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

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of vorinostat when given together with bevacizumab and to see how well they work in treating patients with unresectable or metastatic kidney cancer. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of kidney cancer by blocking blood flow to the tumor. Giving vorinostat together with bevacizumab may kill more tumor cells.

Detailed Description
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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.

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

Conditions
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Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Cancer, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer

Intervention / Treatment
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* Drug: vorinostat
* Drug: bevacizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Drug: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) (Phase II) | Estimated by Kaplan-Meier method | At 6 months |