Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Closed	Over 18	NCI	MCC-14193 6970, NCI-6970, MCC-IRB-103476, NCT00331955

Objectives

Primary

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

Secondary

1. 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.
2. Determine the pharmacokinetics and pharmacodynamics of vorinostat and doxorubicin hydrochloride and their interaction.
3. Determine the effects of vorinostat on histone acetylation in peripheral blood mononuclear cells and tumors.
4. Determine the effects of vorinostat on DNA damage induced by doxorubicin hydrochloride as a function of topoisomerase II expression.
5. Determine the effects of vorinostat on genes and proteins crucial for the maintenance of chromatin structure.

Entry 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

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

Patient Characteristics:

• Life expectancy ≥ 3 months
• ECOG performance status 0-2
• WBC > 3,000/mm³
• Absolute neutrophil count > 1,500/mm³
• Hemoglobin > 9.0 g/dL
• Platelet count > 100,000/mm³ (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

Expected Enrollment

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

Outcomes

Safety and tolerability as assessed by NCI CTCAE v3.0
Maximum tolerated dose of vorinostat as assessed by NCI CTCAE v3.0

Response rate (complete response [CR] and partial response [PR]) and clinical benefits rate (CR, PR, and stable disease > 12 weeks) as assessed by RECIST
Correlation of response (CR, PR, stable disease, and best overall reponse) in target and non-target lesions with biological markers
Duration of response (overall response, complete response, and stable disease)
Pharmacokinetics and pharmacodynamics

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.

Trial Contact Information

Trial Lead Organizations

H. Lee Moffitt Cancer Center and Research Institute at University of South Florida

Robert Wenham, MD, Protocol chair		Ph: 813-745-7205; 888-663-3488

Registry Information
Official Title		Phase I Trial of Vorinostat (NSC-701852, suberoylanilide hydroxamic acid) and Doxorubicin (NSC-123127, Adriamycin)
Trial Start Date		2006-03-09
Trial Completion Date		2007-08-31 (estimated)
Registered in ClinicalTrials.gov		NCT00331955
Date Submitted to PDQ		2006-02-27
Information Last Verified		2008-07-10
NCI Grant/Contract Number		CA76292, CA119213

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