Brief Title
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
Brief Summary
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.
(closed for accrual as of 04/05/2010) 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.
Detailed Description
PRIMARY OBJECTIVES:
I. Determine the pharmacokinetic disposition of vorinostat (SAHA) in patients with metastatic
or unresectable solid tumors or lymphoma and varying degrees of hepatic dysfunction.
II. 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 OBJECTIVES:
I. Document the non-DLTs associated with administration of vorinostat in patients with
hepatic dysfunction.
II. Determine the association of the Child-Pugh classification of hepatic dysfunction with
the observed toxicities, plasma pharmacokinetics, and pharmacodynamics of vorinostat
administration.
III. 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). (closed for accrual
as of 04/05/2010)
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 course of oral vorinostat will be initiated on a
continuous daily oral regimen. Each treatment course 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.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Pharmacokinetic (PK) variables corresponding to the disposition of vorinostat (SAHA) (Group 1)
Secondary Outcome
Toxicity profile of vorinostat
Condition
Adult Grade III Lymphomatoid Granulomatosis
Intervention
vorinostat
Study Arms / Comparison Groups
Treatment (enzyme inhibitor therapy)
Description: 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. One week later (day 1), the first course of oral vorinostat will be initiated on a continuous daily oral regimen. Each treatment course will consist of 21 days of therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
15
Start Date
June 2007
Primary Completion Date
August 2011
Eligibility Criteria
Inclusion Criteria:
- 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
- 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
- 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
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Suresh Ramalingam, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00499811
Organization ID
NCI-2009-00272
Secondary IDs
NCI-2009-00272
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
Suresh Ramalingam, Principal Investigator, University of Pittsburgh
Verification Date
October 2011