Vorinostat and Bevacizumab in Treating Patients With Unresectable or Metastatic Kidney Cancer

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of vorinostat (SAHA) in combination with
bevacizumab in patients with unresectable or metastatic renal cell carcinoma. (Phase I) II.
Determine the recommended dosing in patients treated with this regimen. (Phase I) III.
Determine the proportion of patients who are progression-free at 6 months after receiving
this regimen. (Phase II) IV. Determine the clinical response rate in patients treated with
this regimen. (Phase II)

SECONDARY OBJECTIVES:

I. Determine the toxicity of this regimen in these patients. (Phase II) II. Determine time
to progression and duration of progression-free and overall survival in patients treated
with this regimen. (Phase II) III. Determine the pharmacodynamic effects in peripheral blood
mononuclear cells and tumors before and after treatment with this regimen in these patients.
(Phase II) IV. Determine the antiproliferative and apoptotic effects of this regimen in
these patients. (Phase II) V. Determine the antiangiogenic effects of this regimen in these
patients. (Phase II) VI. Determine the modulation of tumor metabolism and tumor blood flow
in patients treated with this regimen. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of vorinostat (SAHA) followed by a phase
II study.

PHASE I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90
minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or
unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6
patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD.

PHASE II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase
I.

After completion of study treatment, patients are followed at 4 weeks and then every 3
months thereafter.

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