Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and the best dose of alvocidib when given together with cyclophosphamide and rituximab in treating patients with high risk B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Alvocidib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can also block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Other find cancer cells and help kill them or carry cancer-killing substances to them. Giving cyclophosphamide, alvocidib, and rituximab together may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the dose-limiting toxicity and maximum-tolerated dose of treatment with cyclophosphamide, alvocidib, and rituximab in patients with high-risk B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. II. To determine the feasibility of administering this regimen as an outpatient regimen in these patients. SECONDARY OBJECTIVES: I. To determine the complete response rate, partial response rate, and minimal-residual disease-negative response rate in patients treated with this regimen. II. To determine the pharmacokinetics of alvocidib and dexamethasone as part of this regimen. III. To determine the immunologic effects of this regimen as measured by serial T-cell and NK-cell number, T-cell function, and immunoglobulin levels. OUTLINE: This is a dose-escalation study of alvocidib. Patients receive rituximab IV over 4 hours on days 1 (days 1-3 in course 1), cyclophosphamide IV over 30-60 minutes on days 1-3, and alvocidib IV over 4.5 hours on days 1 and 8 (day 8 only in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for pharmacokinetic and pharmacodynamic studies. After completion of study treatment, patients are followed up for up to 5 years.

Official Title
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A Phase I Feasibility Trial of Cyclophosphamide, Alvocidib (Flavopiridol) and Rituximab (CAR) in Patients With High Risk B-cell CLL/SLL

Conditions
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Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage I Small Lymphocytic Lymphoma, Stage II Chronic Lymphocytic Leukemia, Stage II Small Lymphocytic Lymphoma, Stage III Chronic Lymphocytic Leukemia, Stage III Small Lymphocytic Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Alvocidib Hydrochloride
* Drug: Cyclophosphamide
* Other: Diagnostic Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed chronic lymphocytic leukemia (CLL) or B-cell prolymphocytic leukemia* (PLL) arising from CLL Patients must have documented B-cell lymphocytosis > 5 x 10^9/L at some point since initial diagnosis of CLL Patients must have B-cells that co-express CD5 with CD19 or CD20 Patients who do not have dim sIg or CD23 expression on their leukemia cells should be examined for cyclin D1 over-expression or t(11;14) to rule out mantle cell lymphoma To be considered high risk, patients must meet the following criteria: At least 1 of the following: 17p deletion 11q deletion Un-mutated IgV_H (≥ 98% homology) Age > 70 years B_2M > 4 AND at least 1 of the following: Progressive or marked splenomegaly and/or lymphadenopathy Anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100,000/mm^3) Weight loss exceeding 10% of body weight over preceding 6 months NCI grade 2 or 3 fatigue Fevers > 100.5° F or night sweats for > 2 weeks without evidence of infection Progressive lymphocytosis, with an increase exceeding 50% over a 2-month period or a doubling time of < 6 months No other concurrent hormones, chemotherapy, or radiotherapy except for steroids for new adrenal failure or hormones for nondisease-related conditions (e.g., insulin for diabetes) No requirement for chronic corticosteroids ECOG performance status 0-2 Creatinine ≤ 2.0 mg/dL Bilirubin ≤ 1.5 times normal unless due to Gilbert disease, hemolysis, or disease infiltration of the liver AST ≤ 2 times normal unless due to hemolysis or disease infiltration of the liver Negative pregnancy test Not pregnant or nursing Fertile patients must use effective contraception No secondary or other malignancy that will limit survival to < 2 years No uncontrolled concurrent illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that would limit compliance with study requirements No uncompensated HIV without adequate CD4 (> 200/mm^3) and requiring HIV medication No active hepatitis B infection No known G6PD deficiency No history of allergic reactions attributed to compounds of similar chemical or biologic composition to alvocidib, cyclophosphamide, rituximab, or other agents used in this study No prior alvocidib No prior purine analog therapy No more than 1 prior treatment with a biologic or alkylating agent No other concurrent investigational agents

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 (rituximab, cyclophosphamide, alvocidib)<br>Patients receive rituximab IV over 4 hours on days 1 (days 1-3 in course 1), cyclophosphamide IV over 30-60 minutes on days 1-3, and alvocidib IV over 4.5 hours on days 1 and 8 (day 8 only in course 1). | Drug: Alvocidib Hydrochloride<br>* Given IV<br>* Other names: MDL-107826A;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Diagnostic Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose of combination therapy with Cyclophosphamide, Alvocidib, and Rituximab | Determined using the CTEP Active Version of the CTCAE. | 21 days | 
| Treatment related adverse events assessed using the CTEP Active Version of the CTCAE |  | Up to 5 years |