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Vorinostat and Concomitant Whole Brain Radiation Therapy in Patients With Brain Metastases: A Randomized, Double-blind, Placebo-controlled, Phase II Study

Phase 2
20 Years
Open (Enrolling)
Brain Metastasis

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Trial Information

Vorinostat and Concomitant Whole Brain Radiation Therapy in Patients With Brain Metastases: A Randomized, Double-blind, Placebo-controlled, Phase II Study

Whole brain radiotherapy (WBRT) is the treatment of choice for the majority of patients with
brain metastases. Although WBRT yields high radiologic response rate (27~56%) and is
effective in palliation of neurologic symptoms, the response duration is limited and
neurologic progression remains the main cause of death in a significant number of patients.

Vorinostat is reasonably well tolerated and there is also compelling evidence that
vorinostat may serve as a radiosensitizer. Preclinical studies of HDAC inhibition have also
shown efficacy in neuron protection. These data suggest that the addition of vorinostat to
the standard therapy of WBRT may potentially increase their therapeutic efficacy without
increasing neurotoxicity, and support the rationale of this phase II trial of vorinostat
with WBRT in patients with brain metastases.

Inclusion Criteria:

- Patients with a histologic diagnosis of a malignancy (lung and breast cancers) and
radiologic evidence of brain metastases that are not suitable for surgery or
radiosurgery as judged on the basis of the lesion size, number, location and the
patients' personal choices.

- Patients with controlled systemic disease for >6 weeks (as judged on a case by case

- Age≧20 years

- Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≦3

- Life expectancy of ≧6 months

- No prior cranial radiotherapy

- Negative urine pregnancy test done ≤7 days prior to registration, for women of
childbearing potential only.

- Measurable lesions by gadolinium-enhanced MRI or contrast-enhanced CT scans. (≧10mm
on T1-weighted gadolinium enhanced MRI or contrast-enhanced CT)

- Patients must have adequate organ and marrow reserve measured within 7 days prior to
randomization as defined below:

1. Hemoglobin >8.0 gm/dL;

2. Absolute neutrophil count > 1,000/mcL;

3. Platelets >100,000/mcL;

4. Total bilirubin ≤ 1.5 x UNL (upper normal limit);

5. AST(SGOT)/ALT(SGPT) ≤ 2.5 x UNL; for patients with liver metastases,
AST(SGOT)/ALT(SGPT) ≤ 5 x UNL is allowed;

6. Serum creatinine ≤ 1.5 x UNL;

7. PTT ≤ UNL;

8. INR ≤ 1.5;

9. Serum sodium, calcium, potassium, and magnesium levels are within normal limits.

- Patients (or a surrogate) must be able to comply with study procedures and sign
informed consent.

Exclusion Criteria:

- Prior cranial RT.

- Known hypersensitivity to any of the components of vorinostat.

- Use of Valproic acid or other histone deacetylase inhibitor, ≤2 weeks prior to
registration and during treatment.

- Uncontrolled infection.

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
adverse events of the prescribed regimens or limit compliance with study

- History of myocardial infarction or unstable angina ≤6 months prior to registration
or congestive heart failure (CHF) requiring use of ongoing maintenance therapy, or
life-threatening ventricular arrhythmias.

- Inability to take oral medications.

- Receiving any other investigational agent.

- Congenital long QT syndrome.

- Prolonged QTc interval (>450 msec)

- Any of the following Category I drugs that are generally known to have a risk of
causing Torsades de Pointes ≤7 days prior to registration: Quinidine, procainamide,
disopyramide, amiodarone, sotalol, ibutilide, dofetilide, erythromycin,
clarithromycin, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide,
cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,
halofantrine, levomethadyl, pentamidine

- Any of the following:

1. Pregnant women

2. Nursing women

3. Men or women of childbearing potential who are unwilling to employ adequate
contraception throughout the duration of the study and for 3 weeks after
treatment has ended.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

To evaluate brain-specific progression free survival rate at 6 months

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Pei-Fang Wu, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Taiwan University Hospital


Taiwan: Department of Health

Study ID:




Start Date:

August 2012

Completion Date:

June 2015

Related Keywords:

  • Brain Metastasis
  • Neoplasm Metastasis
  • Neoplasms, Second Primary
  • Brain Neoplasms