Combined Alternating Sunitinib and Bevacizumab (Avastin®) in Advanced Renal Cell Carcinoma (CASA)

Study Overview
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Brief Summary
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Combined sunitinib and bevacizumab in advanced renal cell carcinoma.

Detailed Description
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This is a phase I/II trial of combined sunitinib and bevacizumab in advanced renal cell carcinoma ( CASBA) where Bevacizumab will be used only on day 29 of each 6 weeks sunitinib cycle.

Official Title
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Phase I/II Combined Alternating Sunitinib and Bevacizumab (Avastin®) in Advanced Renal Cell Carcinoma (CASA)

Conditions
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Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Sunitinib
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed renal cell carcinoma with clear cell histology ( mixed histology with clear cell component is accepted) Patient should have either locally advanced or metastatic disease No prior anti-cancer therapy Age ≥ 18 years Life expectancy of 3 months or more Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 Performance status 0-2 by ECOG scale Patients with controlled brain metastasis are accepted Adequate renal function: serum creatinine ≤ 2 times the institutional upper limit of normal Adequate hepatic function: total bilirubin within normal institutional limits, serum AST and ALT levels ≤2 times the institutional upper limit of normal or ≤ 5 times the institutional upper limit of normal of elevated because of liver involvement Coagulation (PT ≤ 1.5 times the institutional upper limit of normal) Adequate hematological values: leukocyte count ≥3.0 x 109/L, an absolute neutrophil count ≥1.5 x 109/L, a platelet count ≥100 x 109/L and hemoglobin ≥ 9.0 g/dL Urine dipstick for proteinuria <1+, patients discovered to have ≥ 1+ on dipstick urinanalysis at baseline should have urine protein/urine creatinine ratio ≤1 Singed written informed consent before enrolment Patient should have unresectable disease ( for both the primary tumor and the metastasis) Exclusion Criteria: Inability to comply with the protocol therapy Uncontrolled hypertension defined as BP more than 160 systolic and or more than 100 diastolic despite adequate treatment at the time of treatment initiation. Severe cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, myocardial infarction, significant arrhythmias or Transient ischemic attack (TIA) or cerebrovascular accident (CVA) in the last 6 months Major bleeding disorder, significant traumatic injury or recent major surgery within 28 days of starting therapy. Or minor surgery (FNA/Core biopsy) within 7 days of starting therapy History of abdominal abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months Pre-existing thyroid abnormality Concurrent proarrhythmic medications including terfenadine, quinidine, procainamide, disopyramide, sotalol, bepridil, haloperidol, risperidone, indapamide and flecainide Recent significant hemoptysis (1/2 tea spoon red blood within last month) Concurrent medication that either CYP 450 3A4 inducers or inhibitors Concurrent use of proarrhythmic medications including terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide and flecainide Pregnancy or breast feeding, or patient refusal to use appropriate contraception for female patients in childbirth age Previous malignancy within 5 years, except adequately treated non melanomatous skin cancer or in situ cervical cancer Psychiatric or mental disorder, precluding understanding of the information of the trial related topics and giving valid informed consent Any psychological, familial, geographic or social circumstances which could impair the patient ability to participate in the trial and comply with follow up. Any circumstance which might impair the patient's ability to comply with an out-patient regimen Active uncontrolled infection Serious underlying medical condition (in the judgment of the investigator) which could impair the ability of the patient to participate in the trial Treatment with other experimental drugs within 30 days of entry into the trial Treatment with other anti-cancer therapy Legal incapacity Significant proteinuria (urine protein: creatinine ratio > 1.0)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Sunitinib and Bevacizumab Arm<br>Phase I/II Combined Alternating Sunitinib and Bevacizumab (Avastin®) in Advanced Renal Cell carcinoma (CASA)Combined Alternating Sunitinib and Bevacizumab | Drug: Sunitinib<br>* Oral therapy ( Anti-vascular endothelial growth factor Tyrosin Kinase Inhibitor): given as 50 mg daily from day 1 to day 28- cycle repeated every 42 days<br>* Other names: Sutent;Drug: Bevacizumab<br>* Monoclonal antibody against vascular endothelial growth factor: given intravenously on day 29 of each sunitinib cycle<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bevacizumab maximum tolerated dose, in combination with sunitinib | This is the phase I part of the study. patient will enroll on Bevacizumab dose of 5 mg/kg body weight. If no dose limiting toxicity in 1st 6 patients, the dose will be escalated to 10 mg/kg in the remainder of the patients | 12 weeks from enrolling patient # 6 | 
| Assess response rate to the combination of sunitinib and bevacizumab | response rate is the combination of partial response and complete response | Through study completion, an average of 6 months | 
| Assess the progression free survival on the combination of sunitinib and bevacizumab | Progression free survival will be calculated from time of starting therapy till progression or death whichever comes first | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival of patients in this regimen | Overall survival will be calculated from date of start on therapy till death | Participants will be followed for the duration of hospital stay, up to 5 years | 
| Number of participants with treatment related-adverse effects as assessed by CTCAE v 4.03 | toxicity will be graded according to the NCI-CTC version 4.03 | up to 5 years |