Fludarabine, Cyclophosphamide, and Rituximab Versus Pentostatin, Cyclophosphamide, and Rituximab in Previously Untreated or Treated B-Cell Chronic Lymphocytic Leukemia Patients

Study Overview
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Brief Summary
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The purpose of this research study is to find out what effects (good and bad) the combination of Nipent+Cytoxan+Rituxan has on CLL cancer compared to Fludara+Cytoxan+Rituxan. While all of these drugs are approved by the Food and Drug Administration (FDA) for the treatment of other cancers, these combinations are experimental for the treatment of CLL.

Official Title
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A Prospective, Randomized, Open Label, Phase III Trial of Fludarabine, Cyclophosphamide, and Rituximab vs. Pentostatin, Cyclophosphamide, and Rituximab in Previously Untreated or Treated B-cell Chronic Lymphocytic Leukemia

Conditions
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B-Cell Chronic Lymphocytic Leukemia

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


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients will be eligible for inclusion in this study if they meet all of the following criteria: Progressive, histologically proven B-cell CLL. Stage II, III, or IV B-cell CLL, as defined by Appendix III. Note: The pathology or flow cytometry (of peripheral blood or a bone marrow) report, done by the local laboratory which documents these findings, must be included in the source documents. The SI must review the above pathology report or flow cytometry report results (including bone marrow aspirate analysis and CD5 and CD20 results) by fax, prior to registration, to confirm each patient's eligibility. Results should be consistent with typical B-cell CLL. If Dr. Reynolds is not available to review these documents, they must be reviewed by Dr. Nicholas J. Di Bella. Patient must be CD20 + Patient must be CD5+ (CD5 >70%) No more than 1 prior course (regimen) of chemotherapy, which can include Fludara or Rituxan No prior radiation therapy, except for the treatment of skin cancer or a nonmalignant condition. If patient has lymph node involvement, a CT scan confirming measurable tumor size (lymph node must be >1 cm in its longest transverse diameter). SI has been notified IF patient is on replacement steroids at time of registration. Age greater than 18 years. ECOG performance status of 0-2 (Appendix I). Normal renal function (creatinine <1.5 mg/dL and BUN <25 mg/dL). Absolute neutrophil count (ANC) greater than 1,000 cells/µL, platelet count greater than 50,000 cells/µL, and hemoglobin greater than 9 g/dL. Bilirubin less than 2.0 mg/dL, and AST and ALT less than 5 times the upper limit of normal. Negative serum pregnancy test within 7 days prior to registration (female patients of childbearing potential). Agrees to use an acceptable method of birth control, if fertile patient (male or female), to avoid pregnancy for the duration of the study and for at least 3 months thereafter. A signed Patient Informed Consent Form has been obtained. A signed Patient Authorization Form has been obtained. EXCLUSION CRITERIA: Patients will be excluded from this study if they meet any of the following criteria: Any disease other than histologically confirmed progressive, Stage II, III, or IV CLL. Well differentiated lymphocytic lymphoma in nodes without lymphocytosis. More than 1 prior course (regimen) of chemotherapy. Any radiation for the treatment of CLL. Any prior Nipent. Known to be CD20 negative (CD20 <20%). Pregnant or lactating, or has a positive pregnancy test. Has a history of other malignancy (other than in situ cervical cancer, carcinoma intraepithelial neoplasia, or non-melanoma skin cancer) within the last 5 years, which could affect the administration of these study drugs or assessment of current CLL. Known to be HIV positive. Uncontrolled thyroid disease or uncontrolled abnormal thyroid function. Note: Patients with thyroid disease that is controlled with medication may participate. A history of recent, unstable organic heart disease or stable organic heart disease with LVEF <50%. A known hypersensitivity to Fludara, Nipent, Rituxan, or Cytoxan, or any component of these drugs. Autoimmune hemolytic anemia. Unable to comply with requirements of study.

