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

Condition(s) targeted: Unspecified Adult Solid Tumor, Protocol Specific

Intervention: doxorubicin hydrochloride (Drug); vorinostat (Drug); biopsy (Procedure); gene expression profiling (Procedure); laboratory biomarker analysis (Procedure); pharmacological study (Procedure)

Phase: Phase 1

Status: Recruiting

Sponsored by: H. Lee Moffitt Cancer Center and Research Institute

Official(s) and/or principal investigator(s):
Robert M. Wenham, MD, Study Chair, Affiliation: H. Lee Moffitt Cancer Center and Research Institute

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.

Official title: Phase I Trial of Vorinostat (NSC-701852, Suberoylanilide Hydroxamic Acid) and Doxorubicin (NSC-123127, Adriamycin)

Study design: Treatment, Non-Randomized, Open Label

Primary outcome:

Safety and tolerability as assessed by NCI CTCAE v3.0

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

Secondary outcome:

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

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

H. Lee Moffitt Cancer Center and Research Institute at University of South Florida, Tampa, Florida 33612-9497, United States; Recruiting
Clinical Trials Office - H. Lee Moffitt Cancer Center and Rese, Phone: 800-456-7121, Email: canceranswers@moffitt.usf.edu

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: March 2006
Last updated: June 13, 2008