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

Alternate Title

Vorinostat in Treating Patients With Metastatic or Unresectable Solid Tumors or Lymphoma and Liver Dysfunction

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	PCI-07013 8057, PCI-UPCI 07-013, UPCI 07-013, NCT00499811, NCI-07-C-0228

Special Category: NIH Clinical Center trial

Objectives

Primary

1. Determine the pharmacokinetic disposition of vorinostat (SAHA) in patients with metastatic or unresectable solid tumors or lymphoma and varying degrees of hepatic dysfunction.
2. Establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vorinostat in groups of patients with varying degrees of hepatic dysfunction (mild, moderate, or severe).

Secondary

1. Document the non-DLTs associated with administration of vorinostat in patients with hepatic dysfunction.
2. Determine the association of the Child-Pugh classification of hepatic dysfunction with the observed toxicities, plasma pharmacokinetics, and pharmacodynamics of vorinostat administration.
3. Document any antitumor activity associated with vorinostat treatment in patients enrolled on this study.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed solid malignancy or lymphoma that is metastatic or unresectable
  • Patients with a liver mass, elevated α-fetoprotein level (≥ 500 ng/mL), and positive serology for hepatitis consistent with a diagnosis of hepatocellular carcinoma will be eligible without the need for pathologic confirmation of the diagnosis
• Standard curative or palliative measures do not exist or are no longer effective
  • Patients who have not received any prior therapy for malignancy are also eligible if they are ineligible for standard therapy due to hepatic dysfunction
• Patients with abnormal liver function will be eligible
  • No distinction will be made between liver dysfunction due to metastases and liver dysfunction due to other causes
  • Patients with biliary obstruction for which a shunt has been placed are eligible, provided the shunt has been in place for at least 10 days prior to the first dose of vorinostat (SAHA) and liver function has stabilized
    • Two measurements at least 2 days apart that put the patient in the same hepatic dysfunction stratum will be accepted as evidence of stable hepatic function
  • No evidence of biliary sepsis
• Patients with gliomas or brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to study enrollment
  • Patients with known brain metastases should have had brain irradiation (whole brain or gamma knife) more than 4 weeks before starting protocol treatment
  • Patients with unstable or untreated (non-irradiated) brain metastases should be excluded

Prior/Concurrent Therapy:

• More than 3 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
  • Patients who have been treated with agents that persist in the body for longer than 4 to 6 weeks (such as suramin) are ineligible during the elimination period for those agents
• More than 14 days since prior major surgery
• No prior vorinostat
• At least 2 weeks since prior valproic acid or other histone deacetylase inhibitors
• More than 4 weeks since other prior investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent therapy with enzyme-inducing anticonvulsants
• No concurrent prophylactic granulocyte growth factors during the first cycle of therapy
• No other concurrent investigational or commercial agents or therapies

Patient Characteristics:

• ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
• Life expectancy > 3 months
• Absolute neutrophil count > 1,500/mm³
• Platelets ≥ 100,000/mm³
• Creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Fertile patients must use effective contraception
• HIV-positive patients without an AIDS-defining diagnosis who are not receiving agents with the potential for pharmacokinetic interactions with vorinostat may be eligible
• Able to take oral medications on a continuous basis
• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• No active hemolysis

Expected Enrollment

Outcomes

Pharmacokinetic variables corresponding to the disposition of vorinostat (SAHA)
Maximum tolerated dose and dose-limiting toxicity of vorinostat in groups of patients with varying degrees of hepatic dysfunction (mild, moderate, or severe)

Toxicity profile of vorinostat
Clinical response rate
Child-Pugh classification and liver function test results

Outline

This is a parallel-group, dose-escalation study. Patients are stratified according to level of hepatic dysfunction (normal vs mild vs moderate vs severe).

• Part I: Vorinostat (SAHA) will be administered as a single oral dose on day -6 for all patients.

  Blood samples are obtained periodically on day -6 for pharmacokinetic studies.

• Part II: One week later (day 1), the first cycle of oral vorinostat will be initiated on a continuous daily oral regimen. Each treatment cycle will consist of 21 days of therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.

Dose escalation will proceed within each hepatic dysfunction group (except in the normal group). Only dose-limiting toxicities (DLTs) that occur during the first cycle of treatment will be used to guide dose escalation. The maximum tolerated dose (MTD) is the highest dose at which no more than one instance of DLT is observed (among 6 patients treated). Once the MTD has been determined for a given hepatic dysfunction group, a maximum of 12 patients will be accrued to this dose level.

After completion of study treatment, patients are followed for 4 weeks.

Trial Contact Information

Trial Lead Organizations

UPMC Cancer Centers

Suresh Ramalingam, MD, Protocol chair		Ph: 412-648-6619 Email: sar18@pitt.edu

NCI - Center for Cancer Research

Shivaani Kummar, MD, Principal investigator		Ph: 301-435-5402 Email: kummars@mail.nih.gov

U.S.A.
California
	Duarte
	City of Hope Comprehensive Cancer Center
		Clinical Trials Office - City of Hope Comprehensive Cancer Center	Ph:  800-826-4673
			Email: becomingapatient@coh.org
	Los Angeles
	USC/Norris Comprehensive Cancer Center and Hospital
		Clinical Trials Office - USC/Norris Comprehensive Cancer Center and Hospital	Ph:  323-865-0451
	Sacramento
	University of California Davis Cancer Center
		Clinical Trials Office - University of California Davis Cancer Center	Ph:  916-734-3089
	South Pasadena
	City of Hope Medical Group
		Mark McNamara, MD	Ph:  626-396-2900
			Email: mmcnamara@ccsmg.com
Georgia
	Atlanta
	Winship Cancer Institute of Emory University
		Suresh Ramalingam, MD	Ph:  404-778-1919 888-946-7447
Maryland
	Bethesda
	NCI - Medical Oncology Branch
		Shivaani Kummar, MD	Ph:  301-435-5402
			Email: kummars@mail.nih.gov
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937
Michigan
	Detroit
	Barbara Ann Karmanos Cancer Institute
		Clinical Trials Office - Barbara Ann Karmanos Cancer Institute	Ph:  313-576-9363
New York
	Bronx
	Albert Einstein Cancer Center at Albert Einstein College of Medicine
		Clinical Trials Office - Albert Einstein Cancer Center at Albert Einstein College of Medicine	Ph:  718-904-2730
			Email: aecc@aecom.yu.edu
Ohio
	Cleveland
	Case Comprehensive Cancer Center
		Clinical Trials Office - Case Comprehensive Cancer Center	Ph:  800-641-2422
Pennsylvania
	Hershey
	Penn State Cancer Institute at Milton S. Hershey Medical Center
		Clinical Trials Office - Penn State Cancer Institute at Milton S. Hershey Medical Center	Ph:  717-531-3779
			Email: CTO@hmc.psu.edu
	Pittsburgh
	UPMC Cancer Centers
		Clinical Trials Office - UPMC Cancer Centers	Ph:  412-647-8073
Texas
	San Antonio
	Institute for Drug Development
		Clinical Trials Office - Institute for Drug Development	Ph:  800-340-2872
Wisconsin
	Madison
	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
		Clinical Trials Office - University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Ph:  608-262-5223

Registry Information
Official Title		Phase I and Pharmacokinetic Study of Vorinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction
Trial Start Date		2007-06-08
Trial Completion Date		2012-01-13 (estimated)
Registered in ClinicalTrials.gov		NCT00499811
Date Submitted to PDQ		2007-06-07
Information Last Verified		2009-07-08
NCI Grant/Contract Number		CA47904

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