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, and Rituximab<br>Fludarabine, Cyclophosphamide, and Rituximab (dosage based on day in cycle) | Drug: Fludarabine<br> <br> Drug: Cyclophosphamide<br> <br> Drug: Rituximab<br> <br> |
| Experimental: Pentostatin, Cyclophosphamide, and Rituximab<br>Pentostatin, Cyclophosphamide, and Rituximab (dosage depends on day in cycle) | Drug: Cyclophosphamide<br> <br> Drug: Rituximab<br> <br> Drug: Pentostatin<br> <br> * Other names: Nipent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infection Rate | infection=febrile events requiring treatment | 6 cycles of 28-day for FCR and 8 cycles of 21-day for PCR, or until PD, CR, or intolerable toxicity | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infective Event Rate | infective events=temperature >101 without symptoms or temp <101 with symptoms | 6 cycles of 28-day for FCR and 8 cycles of 21-day for PCR, or until PD, CR, or intolerable toxicity | 
| Percentage of Patients Hospitalized | Percentage of patients who were hospitalized due to any reasons during the study period. | 6 cycles of 28-day for FCR and 8 cycles of 21-day for PCR, or until PD, CR, or intolerable toxicity | 
| Hematologic Recovery | defined as Hb >11g/dL and a platelet count >100 × 10^3/mm^3 | 2 months post-treatment | 
| Mean Absolute Neutrophil Count (ANC) at Post-treatment | mean Absolute Neutrophil Count (ANC) measured 2 months (8-10 weeks) following the last dose of study treatment | 2 months post-treatment | 
| Complete Remission (CR) | Definitions of response is evaluated using guidelines proposed by the National Cancer Institute-Sponsored Working Group for Chronic Lymphocytic Leukemia. Complete remission (CR) requires all of the following for a period of at least 2 months: Absence of lymphadenopathy by physical examination and appropriate radiographic techniques. Lymph nodes must be <1 cm. No evidence of hepatomegaly or splenomegaly. Absence of constitutional symptoms. Normal CBC as exhibited by: Polymorphonuclear leukocytes ≥ 1,500/mm^3 Platelets > 100,000/mm^3 Hemoglobin > 11.0 g/dL (untransfused) Bone marrow aspirate and biopsy should be performed 2 months after clinical and laboratory results demonstrate that all of the requirements listed in 1-4 have been met to demonstrate that a CR has been achieved. The marrow sample must be at least normocellular for age, with less than 30% of the nucleated cells being lymphocytes. Lymphoid nodules should be absent. | 6 cycles of 28-day for FCR and 8 cycles of 21-day for PCR, or until PD, CR, or intolerable toxicity | 
| Objective Remission Rate (ORR) | Complete remission (CR) see Outcome Measure 6. Partial remission (PR) must exhibit criteria 1 and 2 as well as one or more of the remaining features for at least 2 months. ≥50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value. ≥50% reduction in lymphadenopathy. ≥50% reduction in the size of the liver and/or spleen. Polymorphonuclear leukocytes ≥ 1,500/mm^3 or 50% improvement over baseline. Platelets >100,000/mm^3 or 50% improvement over baseline. Hemoglobin >11.0 g/dL or 50% improvement over baseline without transfusions. Nodular partial remission (nPR) is defined as a CR with persistent bone marrow nodules; Objective Remission (OR) = CR + PR + nPR. | 6 cycles of 28-day for FCR and 8 cycles of 21-day for PCR, or until PD, CR, or intolerable toxicity | 
| Progression-free Survival (PFS) Rate at 1-year | PFS is measured from the date of randomization to the date of first documented disease progression or date of death, whichever comes first. If a patient neither progresses nor dies, this patient will be censored at last contact date | 12 months after registered. | 
| Progression-free Survival (PFS) Rate at 2-year | PFS is measured from the date of randomization to the date of first documented disease progression or date of death, whichever comes first. If a patient neither progresses nor dies, this patient will be censored at last contact date. | 24 months after registered. |