A Phase II Trial of Alemtuzumab and Rituximab in Patients With Previously Untreated CLL

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as alemtuzumab and rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving alemtuzumab together with rituximab may kill more cancer cells. PURPOSE: This phase II trial is studying the side effects of giving alemtuzumab together with rituximab and to see how well it works in treating patients with previously untreated B-cell chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: To determine the response rate in patients with previously untreated B-cell chronic lymphocytic leukemia treated with alemtuzumab and rituximab. To evaluate the toxicity of alemtuzumab and rituximab in these patients. OUTLINE: Patients receive alemtuzumab subcutaneously on days 1, 3, and 5 in weeks 1-18 and rituximab IV on day 1 in weeks 3, 5, 7, 9, 11, 13, 15, and 17 in the absence of disease progression or unacceptable toxicity. Peripheral blood and bone marrow samples are collected periodically for laboratory biomarker studies. Samples are analyzed for surface markers (e.g., CD3, CD4, CD8, CD10, CD19, CD20, CD25, CD38, CD52, Zap-70) and IgVH by PCR, flow cytometry, and FISH. Samples are also analyzed for alemtuzumab and anti-alemtuzumab antibody levels by flow cytometry. After completion of study treatment, patients are followed periodically for 5 years.

Official Title
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A Phase II Trial of Alemtuzumab (Campath-1H) and Rituximab (Rituxan) in Patients With Previously Untreated CLL

Conditions
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Leukemia

Intervention / Treatment
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* Biological: Alemtuzumab
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of B-cell chronic lymphocytic leukemia (CLL)*, as defined by the following criteria: Peripheral blood absolute lymphocyte count > 5,000/mm³ Small- to moderate-size lymphocytes with < 55% prolymphocytes, atypical lymphocytes, or lymphoblasts Phenotypically characterized B-CLL expressing CD20 and CD52, as defined by the following: Predominant population of cells share B-cell antigens with CD-5 in the absence of other pan-T-cell markers (e.g., CD-3, CD-2) B-cell expresses either lambda or kappa light chains Surface immunoglobulin with low-cell surface density expression NOTE: *Presence of splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL Requires therapy, as indicated by ≥ 1 of the following criteria: Unintentional weight loss > 10% within the past 6 months Extreme fatigue (i.e., ECOG performance status 2) Fevers > 100.5°F for 2 weeks without evidence of infection Night sweats without evidence of infection Evidence of progressive marrow failure as manifested by the development of or worsening of anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelet count < 100,000/mm³) Massive (i.e., > 6 cm below left costal margin) or progressive splenomegaly Massive nodes/clusters (> 5 cm), progressive symptomatic adenopathy, or adenopathy resulting in end-organ damage Progressive lymphocytosis with an increase of > 50% over 2 months or an anticipated doubling time < 6 months Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for eligibility PATIENT CHARACTERISTICS: ECOG performance status 0-2 ANC ≥ 1,000/mm³* Platelet count ≥ 50,000/mm³* Hemoglobin ≥ 10 g/dL* Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance > 40 mL/min Bilirubin < 2 mg/dL AST and ALT ≤ 2 times normal (unless secondary to tumor infiltration/lymphadenopathy) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after completion of study treatment No active autoimmune anemia or thrombocytopenia No active infection requiring oral or intravenous antibiotics No second malignancy, other than basal cell carcinoma of the skin or in situ carcinoma of the cervix, unless curatively treated ≥ 2 years ago NOTE: *If cytopenias are due to degree of bone marrow involvement, patient may be eligible at the discretion of the principal investigator. PRIOR CONCURRENT THERAPY: Prior corticosteroid therapy allowed No prior cytotoxic therapy (other than corticosteroids)

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: Alemtuzumab and Rituximab<br>Administration of Alemtuzumab combined with Rituximab to test the feasibility of combining these two monoclonal antibodies as a first line therapy in patients with B-cell chronic lymphocytic leukemia. | Biological: Alemtuzumab<br>* Alemtuzumab administered subcutaneously 30mg per day, 3 days per week for 18 weeks<br>* Other names: Campath-1H;Biological: Rituximab<br>* Rituximab administered intravenously at 375mg/m2 every 2 weeks for 18 weeks<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Treated With Alemtuzumab and Rituximab Combination With a Response (CR or PR) Assessed by NCI-WG 1996 Criteria With Lymph-adenopathy and Organomegaly Measured During Physical Examination | Response rate (complete remission(CR) + partial remission(PR)) will be, assessed by NCI-WG 1996 criteria with lymphadenopathy and organomegaly measured during physical examination. CR=Absence of lymphadenopathy and constitutional symptoms, Normal CBC (leukocytes ≥ 1500/μl, Platelets >100,000/μl, Hemoglobin > 11.0 gm/dl), peripheral blood lymphocytes ≤ 4,000/μl.The marrow sample must be at least normocellular with < 30% of nucleated cells being lymphocytes. PR=absence of constitutional symptoms, ≥ 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value, ≥ 50% reduction in lymphadenopathy, ≥ 50% reduction in size of liver and/or spleen and one of the following: polymorphonuclear leukocytes ≥ 1,500/μl or 50% improvement over baseline platelets > 100,000/μl or 50% improvement over baseline or hemoglobin > 11.0 gm/dl or 50% improvement over baseline without transfusions | At week 9, and post-18 weeks then every 3 months for a year and up every 6 months for up to 2 years | 
| Number of Patients Treated With Alemtuzumab and Rituximab Combination With Response (CR or PR) Assessed by NCI-WG 1996 Criteria With Measurements of the Lymph Nodes and Spleen Size by CT Scans | Response rate (complete remission(CR) + partial response(PR)) will be assessed by NCI-WG 1996 criteria with measurements of the lymph nodes and spleen size by CT scans. Best response at any timepoint is captured below. CR= absence of significant lymphadenopathy (e.g. lymph nodes > 1.5 cm in their greatest transverse diameter) and no hepatomegaly or splenomegaly. PR=reduction in lymphadenopathy as defined by the following: (a) a decrease in lymph node size by 50% or more either in the sum products of up to six lymph nodes, or in the largest diameter of the enlarged lymph node(s) detected prior to therapy; (b) no increase in any lymph node, and no new enlarged lymph node; in small lymph nodes (< 2cm), an increase of less than 25% was not considered to be significant and a reduction in the noted pretreatment enlargement of the spleen or liver by 50% or more. | At week 9, and post-18 weeks then every 3 months for a year and up every 6 months for up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity of the Study Medications, Alemtuzumab and Rituximab | Toxicity data will be collected at visits during 18 weeks of treatment and include adverse events considered at least possibly related to either study drugs (Alemtuzumab and Rituximab) and graded 3-5 using CTCAE 3.0. In general grading is as follows: Grade 1=mild Grade 2=moderate Grade 3=severe Grade 4=life threatening Grade 5=death Reported below are the number of patients who experienced each event | During treatment, 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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