Vorinostat and Doxorubicin in Treating Patients With Metastatic or Locally Advanced Solid Tumors

NCT ID: NCT00331955

Last Updated: 2013-07-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-03-31

Brief Summary

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. 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.

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of vorinostat (SAHA) and doxorubicin hydrochloride in patients with metastatic or locally advanced solid tumors.

II. Determine the maximum tolerated dose of vorinostat when administered with doxorubicin hydrochloride in patients treated with this regimen.

SECONDARY OBJECTIVES:

I. 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.

II. Determine the pharmacokinetics and pharmacodynamics of vorinostat and doxorubicin hydrochloride and their interaction.

III. Determine the effects of vorinostat on histone acetylation in peripheral blood mononuclear cells and tumors.

IV. Determine the effects of vorinostat on DNA damage induced by doxorubicin hydrochloride as a function of topoisomerase II expression.

V. 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.

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (vorinostat, doxorubicin hydrochloride)

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.

Group Type: EXPERIMENTAL

doxorubicin hydrochloride

Intervention Type: DRUG

Given IV

vorinostat

Intervention Type: DRUG

Given orally

pharmacological study

Intervention Type: OTHER

Correlative studies

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

Interventions

doxorubicin hydrochloride

Given IV

Intervention Type: DRUG

vorinostat

Given orally

Intervention Type: DRUG

pharmacological study

Correlative studies

Intervention Type: OTHER

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

ADM; ADR; Adria; Adriamycin PFS; Adriamycin RDF; L-001079038; SAHA; suberoylanilide hydroxamic acid; Zolinza; pharmacological studies

Eligibility Criteria

Inclusion Criteria

• 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
• 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
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert Wenham

Role: PRINCIPAL_INVESTIGATOR

H. Lee Moffitt Cancer Center and Research Institute

Locations

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Countries

United States

Other Identifiers

MCC 14193

Identifier Type: -

Identifier Source: secondary_id

CDR0000471997

Identifier Type: -

Identifier Source: secondary_id

NCI-6970

Identifier Type: -

Identifier Source: secondary_id

MCC-IRB-103476

Identifier Type: -

Identifier Source: secondary_id

R21CA112913

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2012-02695

Identifier Type: -

Identifier Source: org_study_id

NCT00365079

Identifier Type: -

Identifier Source: nct_alias