Sunitinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study Overview
=================
Brief Summary
-----------------
This phase II trial is studying how well sunitinib works in treating patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Sunitinib 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.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Assess the response rate (complete response [CR] and partial response) in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma treated with sunitinib malate. II. Assess the toxicity of this drug in these patients. III. Assess duration of response, time to progression, overall survival, and CR rate in patients treated with this drug. SECONDARY OBJECTIVES: I. Evaluate if known risk stratification parameters (i.e., immunoglobulin mutational status, ZAP-70 status, fluorescent in situ hybridization [FISH] defects, and/or CD38 status) are related to clinical response to sunitinib malate. OUTLINE: This is a multicenter study. Patients receive oral sunitinib malate daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection periodically for translational and pharmacological studies, including IgVH gene mutation status and ZAP-70 status. Samples are examined by fluorescent in situ hybridization (FISH) and other assays. After completion of study treatment, patients are followed every 3 months for up to 2 years.

Official Title
-----------------
A Phase II Study of Sunitinib Malate for Treatment of Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Conditions
-----------------
B-cell Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia

Intervention / Treatment
-----------------
* Drug: sunitinib malate
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of 1 of the following: Biopsy proven small lymphocytic lymphoma (SLL) Chronic lymphocytic leukemia (CLL) meeting all of the following criteria: Peripheral blood lymphocyte count > 5,000/mm^3 Lymphocytes must consist of small to moderate size lymphocytes, with < 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically Immunophenotyping consistent with CLL, defined by the following criteria: Predominant population of lymphocytes share both B-cell antigens (i.e., CD19, CD20, or CD23) as well as CD5 in the absence of other pan-T-cell markers (e.g., CD3 or CD2) Dim surface immunoglobulin expression Exclusively kappa and lambda light chains Splenomegaly, hepatomegaly, or lymphadenopathy are not required Refractory or relapsed disease as evidenced by 1 of the following criteria: Progression after ≥ 1 course of a purine nucleoside (i.e., fludarabine phosphate, cladribine, pentostatin) regimen Progression after ≥ 1 course of an alkylator (i.e., cyclophosphamide or chlorambucil) regimen Relapse after ≥ 1 prior purine nucleoside oral kylator (i.e., cyclophosphamide or chlorambucil) regimen Requires chemotherapy, as indicated by any of the following criteria: Measurable (i.e., > 5,000/mm^3) and progressive clonal lymphocytosis Measurable (i.e., single diameter > 2 cm) and progressive lymphadenopathy Disease-related symptoms, including 1 or more of the following: Weight loss > 10% within the past 6 months Extreme fatigue attributed to CLL/SLL Fevers > 100.5^oF for 2 weeks without evidence of infection Night sweats without evidence of infection Evidence of progressive marrow failure, as manifested by the development of or worsening anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelet count < 100,000/mm^3) Massive (i.e. > 6 cm below left costal margin) or progressives plenomegaly No mantle cell lymphoma, as demonstrated by a negative fluorescent in situ hybridization (FISH) analysis fort(11;14)(IgVH/CCND1) on peripheral blood or tissue biopsy ECOG performance status 0-2 Life expectancy ≥ 12 months Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min AST and ALT ≤ 2.5 times ULN Bilirubin normal Alkaline phosphatase ≤ 3 times ULN Platelet count > 30,000/mm^3 (without transfusion) Absolute neutrophil count > 1,000/mm^3 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able to complete patient diaries alone or with assistance No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days No other malignancy except for squamous cell or basal cell carcinoma of the skin or in situ carcinoma of the cervix, unless the tumor was curatively treated within the past 2 years No history of allergic reactions attributed to compounds of similar chemical or biological composition to sunitinib malate No inability to swallow or retain sunitinib malate capsules due to any of the following: Gastrointestinal tract disease Requirement for IV alimentation Prior surgical procedures affecting absorption Active peptic ulcer disease No pre-existing thyroid abnormality that would make the patient unable to maintain normal thyroid function with medication No pulmonary embolism within the past 12 months No serious or nonhealing wound, ulcer, or bone fracture No uncontrolled intercurrent illness including, but not limited to, any of the following: Ongoing or active infections Psychiatric illness or social situation that would limit compliance with study requirements No cerebrovascular accident or transient ischemic attack within the past 12 months No uncontrolled hypertension (i.e., systolic blood pressure [BP] ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg) No significant cardiac arrhythmia, including any of the following: QTc prolongation (i.e., QTc interval ≥ 500 msec) Ventricular tachycardia Atrial fibrillation Atrial flutter Second or third degree heart block No cardiac disease within the past 12 months, including any of the following: Myocardial infarction Cardiac arrhythmia Stable/unstable angina Symptomatic congestive heart failure Coronary/peripheral artery bypass graft or stenting No New York Heart Association (NYHA) class III or IV heart failure The following patients are eligible provided they have NYHA class II cardiac function on baseline ECHO/MUGA: History of NYHA class II heart failure and asymptomatic on treatment No prior anthracycline exposure No prior central thoracic radiation that included the heart in the radiation port See Disease Characteristics At least 4 weeks since prior chemotherapy At least 4 weeks since prior rituximab or alemtuzumab At least 4 weeks since prior major surgery At least 4 weeks since prior oral steroids No prior treatment with any other antiangiogenic agent, including any of the following: Bevacizumab Sorafenib Pazopanib AZD2171 Vatalanib VEGF Trap At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following: Ketoconazole Itraconazole Clarithromycin Erythromycin Diltiazem Verapamil HIV protease inhibitors (i.e., indinavir, saquinavir,ritonavir, atazanavir, nelfinavir) Delavirdine At least 12 days since prior and no concurrent CYP3A4 inducers, including any of the following: Rifampin Rifabutin Carbamazepine Phenobarbital Phenytoin Hypericum perforatum (St. John's wort) Efavirenz Tipranavir No other concurrent investigational agents No concurrent agents with proarrhythmic potential, including any of the following: Terfenadine Quinidine Procainamide Disopyramide Sotalol Probucol Bepridil Haloperidol Risperidone Indapamide Flecainide No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent anticancer agents or therapies No concurrent therapeutic doses of coumarin-derivative anticoagulants (e.g., warfarin) Concurrent prophylactic low molecular weight heparin or warfarin at doses ≤ 2 mg daily for thrombosis prophylaxis allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral sunitinib malate daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. | Drug: sunitinib malate<br>* Given orally<br>* Other names: Sutent;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Confirmed Response [Complete Response (CR) and Partial Response (PR)] on 2 Consecutive Evaluations at Least 4 Weeks Apart | National Cancer Institute working group criteria (NCIWG) was used to assess response.> CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy> PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions | Duration of Treatment (up to 12 cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate in Patients With B-cell Chronic Lymphocytic Leukemia | Complete response is described in the primary outcome | Duration of Treatment (up to 12 cycles) | 
| Survival Time | Survival time was defined as the time from registration to death due to any cause. The distribution of survival time was estimated using the Kaplan-Meier method. | Duration of study (up to 2 years) | 
| Progression-free Survival | Progression-free survival (PFS) was defined as the time from registration to progression or death due to any cause. The distribution of PFS was estimated using the Kaplan-Meier method. | Duration of study (up to 2 years) | 
| Duration of Response | Duration of response was calculated from the documentation (date) of first response (CR or PR) until the date of progression or last follow-up in the subset of patients who responded. The median duration of response with 95%CI was estimated using the Kaplan Meier method | Duration on study (up 2 years) |