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

Phase 2

Completed

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

Interventions: Drug: sunitinib malate
Other: pharmacological study
Other: laboratory biomarker analysis

Registration Number: NCT00398112

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	pharmacological 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.
Arm I	laboratory biomarker analysis	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.
Arm I	sunitinib malate	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Confirmed Response [Complete Response (CR) and Partial Response (PR)] on 2 Consecutive Evaluations at Least 4 Weeks Apart	Duration of Treatment (up to 12 cycles)	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

Secondary Outcome Measures

Name	Time	Method
Survival Time	Duration of study (up to 2 years)	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.
Complete Response Rate in Patients With B-cell Chronic Lymphocytic Leukemia	Duration of Treatment (up to 12 cycles)	Complete response is described in the primary outcome
Progression-free Survival	Duration of study (up to 2 years)	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 Response	Duration on study (up 2 years)	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