Phase 2 Fludarabine, Cytoxan and FCCAM <Alemtuzumab> in Untreated B-Cell Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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The primary objective of this study was to evaluate the safety and efficacy of the combination of fludarabine and cyclophosphamide in previously untreated CLL patients. Participants will receive fludarabine and cyclophosphamide on days 1, 2, and 3 of six 28-day cycles.

Detailed Description
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This single-arm study evaluated the safety and efficacy of the combination of fludarabine 25 mg/m2/d IV and cyclophosphamide 250 mg/m2/d SC in previously untreated CLL patients. Participants received fludarabine and cyclophosphamide on days 1, 2, and 3 of six 28-day cycles, followed by a no-treatment rest period (observation) for 3 to 12 weeks. Responders entered a no-treatment rest period (observation) for 3 to 8 weeks, then depending on status, continued on follow-up or on-study to receive Campath stating at 3 mg/day with the dose adjusted to the maximum tolerated dose.

Official Title
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A Multi-Center Phase 2 Efficacy and Pharmacokinetic Study Evaluating Fludarabine, Cyclophosphamide, and Subcutaneous Campath (FCCam, Alemtuzumab) for Previously Untreated B-Cell Chronic Lymphocytic Leukemia

Conditions
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Leukemia, B-cell Leukemia, Chronic Leukemia, Chronic Lymphocytic Leukemia (CLL)

Intervention / Treatment
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* Drug: Alemtuzumab
* Drug: Fludarabine
* Drug: Cytoxan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ age 18 Karnofsky performance status 60% or above Confirmed immunohistological diagnosis of Chronic Lymphocytic Leukemia (CLL) Rai Stage I to IV as follows: Advanced stage disease (Rai Stage III or IV, or modified Rai High Risk) OR Patients with Rai Stage I - II or (Modified Rai Intermediate-Risk) disease must have an indication for therapy based on 1996 NCI revised criteria for active disease as follows: Any one of the following disease-related symptoms: Weight loss ≥ 10% body weight within the previous 6 months Extreme fatigue Fever greater than 100.5° F for ≥ 2 weeks without evidence of infection Night sweats without evidence of infection Evidence of progressive marrow failure based on the development of worsening of anemia or thrombocytopenia Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid therapy Massive (> 6 cm below the left costal margin) or progressive splenomegaly Bulky (>10 cm in cluster) or progressive lymphadenopathy Progressive lymphocytosis > 50% increase over 2 months, or anticipated doubling time < 6 months Patients with immunoglobulin VH gene in unmutated nucleotide sequence configuration, as defined by ≥ 98% homology with the nearest germline counterpart Serum creatinine ≤ 2x the upper limit of normal Total serum bilirubin ≤ 2x the upper limit of normal. AST ≤ 2x the upper limit of normal. ALT ≤ 2x the upper limit of normal. Signed written informed consent Exclusion Criteria: Prior pharmacological treatment for CLL Past history of anaphylaxis following exposure to monoclonal antibodies Active secondary malignancy or a history of malignant disease (other than CLL or non-melanoma skin cancer) within the preceding 5 years Any medical condition requiring systemic corticosteroids Active systemic infection Major systemic or other illness (including Coombs positivity and active hemolysis) that would, in the opinion of the investigator, interfere with the patient's ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of study results HIV positive by serologic testing Pregnant or nursing female Unwilling/unable to practice an acceptable form of contraception.

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: Fludarabine, cytoxan, then alemtuzumab<br>Fludarabine and cyclophosphamide days 1 to 3 for six 28-day cycles. Minimal residual disease positive responders continued on-treatment to receive alemtuzumab 30 mg weekly. MRD negative responders were observed. | Drug: Alemtuzumab<br>* 3 to 30 mg, IV<br>* Other names: FCCam;Drug: Fludarabine<br>* [(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid<br>* Other names: Fludara;Drug: Cytoxan<br>* (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide<br>* Other names: Revimmune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Maintaining Partial Response (PR) or Complete Response (CR) | Response criteria as per the NCI-WG Revised Guidelines for B-CLL Complete remission: No lymphadenopathy by physical exam No hepatomegaly or splenomegaly Absence of constitutional symptoms Polymorphonuclear leukocytes > 1,500/uL, Platelets > 100,000/uL, Hemoglobin > 11.0 g/dL Bone marrow aspirate and biopsy normocellular with < 30% lymphocytes Absent lymphoid nodules Partial remission: 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value 50% reduction in lymphadenopathy and/or ≥ 50% reduction in the size of the liver and/or spleen AND one or more of the following Polymorphonuclear leukocytes > 1,500/uL or 50% improvement over baseline Platelets > 100,000/uL or 50% improvement over baseline Hemoglobin > 11.0 g/dL or 50% improvement over baseline | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response |  | 105 months |