Phase I Study of Gene Induction Mediated by Sequential Decitabine/Depsipeptide Infusion With or Without Concurrent Celecoxib in Subjects With Pulmonary and Pleural Malignancies

INCLUSION CRITERIA: Patients with histologically or cytologically proven primary small cell or non-small cell lung cancers, advanced esophageal cancer, or pleural mesotheliomas are eligible for evaluation. In addition, patients with cancers of nonthoracic origin with metastases to the lungs or pleura are eligible for evaluation. Patients with intracranial metastases which have been treated by surgery or radiation therapy may be eligible for study provided there is no evidence of active disease and no requirement for anticonvulsant therapy or steroids following treatment. Patients with prior Decitabine or Depsipeptide exposure are eligible for study provided they have not experienced dose limiting toxicity at the dose of DAC or DP that they are scheduled to receive. Patients with prior or current celecoxib exposure are eligible for study provided that it has been intermittent, or of short term duration (less than 1 month). Patients must have had no chemotherapy, biologic therapy, celecoxib exposure, or radiation therapy for their malignancy within 30 days prior to treatment. Patients may have received localized radiation therapy to non-target lesions provided that the radiotherapy is completed 14 days prior to commencing therapy, and the patients has recovered from any toxicity. Patients must have an ECOG performance status of 0-2. Patients must have adequate pulmonary reserve evidenced by FEV1 and DLCO greater than the 30% predicted, and pCO2 less than 50 mm Hg and pO2 greater than 60 mm Hg on room air ABG. Patients must be 18 years of age or older due to the unknown effects of demethylating agents and HDAC inhibitors during childhood and adolescent development. Patients must have a platelet count greater than 100, 000, an ANC equal to or greater than 1500 without transfusion or cytokine support, a normal PT, and adequate hepatic function as evidenced by a total bilirubin of less than 1.5 x upper limits of normal. Serum creatinine less than or equal to 1.6 mg/ml or the creatinine clearance must be greater than 70 ml/min/1.73m(2). All patients will have cardiology consultation. Subsequent evaluation will consist of stress/redistribution thallium, 24th ambulatory EKG monitoring, ECHO, cardiac MR, or coronary angiography as indicated. Patients must be aware of the neoplastic nature of his/her illness, the experimental nature of the therapy, alternative treatments, potential benefits, and risks. The patient must be willing to sign an informed consent, and undergo tumor biopsies to evaluate target gene expression prior to, and after, decitabine/depsipeptide treatment. EXCLUSION CRITERIA: Patients with primary and metastatic cancers involving the lungs or pleura which cannot be readily biopsied by endoscopic or percutaneous fine needle aspiration techniques will be excluded. Patients with untreated limited stage SCLC, and operable NSCLC or operable esophageal cancer will be excluded. Patients who have received three or more systemic cytotoxic treatment regimens will be excluded due to possible cumulative marrow suppression. Patients with active intracranial and leptomeningeal metastases as well as those requiring anticonvulsant medications will be excluded. Patients with life expectancy less than three months will be excluded. Patients with pulmonary embolism, or deep venous thrombosis, or prosthetic heart valves requiring anticoagulation will be excluded. Cardiac exclusion criteria, patients with known cardiac abnormalities such as: -Uncontrolled arrhythmias History of serious ventricular arrhythmias not controlled by coronary artery bypass surgery. Patients with a history of sustained VT, VF, Toursades de Pointes, or cardiac arrest who do not have an automatic implantable cardioverter defibrillator in place Congenital Long QT syndrome or QTc greater than 480 msec Patients with Mobitz II second degree block who do not have a pacemaker Patients with any cardiac arrhythmia requiring anti-arrhythmic medication other than a beta blocker or calcium channel blocker Patients in whom digitalis cannot be discontinued Decompensated heart failure (NYHA Class II or IV) LVEF less than 50% by MUGA scan or echocardiogram Hypertrophic or restrictive cardiomyopathy from prior treatment of other causes and patients with left ventricular hypertrophy Uncontrolled hypertension (i.e greater than or equal to 160/95) Myocardial infarction within one year of study Clinical significant active myocardial ischemia on the basis of nuclear imaging or angiography History of coronary artery disease (e.g. angina Canadian Class II-Iv or positive stress imaging study) Patients with other cardiac disease may be excluded at the discretion of the PI following consultation with cardiology Co-medication causing QTc prolongation unless a 5 half-life washout period has elapsed between discontinuing the drug and entering this study. Pregnant patients and lactating mothers will be excluded due to the unknown, potentially harmful effects of demethylating agents and HDAC inhibitors on fetal and early childhood development. Patients with active infections will be excluded. Patients with HIV infection will be excluded due to the potential risk of opportunistic infection during DAC/DP-induced myelosuppression and potentially deleterious activation of viral gene expression. Patients should not be using hydrochlorothiazide diuretics if entered on this protocol. Therefore, patients who must use hydrochlorothiazide diuretics will be excluded.