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

Condition(s) targeted: Lymphoma; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific

Intervention: vorinostat (Drug); pharmacological study (Procedure)

Phase: Phase 1

Status: Recruiting

Sponsored by: UPMC Cancer Centers

Official(s) and/or principal investigator(s):
Suresh Ramalingam, MD, Study Chair, Affiliation: UPMC Cancer Centers
Shivaani Kummar, MD, Principal Investigator, Affiliation: NCI - Medical Oncology Branch

RATIONALE: Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Vorinostat may have different effects in patients who have changes in their liver function.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat in treating patients with metastatic or unresectable solid tumors or lymphoma and liver dysfunction.

Official title: Phase I and Pharmacokinetic Study of Vorinostat for Solid Tumors and Lymphomas in Patients With Varying Degrees of Hepatic Dysfunction

Study design: Treatment

Primary outcome:

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)

Secondary outcome:

Toxicity profile of vorinostat

Clinical response rate

Child-Pugh classification and liver function test results

Detailed description: OBJECTIVES:

Primary

- Determine the pharmacokinetic disposition of vorinostat (SAHA) in patients with

metastatic or unresectable solid tumors or lymphoma and varying degrees of hepatic dysfunction.

- 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

- Document the non-DLTs associated with administration of vorinostat in patients with

hepatic dysfunction.

- Determine the association of the Child-Pugh classification of hepatic dysfunction with

the observed toxicities, plasma pharmacokinetics, and pharmacodynamics of vorinostat administration.

- Document any antitumor activity associated with vorinostat treatment in patients

enrolled on this study.

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.

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

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

PATIENT CHARACTERISTICS:

- ECOG performance status ≤ 2 (Karnofsky ≥ 60%)

- Life expectancy > 3 months

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

- Platelets ≥ 100,000/mm^3

- 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

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

City of Hope Medical Group, Pasadena, California 91105, United States; Recruiting
Mark V. McNamara, MD, Phone: 626-396-2900, Email: mmcnamara@ccsmg.com

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office, Bethesda, Maryland 20892-1182, United States; Recruiting
Clinical Trials Office - Warren Grant Magnusen Clinical Center, Phone: 888-NCI-1937

Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201-1379, United States; Recruiting
Clinical Trials Office - Barbara Ann Karmanos Cancer Institute, Phone: 313-576-9363

Penn State Cancer Institute at Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033-0850, United States; Recruiting
Clinical Trials Office - Penn State Cancer Institute at Milton, Phone: 717-531-3779, Email: CTO@hmc.psu.edu

UPMC Cancer Centers, Pittsburgh, Pennsylvania 15232, United States; Recruiting
Clinical Trials Office - UPMC Cancer Centers, Phone: 412-647-8073

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

Starting date: June 2007
Last updated: October 18, 2008