Phase I/II Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With the VEGF Inhibitor Bevacizumab in Patients With Metastatic Renal Cell Carcinoma
Phase I/II Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With the VEGF Inhibitor Bevacizumab in Patients With Metastatic Renal Cell Carcinoma
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.
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:
WBC ≥ 3,000/mm^3