INCLUSION CRITERIA:
Subjects meeting all of the following criteria will be considered for enrollment into the study:
1. Pathologic confirmation of metastatic or unsectable renal cell carcinoma with predominant clear cell histology (greater than 70%) by the Laboratory of Pathology, NCI.
2. Progression on or after stopping treatment with a VEGF receptor tyrosine kinase inhibitor (sunitinib and/or sorafenib). Patients must have received one or both agents (sunitinib and/or sorafenib). Prior IL-2, interferon treatment and/or m-TOR treatment is allowed, but not manditory. Patients must be off of prior therapy for at least 4 weeks prior to entry.
3. Eighteen years of age or older.
4. ECOG performance status less than or equal to 2.
5. Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE v.3.0 grade less than or equal to 1 and to baseline laboratory values as defined in inclusion criterion # 6. Beva & Ixa in RCC Version date10/31/08 CTEP 8277:17
6. Adequate organ and bone marrow function as evidenced by hemoglobin greater than or equal to 9.0 g/dL
-absolute neutrophil count greater than or equal to 1.5 x 10(9)/L
-platelet count greater than or equal to 100 x 10(9)/L
-creatinine less than or equal to 1.5 x ULN, and proteinuria less than or equal to 500 mg/24 hours
-AST/SGOT and ALT/SGPT less than or equal to 2.5 x ULN (or less than or equal to 5 x ULN if liver function abnormalities due to underlying malignancy)
-total bilirubin less than or equal to 1.5 x ULN
7. Subjects must be postmenopausal, surgically sterile, or using effective contraception. All female subjects of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days prior to enrollment. Effective contraception includes hormonal or barrier methods.
8. No other invasive malignancies within the past two years (with the exception of nonmelanoma skin cancers, non-invasive bladder cancer, stage I endometrial cancer or cervical cancer).
9. Subjects must agree to sign and date an Institutional Review Board (IRB)-approved subject informed consent form.
10. Subjects must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
11. Patients must have measurable disease either by conventional imaging or clinical examination.
EXCLUSION CRITERIA:
Subjects presenting with any of the following will not be included in the study:
1. Invasive procedures defined as follows:
-Major surgical procedure, open biopsy or significant traumatic injury within 6 weeks prior to Day 1 therapy
-Anticipation of need for major surgical procedures during the course of the study
-Minor surgery, such as port-a-cath placement, and dental procedures, within 2 weeks.
-(There will be no delay for percutaneous core biopsies or PICC/IJ line placement)
2. Cumulative radiation therapy to greater than 25% of the total bone marrow.
3. History of uncontrolled or labile hypertension, defined as blood pressure greater than 160/90 mm Hg (NCI CTCAE v.3.0 grade greater than or equal to 2), on at least 2 repeated determinations on separate days within 15 days prior to study enrollment.
4. Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA class III or IV congestive heart failure; cerebrovascular accident or transient ischemic attack, grade greater than or equal to 2 peripheral neuropathy, peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, or other thromboembolic event.
5. Symptomatic spinal cord compression.
6. Evidence of clinically significant bleeding diathesis or underlying coagulopathy.
7. Antiretroviral therapy for HIV disease.
8. Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy.
9. Other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the subject's safety, Beva & Ixa in RCC Version date10/31/08 CTEP 8277:18 inhibit protocol participation, or interfere with interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.
10. Prior therapy with bevacizumab
11. Prior therapy with ixabepilone.
13. Patients on anticoagulant therapy will be evaluated on a case by case basis for inclusion.
14. Serious or non-healing wound, ulcer or bone fracture
15. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1
16. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
17. Known CNS disease except for treated brain metastasis.
-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 (MRI or CT). (Stable dose of anticonvulsants are allowed). Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.
18. Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies
19. Patients receiving CYP3A4 inhibitors in section 3.6 that can not be discontinued.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 05/05/2009