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

Condition(s) targeted: Kidney Cancer

Intervention: bevacizumab (Drug); vorinostat (Drug); antiangiogenesis therapy (Procedure); enzyme inhibitor therapy (Procedure); monoclonal antibody therapy (Procedure)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Sidney Kimmel Comprehensive Cancer Center

Official(s) and/or principal investigator(s):
Roberto Pili, MD, Principal Investigator, Affiliation: Sidney Kimmel Comprehensive Cancer Center

RATIONALE: 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.

PURPOSE: 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.

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

Study design: Treatment

Primary outcome:

Maximum tolerated dose (phase I)

Progression-free survival at 6 months (phase II)

Response rate (partial or complete response)

Secondary outcome:

Toxicity

Time to progression, disease-free survival, and overall survival as measured by Kaplan-Meier method

Pharmacodynamic effects in peripheral blood mononuclear cells at baseline and after completion of study treatment

Antiproliferative and apoptotic effects

Antiangiogenic effects

Modulation of tumor metabolism and tumor blood flow as measured by fluorine-18-labeled deoxyglucose (FDG) and 15 O water positron-emission tomography (PET) scan

Detailed description: OBJECTIVES:

Primary

- Determine the safety and tolerability of vorinostat (SAHA) in combination with

bevacizumab in patients with unresectable or metastatic renal cell carcinoma. (Phase I)

- Determine the recommended dosing in patients treated with this regimen. (Phase I)

- Determine the proportion of patients who are progression-free at 6 months after

receiving this regimen. (Phase II)

- Determine the clinical response rate in patients treated with this regimen. (Phase II)

Secondary

- Determine the toxicity of this regimen in these patients. (Phase II)

- Determine time to progression and duration of progression-free and overall survival in

patients treated with this regimen. (Phase II)

- Determine the pharmacodynamic effects in peripheral blood mononuclear cells and tumors

before and after treatment with this regimen in these patients. (Phase II)

- Determine the antiproliferative and apoptotic effects of this regimen in these patients.

(Phase II)

- Determine the antiangiogenic effects of this regimen in these patients. (Phase II)

- 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.

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically confirmed renal cell carcinoma

- Clear cell component

- Unresectable or metastatic disease* NOTE: *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

- No known CNS metastasis

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy > 6 months

- LVEF ≥ 45%

- WBC ≥ 3,000/mm^3

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- 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

PRIOR CONCURRENT THERAPY:

- 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 anticancer agents or therapies

- 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

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States; Recruiting
Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce, Phone: 410-955-8804, Email: jhcccro@jhmi.edu

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: February 2006
Last updated: February 19, 2008