Sorafenib in Treating Patients With Relapsed Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. This phase II trial is studying how well sorafenib works in treating patients with relapsed chronic lymphocytic leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the objective response rate in patients with recurrent chronic lymphocytic leukemia (CLL) treated with sorafenib. II. Determine the toxicity in patients treated with sorafenib. SECONDARY OBJECTIVES: I. Correlate bone marrow angiogenesis, CLL tumor cell expression of vascular endothelial growth factor (VEGF), VEGF receptors (flt-1, KDR, flt-4 and neuropilin-1), basic fibroblast growth factor, and plasma interleukin-8 levels with response. OUTLINE: This is a multicenter study. Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: Approximately 40 patients will be accrued for this study.

Official Title
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A Phase II Study of BAY 43-9006 in Relapsed Chronic Lymphocytic Leukemia

Conditions
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Refractory Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed chronic lymphocytic leukemia (CLL) by NCI-WG immunophenotype and blood criteria Documentation of current or prior peripheral blood (PB) or bone marrow (BM) immunophenotype compatible with CLL Patients who currently do not have > 5,000/mm³ absolute lymphocytosis are eligible if they have previously met PB lymphocytosis criteria and have a current immunophenotype documenting monoclonal B lymphocytosis morphologically and immunophenotypically compatible with CLL Intermediate-risk (Rai stage I or II) or high-risk (Rai stage III or IV) disease, including any of the following: Rai stage I disease with lymphocytosis and enlarged nodes Rai stage II disease with lymphocytosis plus splenomegaly and/or hepatomegaly (nodes positive or negative) Rai stage III disease with lymphocytosis plus anemia Rai stage IV disease with lymphocytosis and thrombocytopenia Must require treatment with active disease, experiencing disease related symptoms, or having deterioration of blood counts, meeting ≥ 1 of the following criteria: Presence of ≥ 1 of the following disease-related symptoms: Weight loss > 10% within the past 6 months Extreme fatigue (i.e., ECOG performance status 2: cannot work or unable to perform usual activities) Fever > 100.5°F for 2 weeks without evidence of infection Night sweats without evidence of infection Evidence of progressive marrow failure, as manifested by worsening of anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelet count < 100,000/mm³), and/or neutropenia (neutrophil count < 2,000/mm³) Massive (i.e., > 6 cm below left costal margin) or progressive splenomegaly or discomfort from splenomegaly Massive nodes or clusters (i.e., > 10 cm in longest diameter), progressive adenopathy, or discomfort from lymphadenopathy Deterioration of blood counts and/or progressive lymphocytosis, with an increase of ≥ 10% documented over a 2-month period OR an anticipated doubling time < 6 months Relapsed disease Must receive at least 1, but no more than 3, prior chemotherapy regimens with any cytotoxic agent or antibody therapy No fludarabine refractory disease Responded to prior fludarabine without relapse or disease progression for at least 6 months Patients with a history of Coombs-positive hemolytic anemia are eligible provided recovery from treatment of hemolysis and off steroids No stage 0 CLL No known CNS involvement Life expectancy > 6 months ECOG performance status 0-2 OR Karnofsky performance status 70-100% Absolute neutrophil count ≥ 1,000/mm³ Platelets ≥ 30,000/mm³ Bilirubin ≤ 2 mg/dL AST/ALT ≤ 2.5 times upper limit of normal (ULN) Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min (for patients with creatinine levels above normal) No currently active second malignancy Not pregnant or nursing Negative pregnancy test Fertile patient must use effective contraception prior to and during study participation No uncontrolled hypertension, defined as blood pressure (BP) > 150/100 mm Hg on 2 different measurements at least 1 day apart with either systolic or diastolic number meeting this definition Patients may later enter the study, if they have achieved stable BP (i.e., < 140/90 mm Hg) on a regimen of ≤ 2 drugs after 6-8 weeks of therapy No history of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib No uncontrolled intercurrent illness including, but not limited to, any of the following: Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situations that would limit compliance with the study requirements No active infection requiring systemic antibiotics No evidence of bleeding diathesis No evidence of bowel perforation or obstruction risk No swallowing dysfunction leading to difficulty taking the study drug See Disease Characteristics Recovered from prior therapy At least 2 weeks since prior antibiotic therapy At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy At least 12 weeks since prior monoclonal antibody Concurrent warfarin for anticoagulation allowed provided all of the following are met: On a stable therapeutic dose INR ≤ 3 No active bleeding or pathological condition that carries high-risk of bleeding No prior MAPK signaling inhibitor agents or anti-angiogenesis agents No concurrent combination anti-retroviral therapy for HIV-positive patients No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, or phenobarbital), rifampin, or Hypericum perforatum (St. John's wort) 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 (sorafenib tosylate)<br>Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: sorafenib tosylate<br>* Given orally<br>* Other names: SFN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Objective response is defined as a complete (CR) or partial (PR) remission. Complete remission is defined as no evidence of chronic lymphocytic leukemia (CLL) in marrow with normal hematopoiesis and no palpable lymphadenopathy. Partial remission is defined as improvement in blood counts from baseline with >50% reduction in lymph nodes on examination. These are definitions from the CLL International Working Group (IWG). | Up to week 25 | 
| Time to Disease Progression | Time to disease progression will be defined as the time from treatment start until disease progression and will be evaluated using the Kaplan-Meier estimator. Those who do not progress will be censored at the time that they were last known to be progression free. | Up to 5.5 years | 
| Overall Survival | Overall survival will be defined as time from the start of treatment until death from any cause and will be evaluated using the Kaplan-Meier estimator. | Up to 5.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Mean Microvessel Density From Baseline to Week 25 | Mean microvessel density will serve as a marker of angiogenesis (other markers includes hot spot density). Will be examined using random-effects linear models. | Baseline and week 25 | 
| Changes in Vascular Endothelial Growth Factor (VEGF) From Baseline to Week 25 | Changes in VEGF levels (post-pretreatment) will be assessed. A negative value indicates a decrease with treatment. | Baseline and week 25 | 
| Changes in Plasma Level of Interleukin-8 (IL-8) From Baseline to Week 25 | The change (post-pretreatment) will be calculated and tested using a paired t test. A negative value indicates a decrease with treatment. | Baseline and week 25 |