Depsipeptide/Flavopiridol Infusion for Cancers of the Lungs, Esophagus, Pleura, Thymus or Mediastinum

* INCLUSION CRITERIA:

  1. Patients with histologically or cytologically proven small cell or non-small cell lung cancers, esophageal cancers, malignant pleural mesotheliomas chest wall sarcoma, or epithelial thymomas are eligible for evaluation. In addition, patients with cancers of nonthoracic origin with metastases to the lungs, pleura or germ cell tumors refractory to standard therapy are eligible for evaluation.
  2. Chemo naive patients with inoperable lung and esophageal cancers, pleural mesotheliomas, sarcoma, thymomas, as well as tumors of non-thoracic origin with metastasis within the thorax may be eligible for study provided they have been apprised of, and refused potentially effective first line chemotherapy.
  3. 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.
  4. Patients with prior Depsipeptide or Flavopiridol exposure are eligible for study provided they have not experienced dose limiting toxicity at the dose of DP or FLA that they are scheduled to receive.
  5. Patients must have had no chemotherapy, biologic therapy, or radiation therapy for their malignancy for at least 30 days prior to treatment. At least six weeks must elapse between mitomycin C or nitrosourea treatment and DP/FLA therapy. 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 patient has recovered from any toxicity.
  6. Patients must have an ECOG performance status of 0 - 2.
  7. 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.
  8. Patients must be 18 years of age or older due to the unknown effects of HDAC inhibitors and cdk inhibitors during childhood and adolescent development.
  9. 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, and AST/ALT less than or equal to 1.5 times upper limit 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).
  10. 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.

EXCLUSION CRITERIA:

1. Patients with limited stage SCLC and operable NSCLC or operable esophageal cancer will be excluded.
2. Patients with potentially treatable pulmonary metastases from lymphomas or germ cell tumors will be excluded.
3. Patients who have received three or more systemic cytotoxic treatment regimens will be excluded due to possible cumulative marrow suppression.
4. 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 to160/95).

   Myocardial infarction within one year of study.

   Clinically 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.
5. Co-medication causing QTc prolongation (information at Appendix A and http://georgetowncert.org/gqdrugs\_torsades.asp) unless a 5 half-life washout period has elapsed between discontinuing the drug and entering this study.
6. Patients with active intracranial and leptomeningeal metastases, as well as those requiring anticonvulsant medications or steroids to control cerebral edema will be excluded.
7. Patients with life expectancy less than three months will be excluded.
8. Patients with pulmonary embolism or deep venous thrombosis requiring anticoagulation within six months of protocol entry will be excluded.
9. Pregnant patients and nursing mothers will be excluded due to the unknown, potentially harmful effects of HDAC inhibitors and cdk inhibitors on fetal and early childhood development.
10. Patients with active infections will be excluded.
11. Patients with HIV infection will be excluded due to the potential risk of opportunistic infection during DP/FLA-induced myelosuppression and potentially deleterious activation of viral gene expression.
12. Patients will have a screening 12 lead EKG and those patients with left ventricular hypertrophy will not be eligible.
13. Patients who are taking hydrochlorothiazide (HCTZ) will have this agent stopped or switched to a potassium-conserving combination (e.g. Maxide or Dyazide) or other antihypertensive agent. Patients, who cannot have the agent stopped or switched to a potassium-conserving combination or other antihypertensive agent, will not be eligible.