Bevacizumab, Sorafenib Tosylate, and Temsirolimus in Treating Patients With Metastatic Kidney Cancer
Condition: Clear Cell Renal Cell Carcinoma; Recurrent Renal Cell Carcinoma; Stage IV Renal Cell Cancer AJCC v7
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Bevacizumab; Laboratory Biomarker Analysis; Pharmacological Study; Sorafenib Tosylate; Temsirolimus
Intervention description: Given IV; Correlative studies; Correlative studies; Given PO; Given IV
Intervention MeSH terms: Sirolimus; Bevacizumab; Antineoplastic Agents, Immunological; Sorafenib; Temsirolimus; MTOR Inhibitors; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 361.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies different combinations of bevacizumab, temsirolimus,
      and sorafenib tosylate to see how well they work compared with bevacizumab alone in treating
      patients with kidney cancer that has spread to other places in the body. Monoclonal
      antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and
      spread. Bevacizumab and sorafenib tosylate may stop the growth of tumor cells by blocking
      blood flow to the tumor. Temsirolimus and sorafenib tosylate may stop the growth of tumor
      cells by blocking some of the enzymes needed for cell growth. Giving different combinations
      of bevacizumab, sorafenib tosylate, and temsirolimus may be more effective than bevacizumab
      alone in treating metastatic kidney cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients will be required to have the clear cell variant of renal cell carcinoma with
             less than 25% of any other histology (including, but not limited to, papillary or
             chromophobe or oncocytic); there must be histologic confirmation by treating center of
             either primary or metastatic lesion

          -  Patients will be required to have measurable metastatic disease that is not curable by
             standard radiation therapy or surgery; all sites must be assessed within 4 weeks prior
             to study entry

          -  Previous nephrectomy is required with the following exceptions:

               -  Primary tumor =< 5 cm, or

               -  Extensive liver (> 30% of liver parenchymal) or multiple (> 5) bone metastases,
                  making nephrectomy a clinically questionable procedure

               -  Unresectable primary tumor due to invasion into adjacent organs or encasing the
                  aorta or vena cava

          -  No prior cytotoxic chemotherapy; a maximum of one prior regimen of either vaccine or
             cytokine-based immunotherapy disease is permitted

          -  No prior anti-angiogenic therapy including, but not limited to, SU11248, ZD6474 or
             VEGF Trap; no prior therapy with bevacizumab, mammalian target of rapamycin (mTOR)
             inhibitors (including, but not limited to, temsirolimus), or sorafenib will be
             allowed; thalidomide or interferon alpha (IFNalpha) are allowed either for adjuvant
             therapy or stage IV disease

          -  No immunotherapy within 4 weeks of randomization; toxicities from immunotherapy must
             have resolved and a minimum of two weeks must pass prior to enrollment

          -  Prior radiation therapy is permitted, but toxicities from radiation must have resolved
             and a minimum of 2 weeks must pass prior to randomization

          -  No history or clinical evidence of central nervous system (CNS) disease, including
             primary brain tumor, seizures not controlled with standard medical therapy, any brain
             metastasis, or history of stroke within the past 48 weeks

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Life expectancy of greater than 12 weeks

          -  Hemoglobin (Hgb) >= 9.0 g/dL (transfusions allowed prior to enrollment)

          -  White blood count (WBC) >= 3,000/mm^3

          -  Absolute granulocyte count (AGC) >= 1,200/mm^3

          -  Platelet count >= 100,000/mm^3

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance
             (CrCl) >= 55 ml/min

          -  Total bilirubin =< 1.5 x ULN

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (or
             =< 5.0 x ULN in the presence of liver metastases)

          -  International normalized ratio (INR) =< 1.5

          -  Activated partial thromboplastin time (aPTT) within normal limits

          -  Fasting cholesterol < 350 mg/dL (9.0 mmol/L)

          -  Fasting triglycerides < 400 mg/dL (4.56 mmol/L)

          -  Patients must not have other current malignancies, other than basal cell skin cancer,
             squamous cell skin cancer, in situ cervical cancer, and ductal or lobular carcinoma in
             situ of the breast; patients with other malignancies are eligible if they have been
             continuously disease-free for >= 5 years prior to the time of randomization

          -  No history of allergic reactions attributed to Chinese hamster ovary cell products,
             other recombinant human antibodies, or compounds of similar chemical or biologic
             composition to sorafenib, temsirolimus or bevacizumab

          -  No history of bleeding diathesis or coagulopathy

          -  Any condition that impairs patient's ability to swallow pills will make patient
             ineligible

          -  No major surgical procedure, open biopsy or significant traumatic injury within 28
             days prior to randomization

          -  No anticipated need for major surgery during the course of the study

          -  No current or recent (within 4 weeks of enrollment) use of full-dose of anticoagulants
             or thrombolytic agents (except as required to maintain patency of preexisting or
             permanent indwelling IV catheters, for those patients receiving warfarin, INR must be
             =< 1.5)

          -  No clinically significant cardiovascular disease, defined as one of the following:

               -  Patients with uncontrolled hypertension (blood pressure > 150/100 mm/Hg at the
                  time of enrollment); patients with hypertension and blood pressure =< 150/100
                  mm/Hg on stable antihypertensive regimen are eligible

               -  Myocardial infarction or unstable angina < 24 weeks prior to registration

               -  New York Heart Association grade II or greater congestive heart failure, serious
                  cardiac arrhythmia requiring medication, unstable angina pectoris

               -  Grade II or greater peripheral vascular disease

          -  No serious, non-healing wound, ulcer, or bone fracture

          -  No significant proteinuria at baseline; urine protein must be screened within 2 weeks
             prior to randomization by urine analysis for urine protein creatinine (UPC) ratio; if
             UPC ratio is > 0.5, 24-hour urine protein is to be obtained and the level must be <
             1000 mg for patient enrollment

               -  NOTE: UPC ratio of spot urine is an estimation of the 24 urine protein excretion;
                  a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm

          -  No uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection requiring parenteral antibiotics on day 0 or psychiatric illness/social
             situations that would limit compliance with study requirements

          -  Patients currently taking any of the following cytochrome P450 enzyme-inducing drugs
             are ineligible:

               -  Phenytoin

               -  Carbamazepine

               -  Phenobarbital

               -  Rifampin

          -  Pregnant and breastfeeding women are excluded from the study; breastfeeding should be
             discontinued while receiving therapy; patients must have pregnancy test within 7 days
             prior to patient randomization if woman is of child-bearing capacity

          -  Human immunodeficiency virus (HIV)-positive patients receiving combination
             anti-retroviral therapy are excluded from the study