Clinical trial NCT01600742: Vorinostat and Concurrent Whole Brain Radiotherapy for Brain Metastasis
Official title: Vorinostat and Concomitant Whole Brain Radiation Therapy in Patients With Brain Metastases: A Randomized, Double-blind, Placebo-controlled, Phase II Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Brain Metastasis
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
First posted: 2012-05-17
Enrollment: 4
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: To evaluate brain-specific progression free survival rate at 6 months
timeFrame: 6 months
Secondary outcomes:
measure: brain-specific PFS
timeFrame: from randomization to progression of brain metastasis or death, assessed up to 36 months
measure: PFS
timeFrame: from randomization to progression or death, assessed up to 36 months
measure: response rate
timeFrame: 6 months
measure: time to neuro-cognitive progression
timeFrame: 12 months
measure: time to neurologic progression
timeFrame: 12 months
measure: HRQoL
timeFrame: 12 months
measure: Overall survival
timeFrame: from randomization to death, assessed up to 36 months
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: National Taiwan University Hospital
name: Pei-Fang Wu, MD
role: PRINCIPAL_INVESTIGATOR
References: