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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Adult Grade III Lymphomatoid Granulomatosis, Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Primary Central Nervous System Hodgkin Lymphoma, Primary Central Nervous System Non-Hodgkin Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage III Adult Burkitt Lymphoma, Stage III Adult Diffuse Large Cell Lymphoma, Stage III Adult Diffuse Mixed Cell Lymphoma, Stage III Adult Diffuse Small Cleaved Cell Lymphoma, Stage III Adult Hodgkin Lymphoma, Stage III Adult Immunoblastic Large Cell Lymphoma, Stage III Adult Lymphoblastic Lymphoma, Stage III Adult T-cell Leukemia/Lymphoma, Stage III Cutaneous T-cell Non-Hodgkin Lymphoma, Stage III Grade 1 Follicular Lymphoma, Stage III Grade 2 Follicular Lymphoma, Stage III Grade 3 Follicular Lymphoma, Stage III Mantle Cell Lymphoma, Stage III Marginal Zone Lymphoma, Stage III Mycosis Fungoides/Sezary Syndrome, Stage III Small Lymphocytic Lymphoma, Stage IV Adult Burkitt Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Hodgkin Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Adult T-cell Leukemia/Lymphoma, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Mycosis Fungoides/Sezary Syndrome, Stage IV Small Lymphocytic Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific, Waldenström Macroglobulinemia

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pharmacokinetic (PK) variables corresponding to the disposition of vorinostat (SAHA) (Group 1)

Outcome Description:

The Wilcoxon test will be used for PK data. Concentrations of vorinostat and 2 metabolites (vorinostat glucuronide and 4-anilino-4-oxobutanoic acid) will be quantitated with a liquid chromatography-electrospray ionization tandem mass spectrometric method that was developed and validated in our laboratory. Plasma concentration versus time data for vorinostat and metabolites will be analyzed non-compartmentally using the LaGrange function as implemented by the Lagran computer program.

Outcome Time Frame:

Days -6 and 1 of course 1

Safety Issue:

No

Principal Investigator

Shivaani Kummar

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pittsburgh

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00272

NCT ID:

NCT00499811

Start Date:

June 2007

Completion Date:

Related Keywords:

  • Adult Grade III Lymphomatoid Granulomatosis
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Intraocular Lymphoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Primary Central Nervous System Hodgkin Lymphoma
  • Primary Central Nervous System Non-Hodgkin Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Stage III Adult Burkitt Lymphoma
  • Stage III Adult Diffuse Large Cell Lymphoma
  • Stage III Adult Diffuse Mixed Cell Lymphoma
  • Stage III Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage III Adult Hodgkin Lymphoma
  • Stage III Adult Immunoblastic Large Cell Lymphoma
  • Stage III Adult Lymphoblastic Lymphoma
  • Stage III Adult T-cell Leukemia/Lymphoma
  • Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage III Grade 1 Follicular Lymphoma
  • Stage III Grade 2 Follicular Lymphoma
  • Stage III Grade 3 Follicular Lymphoma
  • Stage III Mantle Cell Lymphoma
  • Stage III Marginal Zone Lymphoma
  • Stage III Mycosis Fungoides/Sezary Syndrome
  • Stage III Small Lymphocytic Lymphoma
  • Stage IV Adult Burkitt Lymphoma
  • Stage IV Adult Diffuse Large Cell Lymphoma
  • Stage IV Adult Diffuse Mixed Cell Lymphoma
  • Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage IV Adult Hodgkin Lymphoma
  • Stage IV Adult Immunoblastic Large Cell Lymphoma
  • Stage IV Adult Lymphoblastic Lymphoma
  • Stage IV Adult T-cell Leukemia/Lymphoma
  • Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Grade 3 Follicular Lymphoma
  • Stage IV Mantle Cell Lymphoma
  • Stage IV Marginal Zone Lymphoma
  • Stage IV Mycosis Fungoides/Sezary Syndrome
  • Stage IV Small Lymphocytic Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Liver Diseases
  • Lymphoma, Large-Cell, Anaplastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Neoplasms
  • Lymphoma, Mantle-Cell

Name

Location

University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Montefiore Medical CenterBronx, New York  10467-2490
City of Hope Medical CenterDuarte, California  91010
University of PittsburghPittsburgh, Pennsylvania  15261
National Institutes of HealthBethesda, Maryland  20892
Case Western Reserve UniversityCleveland, Ohio  44106
Emory UniversityAtlanta, Georgia  30322
Wayne State UniversityDetroit, Michigan  48202
University of Southern CaliforniaLos Angeles, California  90033
Penn State Milton S Hershey Medical CenterHershey, Pennsylvania  17033
West Virginia UniversityMorgantown, West Virginia  26506