Bevacizumab and Interleukin-2 in Treating Patients With Metastatic Kidney Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving bevacizumab together with interleukin-2 works in treating patients with metastatic kidney cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Interleukin-2 may stimulate the white blood cells to kill tumor cells. Giving bevacizumab together with interleukin-2 may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the frequency of major response in patients with metastatic renal cell cancer treated with bevacizumab and interleukin-2. SECONDARY OBJECTIVES I. Compare the median progression-free survival and median overall survival of patients treated with this regimen with risk-stratified historical controls from published risk models. OUTLINE: Patients receive bevacizumab IV over 30-90 minutes on day 1 in weeks 1, 3, 5, 7, 9, and 11. Patients also receive interleukin-2 subcutaneously on days 1-5 in weeks 5-10. Treatment repeats every 12 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease then receive bevacizumab alone in weeks 1, 3, 5, 7, 9, and 11. Courses with bevacizumab alone repeat every 12 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 30 days and then every 3 months for at least 2 years. PROJECTED ACCRUAL: Approximately 10-38 patients will be accrued for this study within 21 months.

Official Title
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Phase 2 Trial of Sequential Bevacizumab Then Subcutaneous Interleukin-2 in Metastatic Renal Cancer

Conditions
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Recurrent Renal Cell Carcinoma, Stage IV Renal Cell Cancer

Intervention / Treatment
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* Biological: Aldesleukin
* Biological: Bevacizumab
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed renal cell cancer Metastatic disease More than 75% clear cell histology Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan No prior refractory disease, defined as clinical or radiologic progression, during or within 3 months after completion of prior interleukin-2 (IL-2) Nominally good or intermediate risk disease, meeting ≥ 4 out of 5 of the following criteria: Hemoglobin > 10 g/dL (except for patients with hereditary hemoglobinopathy) ECOG performance status 0-1 (required) Calcium normal (corrected) Patients with hypercalcemia due to malignancy allowed provided it has been controlled for > 1 month Primary tumor treated or resected by complete nephrectomy, partial nephrectomy, radiofrequency ablation, or other local ablation Lactic dehydrogenase < 1.5 times upper limit of normal (ULN) No history of or current brain or CNS metastasis by CT scan or MRI within the past 30 days Performance status - ECOG 0-1 More than 4 months Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 75,000/mm^3 No history of bleeding diathesis PTT < 1.5 times ULN INR < 1.5 Bilirubin ≤ 1.5 times ULN AST and ALT ≤ 2.5 times ULN No chronic hepatitis B or C Creatinine ≤ 2.0 mg/dL No proteinuria* by dipstick urinalysis Urine protein ≤ 1,000 mg by 24-hour urine collection No symptomatic congestive heart failure No uncontrolled hypertension, defined as systolic blood pressure (BP) > 160 mm Hg and diastolic BP > 90 mm Hg No cardiac arrhythmia No peripheral vascular disease ≥ grade 2 No clinically significant peripheral artery disease None of the following arterial thromboembolic events within the past 6 months: Transient ischemic attack Cerebrovascular accident Unstable angina pectoris Myocardial infarction Not pregnant No nursing during and for 3 months after completion of study treatment Negative pregnancy test Fertile patients must use effective contraception before, during, and for 3 months after completion of study treatment No active infection requiring parenteral antibiotics No known HIV positivity No history of allergic reaction to antibody drugs or IL-2 No psychiatric illness or social situation that would preclude study compliance No non-healing wound or fracture No insulin-dependent diabetes No other uncontrolled illness No other malignancy requiring active treatment within the past 2 years except nonmelanoma skin cancer No prior bevacizumab At least 6 months since prior immunotherapy containing IL-2 At least 2 months since prior investigational antibodies More than 4 weeks since prior conventional cytotoxic chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered No concurrent corticosteroids except replacement corticosteroids for adrenal insufficiency OR inhaled steroids for chronic obstructive pulmonary disease, asthma, or allergic rhinitis More than 3 weeks since prior radiotherapy and recovered No prior radiotherapy to the only site of measurable disease unless there has been subsequent disease progression More than 4 weeks since prior major surgery At least 24 hours since prior minor surgical procedure, placement of vascular access device, or fine needle aspiration At least 30 days since prior and no other concurrent investigational agents More than 10 days since prior anticoagulants Low-dose anticoagulants for maintenance of vascular access device patency allowed No concurrent therapeutic warfarin, including warfarin for treatment of deep vein thrombosis or pulmonary embolism No other concurrent anticancer therapy

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 (bevacizumab, aldesleukin)<br>Patients receive bevacizumab IV over 30-90 minutes on day 1 in weeks 1, 3, 5, 7, 9, and 11. Patients also receive interleukin-2 subcutaneously on days 1-5 in weeks 5-10. Treatment repeats every 12 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease then receive bevacizumab alone in weeks 1, 3, 5, 7, 9, and 11. Courses with bevacizumab alone repeat every 12 weeks in the absence of disease progression or unacceptable toxicity. | Biological: Aldesleukin<br>* Given subcutaneously<br>* Other names: Recombinant Human Interleukin-2;Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;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 |
| --- | --- | --- |
| Number of Evaluable Participants With Complete Response (CR) and Partial Response (PR) at One Year | Major response according to Response Evaluation Criteria In Solid Tumors (RECIST). CR: Disappearance of all target lesions; Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Evaluable Participants With Overall Survival (OS) at 2 Years | Overall Survival tabulation at 2 years from start of treatment. | 2 years from start of treatment | 
| Number of Evaluable Participants With Progression Free Survival (PFS) | Progression Free Survival tabulation at 1 year and at 2 years. Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | Up to 2 years | 
| Pearson Correlation Coefficients of Dendritic Cell (DC):Immature Cell (ImC) Ratio With DC Function | Dendritic cell (DC) phenotype or functionality. Pearson correlation coefficients of DC:ImC ratio with DC function were to be computed and tested for departure from zero. Those with major responses were to be compared to those without major responses with respect to baseline DC:ImC ratio, baseline DC functional assay, post-treatment DC:ImC ratio and post-treatment DC functional assay using pooled t tests. | At baseline, at days 4-5, 9-10 (of course 1), and at the end of treatment | 
| Number of Participants With Possibly Related Serious Adverse Events (SAEs) | Number of Participants with Serious Adverse Events (SAEs) Possibly Related to Study Treatment. Toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 | Up to 30 days after completion of treatment |