Bevacizumab Plus Ixabepilone to Treat Patients With Advanced Kidney Cancer
Condition: Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Bevacizumab; Ixabepilone
Intervention description: Bevacizumab will be administered intravenously every 3 weeks on an outpatient basis with the exception of admissions for the purpose of facilitating research studies. The dose of bevacizumab to be given is 15 mg/kg.; Ixabepilone will be given on days 1, 2, 3, 4, and 5 of each three week cycle as a one hour intravenous infusion. The dose will be 6 mg/m(2)/day on five successive days.
Intervention MeSH terms: Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Renal Cell Carcinoma; Bevacizumab; Ixabepilone; Phase II

Summary:

      Background:

        -  Substantial preclinical antitumor synergy supports the exploration of the combination of
           antiangiogenic compounds (including sunitinib and bevacizumab) plus ixabepilone. In
           Vivo, synergistic activity between ixabepilone and bevacizumab has been demonstrated
           using the 151-B human renal carcinoma xenograft model and this synergy compares
           favorably with other antiangiogenic inhibitors (i.e. sunitinib).

        -  Combination therapies of bevacizumab with chemotherapy demonstrated improved benefit
           compared with single-agent cytotoxics in multiple animal models and in humans.

        -  Clinical activity of both compounds used as single agents has been demonstrated in a
           broad spectrum of solid tumors. Bevacizumab and ixabepilone, when used as a single
           agent, have demonstrated substantial activity in renal cell carcinoma.

        -  Phase II studies with bevacizumab and ixabepilone suggest the absence of overlapping
           toxicities.

        -  Development of a well-tolerated and active bevacizumab/ixabepilone combination has the
           potential to further improve the treatment of metastatic renal cell carcinoma (mRCC),
           and could represent a second-line option after sunitinib or sorafenib are no longer of
           benefit or are intolerable.

      Primary Objectives:

        -  Determine the objective response rate of the combination of ixabepilone and bevacizumab
           in patients with relapsed or refractory mRCC.

        -  Determine progression-free survival.

        -  Characterize the toxicity of the combination of ixabepilone and bevacizumab in patients
           with mRCC.

        -  Determine changes in biomarkers and evaluate correlation with clinical outcomes.

      Eligibility:

        -  Pathologic confirmation of renal cell carcinoma (clear cell histology) by the Laboratory
           of Pathology, National Cancer Institute (NCI), or the Medical University of South
           Carolina.

        -  Presence of metastatic renal carcinoma, after progression or intolerance to Vascular
           endothelial growth factor receptor (VEGFR) inhibitors (sunitinib and/or sorafenib).

        -  Adequate organ and bone marrow function.

      Design:

        -  Multi-center, open labeled phase II study

        -  Following a Simon two-stage optimal design, a maximum of 58 patients with metastatic RCC
           will be accrued.

        -  Ixabepilone will be administered daily as a one hour infusion on five successive days
           (daily x 5), every three weeks (one cycle equals 3 weeks or 21 days +/- 5 days).
           Following cycle 6, cycles will be spread out to 4 weeks or 28 days +/- 5 days. The
           starting dose will be a daily dose of 6 mg/m(2)/day, for a total per cycle dose of 30
           mg/m(2).

        -  In addition, 15 mg/kg bevacizumab will be administered intravenously on day 1 of each
           cycle. The first infusion of bevacizumab will be 90 minutes in duration, the second 60
           minutes in duration, and in all subsequent cycles bevacizumab will be infused over 30
           minutes if prior infusions are well tolerated.
    

Eligibility criteria:

        -  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,
             National Cancer Institute (NCI) or the Medical University of South Carolina..

          2. Progression on or after stopping treatment with an agent approved by the Food and Drug
             Administration (FDA) for the treatment of renal cell carcinoma (RCC). Patients must
             have received at least one FDA approved agent (axitinib, sunitinib, sorafenib,
             pazopanib, temsirolimus, interleukin-2 (IL-2), interferon or everolimus). Patients
             must be off prior IL-2 or interferon for 4 weeks prior to entry. They must be off
             sunitinib, sorafenib, pazopanib, axitinib, temsirolimus or everolimus or other
             tyrosine kinase inhibitor (TKIs) for 2 weeks prior to entry.

          3. Eighteen years of age or older.

          4. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

          5. Resolution of any toxic effects of prior therapy (except alopecia) to NCI Common
             Terminology Criteria in Solid Tumors (CTCAE) v.3.0 through 12/31/10 and version 4.0
             beginning 1/1/11 grade less than or equal to 1 and to baseline laboratory values as
             defined in inclusion criterion # 6.

          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 times the ULN, OR measured creatinine
                  clearance greater than or equal to 40 ml/min

               -  urine proteinuria less than 20mg/dL on random protein creatinine ratio urine
                  samples or a 24-hour urine protein less than 500 mg. NOTE: If on a random protein
                  creatinine ratio the urine protein is greater that or equal to 20mg/dL, then
                  obtain a 24 hour urine collection to accurately demonstrate that the 24 hour
                  total is less than 500 mg/24 hours.

               -  aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)
                  and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT)
                  less than or equal to 2.5 times the upper limit of normal (ULN) (or less than or
                  equal to 5 times the ULN if liver function abnormalities due to underlying
                  malignancy)

               -  total bilirubin less than or equal to 1.5 times the 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 peripherally inserted
                  central catheter (PICC)/internal jugular (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 through 12/31/10 and version 4.0 beginning 1/1/11 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, New York
             Heart Association (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 human immunodeficiency virus (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 subjects safety, 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.

         12. Patients on anticoagulant therapy will be evaluated on a case by case basis for
             inclusion.

         13. Serious or non-healing wound, ulcer or bone fracture

         14. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
             within 6 months prior to day 1

         15. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to Day 1

         16. Known central nervous system (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 (magnetic resonance imaging
             (MRI) or computed tomography (CT)). (Stable dose of anticonvulsants are allowed).
             Treatment for brain metastases may include whole brain radiotherapy (WBRT),
             radiosurgery (RS; Gamma Knife, linear particle accelerator (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.

         17. Patients with known hypersensitivity of Chinese hamster ovary cell products or other
             recombinant human antibodies

         18. Patients receiving cytochrome P450 3A4 (CYP3A4) inhibitors in section 3.6 that cannot
             be discontinued.