Fludarabine, Rituximab, and Alemtuzumab in Treating Patients With Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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This phase II trial is studying how well giving fludarabine together with rituximab followed by alemtuzumab works in treating patients with chronic lymphocytic leukemia. Monoclonal antibodies, such as rituximab and alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others can find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving fludarabine together with rituximab followed by alemtuzumab may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the rate of complete response and toxicity of concurrent treatment with fludarabine and rituximab followed by consolidative alemtuzumab in patients with previously untreated, but symptomatic, CLL. II. To determine if alemtuzumab improves the CR rate with acceptable toxicity when administered as consolidation therapy following induction therapy with fludarabine and rituximab. III. To estimate the progression-free and overall survival of high risk (VH gene unmutated and those with p53 dysfunction) and low-risk (others) patients following therapy with fludarabine and rituximab induction and consolidative alemtuzumab. IV. To determine the frequency of molecular (PCR) remission following fludarabine and rituximab induction therapy and alemtuzumab consolidation therapy and if this serves as a surrogate marker for prolonged progression-free and overall survival. SECONDARY OBJECTIVES: I. To determine the effect of concurrent treatment with fludarabine and rituximab followed by consolidative alemtuzumab on recovery of T-cells, NK cells, and serum immunoglobulin levels. II. To determine clinical and molecular features that predict for poor response to fludarabine and rituximab induction and subsequent alemtuzumab consolidation therapy. III. To assess preliminarily the molecular features of CLL at relapse in patients responding to chemoimmunotherapy for CLL. IV. To determine the frequency of patients who remain at high risk for progression of CLL despite this therapy and who are thus eligible for nonmyeloablative stem cell transplantation studies such as CALGB 109901. V. To perform limited rituximab pharmacokinetics to determine the ideal schedule of administration for a subsequent rituximab maintenance treatment approach following induction therapy with fludarabine and rituximab. OUTLINE: Patients receive induction therapy comprising rituximab IV over 4 hours on days 1, 3, and 5 of course 1 and day 1 of all subsequent courses and fludarabine IV over 30 minutes on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Approximately 4 months after completion of induction therapy, patients achieving a partial response, nodular partial response, or stable disease receive consolidation therapy comprising alemtuzumab subcutaneously on days 1-3. Treatment repeats weekly for up to 6 courses in the absence of disease progression. Patients are followed at 2 months, every 3 months for 1 year, and then every 6 months for 7 years from study entry.

Official Title
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A Phase II Study of Fludarabine + Rituximab Induction Followed by Alemtuzumab (Campath-1H, NSC #715969, IND #10864) Administered Subcutaneously as Consolidation in Untreated Patients With B-Cell Chronic Lymphocytic Leukemia

Conditions
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B-cell Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Biological: alemtuzumab
* Biological: rituximab
* Drug: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Specific Diagnosis of B-Cell CLL An absolute lymphocytosis of > 5,000/μL Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes Bone marrow examination must include at least a unilateral aspirate and biopsy; the aspirate smear must show > 30% of all nucleated cells to be lymphoid or the bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL; the overall cellularity must be normocellular or hypercellular Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (CD19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers; additionally, the B-cells must be monoclonal with regard to expression of either κ or λ and have surface immunoglobulin expression of low density; patients with bright surface immunoglobulin levels must have CD23 co-expression Patients must be in the intermediate- or high-risk categories of the modified three-stage Rai staging system (i.e., stages I, II, III, or IV) Patients in the intermediate-risk group must have evidence of active disease as demonstrated by at least one of the following criteria: Massive or progressive splenomegaly, hepatomegaly and/or lymphadenopathy; Presence of weight loss > 10% over the preceding 6 month period; Grade 2 or 3 fatigue; Fevers > 100.5°F or night sweats for greater than 2 weeks without evidence of infection; Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months No prior therapy for CLL including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL No medical condition requiring chronic use of oral corticosteroids Performance Status 0 - 2 Due to alterations in host immunity, patients with HIV may not be enrolled Due to the unknown teratogenic potential of alemtuzumab, pregnant or nursing women may not be enrolled; women and men of reproductive potential should agree to use an effective means of birth control Creatinine =< 1.5 x upper limit of institutional normal value Coomb's Testing NEGATIVE

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (alemtuzumab, rituximab, fludarabine phosphate)<br>Patients receive induction therapy comprising rituximab IV over 4 hours on days 1, 3, and 5 of course 1 and day 1 of all subsequent courses and fludarabine IV over 30 minutes on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Approximately 4 months after completion of induction therapy, patients achieving a partial response, nodular partial response, or stable disease receive consolidation therapy comprising alemtuzumab subcutaneously on days 1-3. Treatment repeats weekly for up to 6 courses in the absence of disease progression. | Biological: alemtuzumab<br>* Given SC<br>* Other names: Monoclonal Antibody CD52;Biological: rituximab<br>* Given IV<br>* Other names: Rituxan;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Complete Response After Treatment With Fludarabine & Rituximab Followed by Alemtuzumab | A complete response, as defined by the National Cancer Institute Working Group (NCIWG): - CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy | Duration of treatment (up to 13.5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Complete or Partial Response After Induction Therapy With Fludarabine & Rituximab | Response, as defined by the National Cancer Institute Working Group (NCIWG): CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions | Up to 9 months | 
| 2 Year Progression Free Survival | Percentage of patients who were alive and progression free at 2 years. The 2-year progression free survival was estimated using the Kaplan Meier method. | 2 years from registration | 
| 2 Year Survival | Percentage of participants who were alive at 2 years. The 2 year survival was estimated using the Kaplan Meier method. | 2 years from registration | 
| Number of Participants With Severe Non-Hematologic Adverse Events During Treatment With Alemtuzumab | The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0 was used to evaluate toxicity. Severe Adverse events are defined as grade 3, 4 or 5, at least possibly related to treatment. Grade 1: mild; Grade 2: moderate; Grade 3: Severe; Grade 4: Life Threatening; Grade 5: Death. | 6 weeks beginning at study week 36 |