Vorinostat and Concurrent Whole Brain Radiotherapy for Brain Metastasis

Brain Metastasis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01600742
• Other study ID #: 201110052MB
• Status: Terminated
• Phase: Phase 2
• First received: April 23, 2012
• Last updated: January 7, 2014
• Start date: August 2012
• Est. completion date: December 2013

Study information

• Verified date: January 2014
• Source: National Taiwan University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Taiwan: Department of Health
• Study type: Interventional

Clinical Trial Summary

Vorinostat is a potent and well tolerated HDAC inhibitor. It has been reported to enhance radiosensitivity of cancer cells. We hypothesize that the addition of vorinostat to WBRT may increase therapeutic efficacy for patients with brain metastases.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

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 situation)

• 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 requirements.

• 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.

Study Design

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

Related Conditions & MeSH terms

• Brain Metastasis
• Brain Neoplasms
• Neoplasm Metastasis

Intervention

Drug:
• Vorinostat
Run-in phase: WBRT: 2.5 Gy per fraction per day, day 1 through day 5 every week for 15 days, to a total dose of 37.5Gy. Vorinostat: 400 mg/day during WBRT, day 1 through day 7 every week till one day after WBRT. Randomization phase: WBRT: 2.5 Gy per fraction per day, day 1 through day 5 every week for 15 days, to a total dose of 37.5Gy. Vorinostat or placebo: 400 or 300 mg/day during radiation therapy (based on the results of run-in phase), day 1 through day 7 every week till one day after WBRT.
• Placebo
Randomization phase: WBRT: 2.5 Gy per fraction per day, day 1 through day 5 every week for 15 days, to a total dose of 37.5Gy. Vorinostat or placebo: 400 or 300 mg/day during radiation therapy (based on the results of run-in phase), day 1 through day 7 every week till one day after WBRT.

Locations

Country	Name	City	State
Taiwan	National Taiwan University Hospital	Taipei

Sponsors (1)

Lead Sponsor	Collaborator
National Taiwan University Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To evaluate brain-specific progression free survival rate at 6 months		6 months	No
Secondary	brain-specific PFS		from randomization to progression of brain metastasis or death, assessed up to 36 months	No
Secondary	PFS		from randomization to progression or death, assessed up to 36 months	No
Secondary	response rate		6 months	No
Secondary	time to neuro-cognitive progression		12 months	No
Secondary	time to neurologic progression		12 months	No
Secondary	HRQoL		12 months	No
Secondary	Overall survival		from randomization to death, assessed up to 36 months	No