Vorinostat and Doxorubicin in Treating Patients With Metastatic or Locally Advanced Solid Tumors - Full Text View

Sponsors and Collaborators:	H. Lee Moffitt Cancer Center and Research Institute National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00331955

Purpose

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may help doxorubicin work better by making tumor cells more sensitive to the drug.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat when given together with doxorubicin in treating patients with metastatic or locally advanced solid tumors.

Condition	Intervention	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: doxorubicin hydrochloride Drug: vorinostat Procedure: biopsy Procedure: gene expression profiling Procedure: laboratory biomarker analysis Procedure: pharmacological study	Phase I

MedlinePlus related topics: Cancer

Drug Information available for: Doxorubicin Doxorubicin hydrochloride Suberoylanilide hydroxamic acid

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label
Official Title:	Phase I Trial of Vorinostat (NSC-701852, Suberoylanilide Hydroxamic Acid) and Doxorubicin (NSC-123127, Adriamycin)

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Safety and tolerability as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
Maximum tolerated dose of vorinostat as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Response rate (complete response [CR] and partial response [PR]) and clinical benefits rate (CR, PR, and stable disease > 12 weeks) as assessed by RECIST [ Designated as safety issue: No ]
Correlation of response (CR, PR, stable disease, and best overall reponse) in target and non-target lesions with biological markers [ Designated as safety issue: No ]
Duration of response (overall response, complete response, and stable disease) [ Designated as safety issue: No ]
Pharmacokinetics and pharmacodynamics [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	March 2006
Estimated Primary Completion Date:	August 2007 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

Determine the safety and tolerability of vorinostat (SAHA) and doxorubicin hydrochloride in patients with metastatic or locally advanced solid tumors.
Determine the maximum tolerated dose of vorinostat when administered with doxorubicin hydrochloride in patients treated with this regimen.

Secondary

Determine the response rate (complete response [CR] and partial response [PR]) and clinical benefits rate (CR, PR, and stable disease > 12 weeks) in patients treated with this regimen.
Determine the pharmacokinetics and pharmacodynamics of vorinostat and doxorubicin hydrochloride and their interaction.
Determine the effects of vorinostat on histone acetylation in peripheral blood mononuclear cells and tumors.
Determine the effects of vorinostat on DNA damage induced by doxorubicin hydrochloride as a function of topoisomerase II expression.
Determine the effects of vorinostat on genes and proteins crucial for the maintenance of chromatin structure.

OUTLINE: This is a non-randomized, open-label, dose-escalation study of vorinostat.

Patients receive oral vorinostat twice daily for 5 doses on days 1-3, 8-10, and 15-17 and doxorubicin hydrochloride IV on days 3, 10, and 17. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients with responding or stable disease after 6 courses of treatment may continue to receive vorinostat alone in the absence of disease progression.

Cohorts of 3-6 patients receive escalating doses of vorinostat 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. Up to15 patients are treated at the MTD. Mandatory biopsies are required in these patients.

Patients undergo blood collection and tumor biopsies periodically during the study for pharmacologic, pharmacokinetic, pharmacodynamic, and biomarker correlative studies.

After completion of study treatment, patients are followed for at least 30 days.

PROJECTED ACCRUAL: A total of 40 patients will be accrued to this study.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed solid tumor malignancies for which no curative therapy exists
Measurable or evaluable disease with tumor that is accessible to biopsy as determined by CT scan or ultrasound
Skin, lymph nodes, or chest wall lesions are allowed provided measurements are confirmed by 2 independent health care professionals
No uncontrolled CNS metastases
- Patients with stable CNS metastases (either surgically resected, treated with gamma knife, or stable for 3 months after whole-brain radiotherapy and documented by MRI within the past 4 weeks) are eligible
Willing to undergo pre- and post-vorinostat tumor biopsies

PATIENT CHARACTERISTICS:

Life expectancy ≥ 3 months
ECOG performance status 0-2
WBC > 3,000/mm^3
Absolute neutrophil count > 1,500/mm^3
Hemoglobin > 9.0 g/dL
Platelet count > 100,000/mm^3 (transfusion independent)
Creatinine ≤ 2.0 mg/mL
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST and ALT ≤ 1.5 times ULN
LVEF > 50%
Fertile patients must use effective contraception during and for 6 months after completion of study treatment
Negative pregnancy test
Not pregnant or nursing
No significant active infection (e.g., pneumonia, cellulitis, or wound abscess)
No history of cardiac failure
No history of long QT syndrome (QTc > 470 msec)
No history of ventricular tachycardia or fibrillation
No history of seizures
No history of allergic reactions attributed to compounds of similar chemical or biological composition to vorinostat or other agents used in the study

PRIOR CONCURRENT THERAPY:

More than 3 weeks since prior chemotherapy or radiotherapy (2 weeks for weekly regimens)
More than 2 weeks since prior valproic acid or any other histone deacetylase inhibitors
No prior anthracycline exposure
No other concurrent chemotherapy
No concurrent hormonal therapy except for maintenance therapy with luteinizing-hormone releasing-hormone agonists
No concurrent antiarrhythmics
No concurrent steroids to control brain metastasis
No concurrent colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) during the first course of study treatment
No other concurrent investigational agents for primary disease

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00331955

Locations

United States, Florida
H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
Tampa, Florida, United States, 33612-9497

Sponsors and Collaborators

H. Lee Moffitt Cancer Center and Research Institute

National Cancer Institute (NCI)

Investigators

Study Chair:

Robert M. Wenham, MD

H. Lee Moffitt Cancer Center and Research Institute

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000471997, MCC-14193, NCI-6970, MCC-IRB-103476
Study First Received:	May 30, 2006
Last Updated:	July 23, 2008
ClinicalTrials.gov Identifier:	NCT00331955
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

unspecified adult solid tumor, protocol specific

Study placed in the following topic categories:

Vorinostat
Doxorubicin

Additional relevant MeSH terms:

Anticarcinogenic Agents
Anti-Inflammatory Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Enzyme Inhibitors
Antibiotics, Antineoplastic
Protective Agents
Pharmacologic Actions

Analgesics, Non-Narcotic
Sensory System Agents
Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal
Analgesics
Peripheral Nervous System Agents
Antirheumatic Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on January 15, 2009