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

Phase 1
18 Years
Open (Enrolling)
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

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


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.


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

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.

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

- More than 2 weeks since prior valproic acid or any other histone deacetylase

- 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

Type of Study:


Study Design:

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

Outcome Measure:

Safety and tolerability as assessed by NCI CTCAE v3.0

Outcome Time Frame:

Up to 30 days after completion of treatment

Safety Issue:


Principal Investigator

Robert Wenham

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

March 2006

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific



Moffitt Cancer Center at Tampa General Hospital Tampa, Florida  33612