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

Background: In preclinical studies we have demonstrated that the histone deacetylase (HDAC) inhibitor Depsipeptide FR901228 (DP) mediates cell cycle arrest and apoptosis in cultured lung and esophageal cancer, and malignant pleural mesothelioma cells. We have observed that the cdk inhibitor Flavopiridol (FLA) markedly potentiates Depsipeptide-mediated apoptosis in cultured cancer cells, but not cultured normal epithelial cells. Patients with advanced malignancies involving lungs, esophagus, or pleura will receive 4-hour Depsipeptide infusion followed by 72-hour FLA infusion using a phase I study design. Tumor and buccal mucosa biopsies as well as PBMC may be obtained prior to, and after therapy to evaluate gene expression using cDNA array long-oligo and protein lysate array techniques, and determine if sequential DP/FLA mediates apoptosis in target tissues. Results of these studies may provide the rationale for phase II evaluation of sequential DP/FLA infusion in thoracic oncology patients. Objectives:\<TAB\> Primary objectives: To define the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of sequential 4 hour Depsipeptide(DP)/72 hour Flavopiridol (FLA) To evaluate the pharmacokinetics of sequential DP/FLA infusion Secondary objectives To analyze gene expression profiles in laser-captured tumor cells, buccal mucosa, and PBMC before and after sequential DP/FLA exposure. To analyze mcl-1 protein expression and apoptosis in tumor biopsies before and after sequential DP/FLA treatment. Tertiary objectives: The development of tissue and serum proteomic techniques to assess treatment response in patients receiving sequential DP/FLA infusions. Eligibility: Patients with histologically or cytologically proven primary small cell or non-small cell lung cancers, esophageal cancers, malignant pleural mesotheliomas or chest wall sarcoma, or thymomas are eligible for evaluation. In addition, patients with cancers of nonthoracic origin with metastases to the lungs or pleura, or germ cell tumors refractory to standard therapy are eligible for evaluation. 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 percent 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. Adequate organ function as evidenced by standard laboratory parameters. The patient must be willing to sign an informed consent. Design:\<TAB\>\<TAB\> A phase 1 study where patient cohorts will receive escalating doses of Depsipeptide, administered on day 1 and day 21, and a dose of flavopiridol (either 40 mg/m2/d or 50 mg/m2/d) administered on days 1-3, and 21-24 of a 42-day course. Pharmacokinetics, systemic toxicity, and response to therapy will be recorded. Two cycles of therapy (one course) will be administered, following which treatment evaluation will be performed using standard clinical criteria. 48 patients will be enrolled over a period of 2-4 years.