Rituximab and Alemtuzumab in Treating Older Patients With Progressive Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: 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 find cancer cells and help kill them or carry cancer killing substances to them. Giving rituximab together with alemtuzumab may kill more cancer cells. PURPOSE: This randomized phase II trial is studying two different doses of rituximab to compare how well they work when given together with alemtuzumab in treating older patients with progressive chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary To compare the rate of complete and overall response in elderly patients with progressive chronic lymphocytic leukemia (CLL) treated with one of two doses of rituximab combined with alemtuzumab to determine if the use of modified-dose rituximab significantly affects outcome. Secondary To monitor and assess toxicity of these regimens. To determine the overall and progression-free survival, time to clinical response, time to next treatment, and duration of response in patients treated with these regimens To assess the correlation between risk stratification prognostic markers (i.e., CD38, ZAP-70, fluorescent in situ hybridization (FISH), and IgVH mutation) and clinical outcome. To assess response to these regimens using both the 1996 National Cancer Institute Working Group (NCI-WG 96) criteria and an expanded definition of response for patients in complete remission, including immunohistochemical examination of the bone marrow and sensitive flow cytometry (4-6 color) of blood for minimal residual disease and computed tomography (CT) scans for residual adenopathy. To determine the mechanism of action of rituximab and alemtuzumab and to determine mechanisms of resistance of a subpopulation of CLL cells to these drugs. OUTLINE: This is a multicenter study. Patients are stratified according to FISH risk (low [13q14-] vs intermediate [12+, no abnormality, all other abnormalities] vs high [17p13-,11q22-]). Patients are randomized to 1 of 2 treatment arms. Arm A: Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Arm B: Patients receive alemtuzumab as in arm A. Patients also receive low-dose rituximab IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 and on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in cycless 2 and 3. Treatment repeats every 28 days for up to 3 cycles. Blood and bone marrow samples are collected periodically for cytogenetic and biomarker analysis. Alemtuzumab dose for Cycle 1 Week 1 of both Arms A and B requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1). After completion of study therapy, patients are followed up periodically for 5 years.

Official Title
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A Phase II Randomized Trial Comparing Standard and Low Dose Rituximab: Initial Treatment of Progressive Chronic Lymphocytic Leukemia in Elderly Patients Using Alemtuzumab and Rituximab

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Biological: alemtuzumab
* Biological: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria: Minimum threshold peripheral lymphocyte count of 5 x 10^9/L (CLL variant) OR palpable adenopathy > 1 cm or palpable splenomegaly 9small lymphocytic lymphoma [SLL] variant) Immunophenotypic demonstrations of a population of B-lymphocytes (as defined by CD19+) that are monoclonal (by light-chain exclusion) AND have ≥ 3 of the following characteristics: CD5+ CD23+ Dim surface light chain expression Dim surface CD20 expression FISH analysis is negative for immunoglobulin heavy chain/cyclin D1 gene (IGH/CCND1) and/or immunostaining is negative for cyclin D1 expression (to exclude mantle cell lymphoma) Progressive, symptomatic CLL, defined by at least one of the following: Weight loss > 10% within the past 6 months attributable to progressive CLL (grade 2 or higher) Extreme fatigue attributable to progressive CLL (grade 3 or higher) Fevers > 100.5° F for 2 weeks without evidence of infection (grade 1 or higher) Night sweats without evidence of infection (drenching) Evidence of progressive bone marrow failure with hemoglobin < 11 g/dL or platelet count < 100 x 10^9/L Rapidly progressive lymphadenopathy for which the largest node is ≤ 5 cm in any dimension Largest lymph nodes involved in the neck, axilla, and groin need to be measured and followed for response Exclusion Criteria: Prior treatment for CLL Massive splenomegaly > 6 cm below left costal margin, at rest, on clinical examination Lymphadenopathy > 5 cm in any diameter New York Heart Association class III or IV heart disease Recent myocardial infarction (within the past month) Uncontrolled infection Infection with the human immunodeficiency virus (HIV/AIDS) Serological evidence of active hepatitis B infection (HBsAg or HBeAg positive) Positive hepatitis C serology Evidence of active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia Other active primary malignancy requiring treatment or that limits survival to ≤ 2 years, except for in situ carcinoma of the cervix or breast or non-metastatic basal cell or squamous cell carcinoma of the skin Major surgery within 4 weeks prior to pre-registration Concomitant use of continuous systemic corticosteroids Prior corticosteroids are allowed but not at time of pre-registration to the study

