Alvocidib in Treating Patients With 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 best dose of flavopiridol in treating patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Drugs used in chemotherapy, such as alvocidib, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the toxicity profile, dose-limiting toxicity, and maximum tolerated dose of flavopiridol (alvocidib) as consolidation chemotherapy after cytoreduction chemotherapy in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. SECONDARY OBJECTIVES: I. Determine the pharmacokinetics and cellular pharmacodynamics of flavopiridol in these patients. II. Determine the complete response (CR) and overall response rate (CR and partial response) of patients treated with flavopiridol. OUTLINE: This is a dose-escalation study. Patients receive alvocidib intravenously (IV) over 30 minutes (loading dose), followed by alvocidib IV over 4 hours on days 1, 8, and 15. Treatment repeats every 5 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A total of 12 patients are treated at the MTD (i.e., recommended phase II dose). Patients undergo blood collection at baseline and periodically during study for pharmacokinetic and cytokine studies (levels of tumor necrosis factor-alpha, interleukin [IL]-6, -11, and -16) by enzyme-linked immunosorbent assay (ELISA). Interphase cytogenetics, p53 mutational status, p53/ATM function, V_H mutational status, zeta-chain-associated protein kinase 70 (ZAP-70) overexpression, and single nucleotide polymorphisms are also examined. After completion of study treatment, patients are followed at 2 months and then every 3 months for 5 years.

Official Title
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A Phase I Dose-Escalation Study of Flavopiridol (NSC 649890) Administered as a 30 Minute Loading Dose Followed by a 4-Hour Infusion in Patients With B-Cell Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Following Cytoreduction With Chemotherapy

Conditions
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B-cell Chronic Lymphocytic Leukemia, Contiguous Stage II Small Lymphocytic Lymphoma, Noncontiguous Stage II Small Lymphocytic Lymphoma, Stage I Chronic Lymphocytic Leukemia, Stage I Small Lymphocytic Lymphoma, Stage II Chronic Lymphocytic Leukemia, 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
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of 1 of the following: B-cell chronic lymphocytic leukemia (CLL) Small lymphocytic lymphoma (SLL) Must have received 1-3 prior therapies for CLL Completed therapy 2-12 months ago Prior therapy must have led to a partial response or greater No evidence of progressive disease ECOG performance status 0-2 Absolute neutrophil count ≥ 1,000/mm³ WBC ≤ 5,000/mm³ Platelet count ≥ 50,000/mm³ Cytopenia allowed Creatinine < 2.0 mg/dL Bilirubin ≤ 1.5 times normal (unless due to Gilbert's disease or hemolysis) AST ≤ 2 times normal (unless due to hemolysis) No secondary malignancy or other disease that would limit survival to < 2 years No history of inflammatory bowel disease unless inactive for > 2 years Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception See Disease Characteristics No other concurrent chemotherapy No concurrent radiotherapy No concurrent dexamethasone or other corticosteroid-based antiemetics No concurrent chronic corticosteroid therapy No other concurrent hormonal therapy except for the following: Steroids for new adrenal failure Hormones for nondisease-related conditions (e.g., insulin for diabetes)

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 (chemotherapy)<br>Patients receive alvocidib IV over 30 minutes (loading dose), followed by alvocidib IV over 4 hours on days 1, 8, and 15. Treatment repeats every 5 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: alvocidib<br>* Given IV<br>* Other names: L-868275;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity profile of alvocidib administered as a 30 minute loading dose followed by a 4-hour infusion once weekly for 3 consecutive weeks every 5 weeks as consolidation therapy following cytoreduction chemotherapy | Assessed utilizing the NCI Common Terminology Criteria for Adverse Events version 3.0. | Day 1, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment | 
| Dose-limiting toxicity of alvocidib as consolidation chemotherapy after cytoreduction chemotherapy in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma | The National Cancer Institute Common Toxicity Criteria version 3.0 will be used to characterize toxicity. If no patients experience dose-limiting toxicity, dose escalation will occur. If 1 patient has a dose limiting toxicity, 3 additional patients will be enrolled at that dose. If fewer than 2 of 6 patients experiences dose limiting toxicity, then the next highest dose level will be used for the subsequent cohort of 3 patients. If at any dose level two or more of the six patients experience a dose limiting toxicity, 3 additional patients will be treated at the previous dose level. | Course 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics and cellular pharmacodynamics of alvocidib administered in this schedule | Cytokine studies will be examined by standard ELISA assays to determine if increase IL-6 correlates with hypotension, hypoxemia, and tachycardia observed following treatment and to identify the source of production of this cytokine. We will examine interphase cytogenetics, p53 mutational status, p53/ATM functional assay, VH mutational status, and ZAP-70 over-expression. | Baseline and day 1 | 
| Complete response (CR) and overall response rate (CR and partial response) of alvocidib in patients with previously-treated CLL | Criteria for response will utilize the Revised National Cancer Institute-sponsored Working Group Guidelines. | Baseline, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment |