Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Active	18 and over	NCI	JHOC-J0570 J0570, JHOC-00001107, NCI-6884, 6884, NCT00324870

Objectives

Primary

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

Secondary

1. Determine the toxicity of this regimen in these patients. (Phase II)
2. Determine time to progression and duration of progression-free and overall survival in patients treated with this regimen. (Phase II)
3. Determine the pharmacodynamic effects in peripheral blood mononuclear cells and tumors before and after treatment with this regimen in these patients. (Phase II)
4. Determine the antiproliferative and apoptotic effects of this regimen in these patients. (Phase II)
5. Determine the antiangiogenic effects of this regimen in these patients. (Phase II)
6. Determine the modulation of tumor metabolism and tumor blood flow in patients treated with this regimen. (Phase II)

Entry 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

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

Patient Characteristics:

• ECOG performance status 0-2
• Life expectancy > 6 months
• LVEF ≥ 45%
• WBC ≥ 3,000/mm³
• 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

Expected Enrollment

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

Outcomes

Maximum tolerated dose (phase I)
Progression-free survival at 6 months (phase II)
Response rate (partial or complete response)

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

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.

Pili R, Wilky B, Salumbides B, et al.: Phase I/II trial of the histone deacetylase inhibitor vorinostat in combination with bevacizumab in patients with renal cell carcinoma: phase I safety and pharmacokinetic/pharmacodynamic results. [Abstract] American Society of Clinical Oncology 2008 Genitourinary Cancers Symposium, Feb 14-16, 2008, San Francisco, CA. A-371, 2008.

Trial Contact Information

Trial Lead Organizations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Michael Carducci, MD, Principal investigator		Ph: 410-614-3977 Email: carducci@welchlink.welch.jhu.edu

U.S.A.
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Ph:  410-955-8804
			Email: jhcccro@jhmi.edu

Registry Information
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
Trial Start Date		2006-02-21
Trial Completion Date		2007-08-15 (estimated)
Registered in ClinicalTrials.gov		NCT00324870
Date Submitted to PDQ		2006-01-18
Information Last Verified		2009-07-05
NCI Grant/Contract Number		CA121590, CA06973

Back to Top