Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy
Condition: Clear Cell Renal Cell Carcinoma; Recurrent Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Bevacizumab; Everolimus; Laboratory Biomarker Analysis; Pharmacological Study
Intervention description: Given IV; Given PO; Correlative studies; Correlative studies
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Everolimus; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 77.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase III trial studies giving everolimus together with bevacizumab to see
      how well it works compared to everolimus alone in treating patients with advanced kidney
      cancer that progressed after first-line therapy. Everolimus may stop the growth of tumor
      cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as
      bevacizumab, can interfere with tumor growth by blocking the ability of tumor cells to grow
      and spread. Everolimus and bevacizumab may also stop the growth of kidney cancer by blocking
      blood flow to the tumor. It is not yet known whether giving everolimus together with
      bevacizumab is better than everolimus alone in treating patients with advanced kidney cancer
      that has progressed after first-line therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Renal cell carcinoma with some component of clear cell histology

          -  Metastatic or unresectable disease

          -  Must have been treated with at least 1 prior VEGFR tyrosine kinase inhibitor treatment
             and have progressed or have been intolerant to treatment

          -  No prior systemic therapy with a vascular endothelial growth factor (VEGF) binding
             agent (e.g., bevacizumab)

          -  No prior systemic therapy with any mechanistic target of rapamycin (mTOR) inhibitor
             (e.g., sirolimus, temsirolimus, everolimus)

          -  Prior cytokine therapy is allowed

          -  Any systemic therapy must be completed at least 4 weeks prior to registration

          -  >= 2 weeks since any prior radiation (including palliative)

          -  Patients must not have had a major surgical procedure, open biopsy, or significant
             traumatic injury within 4 weeks prior to study registration, and must have fully
             recovered from any such procedure

               -  The following are not considered to be major procedures: thoracentesis,
                  paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic
                  ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies
                  and routine dental procedures

          -  Patients must have measurable disease by RECIST criteria; lesions that can be
             accurately measured in at least one dimension (longest diameter to be recorded) as >=
             2 cm with conventional techniques or as >= 1 cm with spiral computed tomography (CT)
             scan

          -  No active brain metastases: patients with treated, stable brain metastases for at
             least three months are eligible as long as they meet the following criteria:

               -  Treated brain metastases are defined as having no ongoing requirement for
                  steroids and no evidence of progression or hemorrhage after treatment for at
                  least 3 months, as ascertained by clinical examination and brain imaging
                  (magnetic resonance imaging [MRI] or CT) (stable dose of anticonvulsants are
                  allowed); treatment for brain metastases may include whole brain radiotherapy
                  (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent)
                  or a combination as deemed appropriate by the treating physician; patients with
                  central nervous system (CNS) metastases treated by neurosurgical resection or
                  brain biopsy performed within 3 months prior to day 1 are not eligible

               -  Baseline brain imaging (MRI/CT) is required

          -  No serious non-healing wound, ulcer, or bone fracture

          -  No arterial thrombotic events within 6 months of registration:

               -  Including transient ischemic attack (TIA), cerebrovascular accident (CVA),
                  peripheral arterial thrombus, unstable angina or angina requiring surgical or
                  medical intervention in the past 6 months, or myocardial infarction (MI);
                  patients with clinically significant peripheral artery disease (i.e.,
                  claudication on less than one block), significant vascular disease (i.e., aortic
                  aneurysm, history of aortic dissection), or any other arterial thrombotic event
                  are ineligible

          -  Patients who have experienced a deep venous thrombosis or pulmonary embolus within the
             past 6 months must be on stable therapeutic anticoagulation to be enrolled to this
             study

          -  Patients receiving anti-platelet agents and prophylactic anticoagulation are eligible

          -  No inadequately controlled hypertension: (defined as a blood pressure of >= 160 mmHg
             systolic and/or >= 90 mmHg diastolic on medication), or any prior history of
             hypertensive crisis or hypertensive encephalopathy

          -  No known severe impairment of lung function, defined as >= grade 2 dyspnea or cough,
             or either:

               -  Requirement of supplemental oxygen, or

               -  In cases where pulmonary function or pulse oximetry tests have been obtained,
                  forced expiratory volume of the lung in one second (FEV1) or forced vital
                  capacity (FVC) are < 50% of predicted, or single breath diffusing capacity of the
                  lung for carbon monoxide (DLCO) is < 35% of predicted or resting room oxygen
                  saturation is less than 90%

          -  No active or severe liver disease (e.g. acute or chronic hepatitis, cirrhosis)

          -  No positive serology for anti-hemoglobin C (HBC) or anti-hepatitis C virus (HCV)
             antibodies; hepatitis B virus (HBV) seropositive patients (hepatitis B surface antigen
             [HBsAg] positive) are eligible if they are closely monitored for evidence of active
             HBV infection by HBV deoxryribonucleic acid (DNA) testing and agree to receive
             suppressive therapy with lamivudine or other HBV-suppressive therapy until at least 4
             weeks after the last dose of everolimus

          -  No New York Heart Association (NYHA) class >= 2 congestive heart failure

          -  No active bleeding or chronic hemorrhagic diathesis or increased risk for bleeding:
             Including but not limited to history of major bleeding within 6 months (e.g.
             gastrointestinal, lung, CNS sites; or required transfusion support)

          -  No history of abdominal fistula, gastrointestinal perforation or intra-abdominal
             abscess within 6 months prior to the initiation of treatment

          -  No ongoing immunosuppressive therapy: including chronic systemic treatment with
             corticosteroids (>= 10 mg/day prednisone equivalent)

          -  Archival tissue must be available for submission: though it is optional patients to
             choose to participate in the correlative substudies or not

          -  Patients who are pregnant or nursing are not eligible

               -  Women of child bearing potential must have a negative serum or urine pregnancy
                  test within 16 days prior to registration

               -  Women of child-bearing potential include:

                    -  Any female who has experienced menarche and who has not undergone surgical
                       sterilization (hysterectomy, bilateral tubal ligation or bilateral
                       oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12
                       consecutive months)

                    -  Women on hormone replacement therapy (HRT) with documented serum follicle
                       stimulating hormone (FSH) level > 35m IU/mL

                    -  Women who are using oral, implanted or injectable contraceptive hormones or
                       mechanical products such as an intrauterine device or barrier methods
                       (diaphragm, condoms, spermicides) to prevent pregnancy or practicing
                       abstinence or where partner is sterile (e.g., vasectomy)

          -  Performance status Eastern Cooperative Oncology Group (ECOG) 0-2 or Karnofsky score >=
             60%

          -  Granulocytes >= 1,500/μL

          -  Platelet count >= 100,000/μL

          -  Calculated creatinine clearance >= 30 mL/minute (modified Cockroft and Gault formula)

          -  Bilirubin =< 1.5 x upper limits of normal

          -  Aspartate aminotransferase (AST) =< 2.5 x upper limits of normal (ULN)

          -  Fasting serum triglycerides =< 200 mg/dL

          -  Serum cholesterol =< 300 mg/dL

          -  Fasting serum glucose =< 1.5 x ULN

          -  Urine protein to creatinine ratio < 1.0 or urine protein =< 1+