This is a dose escalation study that will assess the safety of Vorinostat, a Histone Deacetylase (HDAC) inhibitor, in combination with palliative radiotherapy in patients with advanced or metastatic Non-Small Cell Lung Cancer (NSCLC). Vorinostat has been approved for use in patients with cutaneous T-cell lymphomas, but several pre-clinical studies suggest activity in lung cancer cell lines. Several HDAC inhibitors,including Vorinostat, may enhance the effect of radiotherapy, and this study will seek to confirm this.

Inclusion Criteria:

• Eligibility Criteria
• Patients must have histologically or cytologically confirmed NSCLC. Patients must have metastatic disease, stage IIIB with malignant pleural effusion, or be otherwise unsuitable for potentially curative therapy due to bulk of disease or comorbid medical illness. There must be disease apparent on imaging which offers a medical indication for radiation therapy. Palliative radiotherapy would be offered as appropriate standard therapy outside of a study setting. (NOTE: Radiotherapy utilized in this regimen is the same as that which would be offered as standard treatment outside of this study). Indications for palliative radiation include pain, pathologic fracture or risk of fracture, lymphovascular obstruction, bronchial obstruction, neural impingement, dyspnea, or bleeding.
• There must be a measurable tumor target (visible, palpable, or radiographically evident) for palliative radiation. The target for radiotherapy must be in the thoracic region (i.e., there must be normal lung tissue at the same anatomic level).
• Previous systemic therapy for NSCLC is allowed, as long as all prior therapy was completed at least two weeks before enrollment. Patients treated with nitrosurea or radioisotope may not be enrolled unless such treatment was at least 6 weeks prior to enrollment. Patients must have no previous exposed to HDAC inhibitors (patients previously treated with valproic acid are eligible if the exposure was greater than 30 days prior to enrollment).
• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of vorinostat alone, or in combination radiation in patients <18 years of age, children are excluded from this study.
• ECOG performance status ≤3
• Life expectancy of greater 3 months.
• Patients must have normal organ and marrow function as defined below, all laboratory values to be obtained within 2 weeks prior to enrollment:
• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• hemoglobin ≥9 g/ dL
• serum bilirubin <1.5 times the upper limit of normal (ULN) serum AST, ALT, ALP <2.5 times ULN
• serum Creatinine <1.5 times ULN
• serum Potassium, Magnesium, Calcium - within normal range
• The effects of radiation on the developing human fetus are known to be teratogenic. For this reason, women of child-bearing potential and sexually active men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.
• Ability to swallow a capsule
• Patients must have had a CT scan of the chest, abdomen, and pelvis (or PET/CT of the body), as well as an MRI or contrasted CT of the brain within 30 days of enrollment

Exclusion Criteria:

• Patients with known, untreated brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients who have received whole brain radiotherapy within 2 weeks of enrollment will also be excluded.
• Patients treated on an investigational drug trial within 30 days of study enrollment.
• Patients with active grade 2 or greater acute toxicity related to prior cancer-directed therapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat, or patients with a history of an unanticipated severe normal tissue reaction to previous radiation treatment.
• Patients with congenital long QT-syndrome will be excluded, as a known side effect of vorinostat is prolongation of QT interval. Patients on anti-arrhythmic medications or other medications known to lead to prolonged QT interval will be exclude unless an ECG has been obtained documenting a normal QT interval within 90 days prior to enrollment.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (fever >38ºC within 48 hours of enrollment), symptomatic congestive heart failure (i.e., NYHA class 3 or greater), unstable angina pectoris, coronary angioplasty within 6 months prior to enrollment, or cardiac arrhythmia. Additionally, patients with suspected or confirmed poor compliance, mental instability, or prior or current alcohol or drug abuse deemed by the investigator to be likely to affect their ability to sign the informed consent, or undergo study procedures will be excluded.
• Pregnant women are excluded from this study because radiation has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with vorinostat, breastfeeding should be discontinued if the mother is treated. Women of childbearing potential must have a negative pregnancy test prior to enrollment.
• Patients with active HIV or viral hepatitis.
• Patients in whom primary radiation therapy, with potentially curative intent, is indicated will be excluded.

1 year