B-cell Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia
Conditions
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.
Interventions
DRUGsunitinib malate
Given orally
OTHERpharmacological study
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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 |
Countries
United States
Participant flow
Recruitment details
Between August 2007 and December 2008, 18 participants were recruited.
Pre-assignment details
All participants were eligible and included in all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Sunitinib Malate Patients receive oral sunitinib malate 37.5 mg daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Alternative treatment | 1 |
| Overall Study | Death | 1 |
| Overall Study | Disease progression | 9 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Sunitinib Malate |
|---|---|
| Age, Continuous | 67.5 years |
| CD38 Status Negative | 9 participants |
| CD38 Status Positive | 9 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities del 11q23 | 1 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities del 13q14 | 2 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities del 17p13 | 6 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities Normal | 4 participants |
| Fluorescence In Situ Hybridization (FISH) Abnormalities Trisomy 12 | 5 participants |
| Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status Missing | 17 participants |
| Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status Mutated | 0 participants |
| Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status Unmutated | 1 participants |
| Rai Stage High (Rai III-IV) | 10 participants |
| Rai Stage Intermediate (Rai I-II) | 8 participants |
| Rai Stage Low (Rai 0) | 0 participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 9 Participants |
| ZAP-70 Status Negative | 8 participants |
| ZAP-70 Status Positive | 10 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
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
Time frame: Duration of Treatment (up to 12 cycles)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib Malate | Number of Participants With a Confirmed Response [Complete Response (CR) and Partial Response (PR)] on 2 Consecutive Evaluations at Least 4 Weeks Apart | 0 participants |
Secondary
Complete Response Rate in Patients With B-cell Chronic Lymphocytic Leukemia
Complete response is described in the primary outcome
Time frame: Duration of Treatment (up to 12 cycles)
Population: No participants had a confirmed response, there for this analysis cannot be completed.
Secondary
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
Time frame: Duration on study (up 2 years)
Population: No participants had a confirmed response, there for this analysis cannot be completed.
Secondary
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.
Time frame: Duration of study (up to 2 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib Malate | Progression-free Survival | 2.7 months |
Secondary
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.
Time frame: Duration of study (up to 2 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib Malate | Survival Time | 20.6 Months |