Dose Escalation Study of Gleevec and Chlorambucil in Previously Treated Chronic Lymphocytic Leukemia Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine maximum tolerated dose of Gleevec in combination with Chlorambucil in previously treated CLL patients.

Detailed Description
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A recent study by Aloyz et al demonstrated a synergistic effect of imatinib on chlorambucil-mediated cytotoxicity in CLL cells in vitro. Imatinib inhibits c-abl and sensitizes cells to chlorambucil. The Phase I component of the study will determine the maximum tolerated dose and recommended Phase II dose of Gleevec when used in combination with chlorambucil. Once the maximum tolerated dose has been determined, a total of 16 patients will be enrolled in the Phase II component of the study. This study will determine the dose limiting toxicities, pharmacokinetics and pharmacodynamics of Gleevec in combination with chlorambucil.

Official Title
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A Phase I-II Trial of Gleevec (Imatinib Mesylate) in Combination With Chlorambucil in Previously Treated Chronic Lymphocytic Leukemia (CLL) Patients

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Gleevec and Chlorambucil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: B-cell chronic lymphocytic leukemia (a) Rai stage 0-II with indication for treatment by NCI Working Group Criteria: or (b) Rai stage III or IV. Received a minimum of one prior chemotherapy regimen. Prior treatment with corticosteroids, immunotherapies, monoclonal antibodies or radiation therapy is permitted. White blood cell count > 25 x 10^9/L ECOG 0, 1,or 2. Adequate renal and hepatic function Platelets > 75 x 10^9/L, transfusion independent. Neutrophils > 1.0 x 10^9/L, transfusion independent Exclusion Criteria: Documented prolymphocytic leukemia (PLL; prolymphocytes, 55% in blood) Active cardiovascular disease as defined by NYHA class III-IV categorization. Intercurrent illness or medical condition precluding safe administration of ribavirin. Concurrent use of chronic steroids, except as replacement therapy for adrenal insufficiency Known infection with HIV, Hepatitis B or C. Concurrent malignancy (other than resected basal or squamous cell skin cancers or in-situ carcinoma). Received any previous therapy for CLL within 28 days prior to study entry.

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: I<br>Gleevec Chlorambucil | Drug: Gleevec and Chlorambucil<br>* The first cohort will receive Gleevec at 300 mg daily on days 1-10 and chlorambucil 8mg/m2/d from day 3-7. This will be repeated every 28 days. Cohort 2 will receive 400 mg Gleevec and Cohort 3 will receive 600 mg Gleevec. Each dose level may be expanded up to 6 patients if 1 of 3 patients experiences any dose limiting toxicities.<br>* Other names: Chlorambucil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure number of patients at maximum tolerated dose of Gleevec in combination with chlorambucil |  | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Report adverse events as a measure of safety |  | 6 months | 
| Report response to treatment as a measure of efficacy |  | 6 months | 
| Report level of gleevec concentration at different doses as a measure of pharmacokinetics |  | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, chronic lymphocytic leukemia, leukemia, gleevec, chlorambucil