Ages Eligible for Study
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Minimum Age: 65 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: Arm A (standard dose)<br>Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week. | Biological: alemtuzumab<br>* Given IV<br>Biological: rituximab<br>* Given IV<br>|
| Experimental: Arm B (low dose)<br>Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week. | Biological: alemtuzumab<br>* Given IV<br>Biological: rituximab<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Complete Response (CR) | Response was evaluated using NCI-WG96 criteria. A CR requires all of the following for >= 2 months: Absence of lymphadenopathy > 1 cm in diameter by physical examination No hepatomegaly or splenomegaly on physical exam No constitutional symptoms Normal complete blood count (CBC) Patients achieving a clinical CR with negative CT scan after 2 cycles of therapy are re-evaluated using immunohistochemical examination of bone marrow biopsy for residual CLL cells. Patients with no evidence of residual disease and no radiological evidence of residual CLL on CT scan of chest-abdomen-pelvis and no clinical evidence of CLL on clinical evaluation after completion of 2 cycles of therapy will be considered to have a CR with no evidence of residual disease | Assessed after 2 cycles of treatment and 2 months after completion of therapy | 
| Proportion of Patients With Overall Response (OR) | OR is defined as either CR, clinical CR, or partial response (PR) evaluated by NCI-WG96 criteria. CR has been defined in the other primary endpoint. A clinical CR requires all of the following: Absence of lymphadenopathy by physical examination No hepatomegaly or splenomegaly. Spleen and/or liver, if considered enlarged at baseline, should not be palpable, due to disease, on physical exam Absence of constitutional symptoms Normal CBC as exhibited by: A PR requires all the following for ≥2 months: ≥50% decrease in peripheral blood lymphocyte count from baseline ≥50% reduction in lymphadenopathy ≥50% reduction in size of liver and/or spleen Polymorphonuclear leukocytes ≥1.5x10^9/L or 50% improvement over baseline Platelets >100x10^9/L or 50% improvement over baseline Hemoglobin >11.0 gm/dl or 50% improvement over baseline without transfusions Any constitutional symptoms | Assessed after 2 cycles of treatment and 2 months after completion of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined to be time from randomization to death from any cause. Those still alive are censored at the date of last contact. | Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years | 
| Progression-free Survival (PFS) | PFS is defined to be time from randomization to progression (PD) or to death without documentation of progression. For patients without PD, follow-up is censored at the date of last disease assessment without PD, unless death occurs within three months following the date last known progression free. PD is characterized by at least one of the following: ≥50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive examinations 2 weeks apart (at least 1 node must be >2 cm). Appearance of new palpable lymph nodes (>1 cm in diameter). ≥50% increase in the size of liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly which was not previously present. Absolute number of circulating lymphocytes with a count of >5x10^9/L Transformation to a more aggressive histology | Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years | 
| Time to Response | Time to response is defined to be time from randomization to first confirmed CR, PR or clinical CR. Those without confirmed CR, PR or clinical CR are censored at the date of last disease assessment. | Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years | 
| Duration of Response | Duration of response is defined to be time from first confirmed CR, PR or clinical CR to progression or to death without documentation of progression. Patients without confirmed CR, PR or clinical CR are censored at time 0. Those without documentation of progression are censored at the date of last disease assessment without progression, unless death occurs within three months following the date last known progression free. | Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic lymphocytic leukemia, small lymphocytic lymphoma, CLL, elderly, low dose rituximab, alemtuzumab, monoclonal antibodies