Phase I/II Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With the VEGF Inhibitor Bevacizumab in Patients With Metastatic Renal Cell Carcinoma

Inclusion Criteria:

- No known CNS metastasis

- ECOG performance status 0-2

- Life expectancy > 6 months

- LVEF ≥ 45%

- Absolute neutrophil count ≥ 1,500/mm3

- Platelet count ≥ 100,000/mm3

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST/ALT ≤ 2.5 times ULN

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 50 mL/min

- PT/INR ≤ 1.5

- Urine protein < 1+ by urinalysis OR < 1 g by 24-hour urine collection

- Not pregnant

- No nursing during and for 6 months after completion of study treatment

- Negative pregnancy test

- Fertile patients must use effective contraception for 2 weeks prior, during, and for
6 months after completion of study treatment

- No other currently active malignancy defined as > 30% risk of relapse upon completion
of anticancer therapy, except nonmelanoma skin cancer

- No history of allergic reaction attributed to compounds of similar chemical or
biologic composition to vorinostat (SAHA)

- No hypersensitivity to Chinese hamster ovary cell products or other recombinant human
antibodies

- No evidence of bleeding diathesis or coagulopathy

- No active bleeding or pathological conditions that carry high risk of bleeding (i.e.,
tumor involving major vessels or known varices)

- No ongoing, active infection

- No New York Heart Association class II-IV congestive heart failure

- No angina pectoris requiring nitrate therapy

- No cardiac arrhythmia

- No myocardial infarction within the past 6 months

- No history of cerebrovascular accident within the past 6 months

- No uncontrolled hypertension (defined as systolic blood pressure (BP) > 160 mm Hg
and/or diastolic BP > 90 mm Hg on medication)

- No history of peripheral vascular disease

- No psychiatric illness or social situation that would preclude study compliance

- No other uncontrolled illness

- No serious nonhealing wound, ulcer, or bone fracture

- No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within the past 28 days

- No significant traumatic injury in the past 28 days

- At least 4 weeks since prior major surgery or open biopsy

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

- More than 4 weeks since prior radiotherapy

- At least 2 weeks since prior tyrosine kinase inhibitor

- Prior palliative radiotherapy to metastatic lesions allowed provided ≥ 1 measurable
and/or evaluable lesion has not been irradiated

- No more than 2 prior systemic treatments for metastatic disease, including
immunotherapy, receptor tyrosine kinase inhibitor therapy, chemotherapy, or
investigational therapy

- No prior therapy with bevacizumab, vascular endothelial growth factor-trap, or
histone deacetylase inhibitors, including valproic acid

- No core biopsy within 1 week prior to day 1 of study treatment

- No planned major surgery during study treatment

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- Concurrent stable-dose prophylactic anticoagulation (i.e., warfarin or low molecular
weight heparin) allowed provided requirements for INR are met

- Histologically confirmed renal cell carcinoma, clear cell component, unresectable or
metastatic disease (patients with a primary tumor in place who are eligible for
surgery are strongly encouraged to undergo a nephrectomy prior to study entry to
increase potential survival)

- Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by
conventional techniques OR ≥ 10 mm with spiral CT scan

- The following histologies are not allowed:

- Papillary, sarcomatoid carcinoma

- Chromophobe carcinoma

- Oncocytoma

- Collecting duct tumor

- Transitional cell carcinoma

- WBC ≥ 3,000/mm^3