR vs. FC Alone in Previously Treated Patients With CD20 Positive B-cell CLL

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Rituximab
* Drug: Fludarabine Phosphate
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Established diagnosis of B-cell CLL by NCI Working Group criteria ≤1 previous line of chemotherapy Expected survival >6 months Acceptable hematologic status, liver function, renal function, and pulmonary function Negative serum pregnancy test for both pre-menopausal women and for women who are < 2 years after the onset of menopause Written informed consent Exclusion Criteria: Prior treatment with interferon, rituximab or other monoclonal antibody Prior allogeneic bone marrow transplant (BMT) or autologous BMT or peripheral stem cell transplant (PBSCT) or patients who are considered to be candidates for allogeneic or autologous BMT or PSCT as assessed by their treating physician Fertile men or women of childbearing potential not using adequate contraception Severe Grade 3 or 4 non-hematological toxicity or prolonged (> 2 weeks) Grade 3 or 4 cytopenia on prior fludarabine or nucleoside analogue regimen History of fludarabine-induced or clinically significant autoimmune cytopenia History of other malignancies within 2 years prior to study entry, except for adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low-grade early stage localized prostate cancer treated surgically with curative intent; good prognosis ductal carcinoma in situ (DCIS) of the breast treated with lumpectomy alone with curative intent. Medical conditions requiring long term use (> 1 month) of systemic corticosteroids Active bacterial, viral, or fungal infection requiring systemic therapy Severe cardiac disease Seizure disorders requiring anticonvulsant therapy Severe chronic obstructive pulmonary disease with hypoxemia Uncontrolled diabetes mellitus or hypertension Transformation to aggressive B-cell malignancy. Known infection with HIV, HCV, or hepatitis B Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to entering this study Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins Any co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fludarabine+Cyclophosphamide (FC)<br> | Drug: Fludarabine Phosphate<br>* Intravenous repeating dose<br>Drug: Cyclophosphamide<br>* Intravenous repeating dose<br>|
| Experimental: Fludarabine+Cyclophosphamide+Rituximab (FCR)<br> | Drug: Rituximab<br>* Intravenous repeating dose<br>Drug: Fludarabine Phosphate<br>* Intravenous repeating dose<br>Drug: Cyclophosphamide<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC) | Progression-free survival as assessed by the IRC was defined as the time between randomization and the date of first documented disease progression, relapse after response, or death from any cause, whichever came first. Patients without a PFS event were censored at their last tumor assessment date. | Mean observation time at time of analysis was approximately 26 months | 
| Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC) | Progression-free survival as assessed by the IRC was defined as the time between randomization and the date of first documented disease progression, relapse after response, or death from any cause (PFS events), whichever came first. Patients without a PFS event were censored at their last tumor assessment date. | Mean observation time at time of analysis was approximately 26 months | 
| Final Analysis: Time to Progression-Free Survival Event | Time to progression-free survival (PFS) event was defined as the time between randomization and the date of first documented PFS event: disease progression, relapse or death by any cause, whichever came first. | Median observation time was approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival was determined from the date of randomization to the date of death irrespective of cause. Patients who had not died at the time of the final analysis (clinical data cut-off) were censored at the date of the last contact. | Mean observation time at time of analysis was approximately 26 months | 
| Number of Participants With Overall Survival (OS) Events | Overall survival was determined from the date of randomization to the date of death (OS event) irrespective of cause. Patients who had not died at the time of the final analysis (clinical data cut-off) were censored at the date of the last contact. | Mean observation time at time of analysis was approximately 26 months | 
| Event-free Survival (EFS) | Event free survival was measured from the day of randomization to the date of first documented PD, relapse after response, start of a new treatment or death from any cause. Patients without an EFS event were censored at their last tumor assessment date. | Mean observation time at time of analysis was approximately 26 months | 
| Number of Participants With Event-free Survival (EFS) Events | Event free survival was measured from the day of randomization to the date of first documented Progressive Disease (PD), relapse after response, start of a new treatment or death from any cause (EFS events). Patients without an EFS event were censored at their last tumor assessment date. | Mean observation time at time of analysis was approximately 26 months | 
| Disease-free Survival (DFS) | Disease free survival was defined for all patients with a best overall response (BOR) of Complete Response (CR) and measured the time from first documented CR in a sequence of consecutive CRs until documented disease progression, relapse or death from any cause. Patients without a DFS event at the time of the analysis (clinical data cut-off) were censored at their last tumor assessment date. | Mean observation time at time of analysis was approximately 26 months | 
| Number of Participants With Disease-free Survival (DFS) Events | Disease free survival was defined for all patients with a best overall response (BOR) of Complete Response (CR) and measured the time from first documented CR in a sequence of consecutive CRs until documented disease progression, relapse or death from any cause (DFS events). Patients without a DFS event at the time of the analysis (clinical data cut-off) were censored at their last tumor assessment date. | Mean observation time at time of analysis was approximately 26 months | 
| Final Analysis: Time to Overall Survival Event | Overall survival (OS) was determined from the date of randomization to the date of death (OS event) irrespective of cause. | Median observation time was approximately 5 years | 
| Final Analysis: Time to Event-Free Survival Event | Event free survival (EFS) was defined as the time from the day of randomization to the date of first EFS event: documented disease progression, relapse after response, start of a new treatment or death from any cause. | Median observation time was approximately 5 years | 
| Final Analysis: Percentage of Participants With Complete Response | Complete response was defined as the disappearance of all signs of cancer in response to treatment. | Median observation time was approximately 5 years | 
| Final Analysis: Time to Disease-Free Survival Event | Time to disease-free survival (DFS) event was defined as the time from first documented response until the first documented DFS event: disease progression, relapse or death from any cause. | Median observation time was approximately 5 years | 
| Final Analysis: Duration of Response | Duration of response was defined as the time between the date of the earliest qualifying response and the date of disease progression or death due to any cause. | Median observation time was approximately 5 years | 
| Final Analysis: Time to New Chronic Lymphocytic Leukemia (CLL) Treatment | Time to new CCL treatment was defined as the time from randomization to the first day of new treatment for CCL or death. | Median observation time was approximately 5 years |