3 Clinical Trials for Various Conditions
Background: During recent years, cancer-testis (CT) antigens (CTA), particularly those encoded by genes on the X chromosome (CT-X genes), have emerged as attractive targets for cancer immunotherapy. Whereas malignancies of diverse histologies express a variety of CTAs, immune responses to these proteins appear uncommon in cancer patients, possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive regulatory T cells present within tumor sites and systemic circulation of these individuals. Conceivably, vaccination of cancer patients with tumor cells expressing high levels of CTAs in combination with regimens that deplete or inhibit T regulatory cells will induce broad immunity to these antigens. In order to examine this issue, patients with primary lung and esophageal cancers, pleural mesotheliomas, thoracic sarcomas, thymic neoplasms and mediastinal germ cell tumors, as well as sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs, pleura or mediastinum with no evidence of disease (NED) or minimal residual disease (MRD) following standard multidisciplinary therapy will be vaccinated with H1299 tumor cell lysates with Iscomatrix adjuvant. Vaccines will be administered with or without metronomic oral cyclophosphamide (50 mg by mouth (PO) twice a day (BID) x 7day (d) every (q) 14d), and celecoxib (400 mg PO BID). Serologic responses to a variety of recombinant CTAs as well as immunologic responses to autologous tumor or epigenetically modified autologous Epstein-Barr virus (EBV) transformed lymphocytes will be assessed before and after a six month vaccination period. Primary Objectives: 1. To assess the frequency of immunologic responses to CTAs in patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix(TM) vaccines alone in comparison to patients with thoracic malignancies following vaccinations with H1299 cell lysate/Iscomatrix vaccines in combination with metronomic cyclophosphamide and celecoxib. Secondary Objectives: 1. To examine if oral metronomic cyclophosphamide and celecoxib therapy diminishes the number and percentage of T regulatory cells and diminishes activity of these cells in patients with thoracic malignancies are at risk of recurrence. 2. To examine if H1299 cell lysate/Iscomatrix(TM) vaccination enhances immunologic response to autologous tumor or epigenetically modified autologous EBV-transformed lymphocytes (B cells). Eligibility: * Patients with histologically or cytologically proven small cell or non-small cell lung cancer (SCLC;NSCLC), esophageal cancer (EsC), malignant pleural mesothelioma (MPM), thymic or mediastinal germ cell tumors, thoracic sarcomas, or melanomas, sarcomas, or epithelial malignancies metastatic to lungs, pleura or mediastinum who have no clinical evidence of active disease (NED), or minimal residual disease (MRD) not readily accessible by non-invasive biopsy or resection/radiation following standard therapy completed within the past 26 weeks. * Patients must be 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2. * Patients must have adequate bone marrow, kidney, liver, lung and cardiac function. * Patients may not be on systemic immunosuppressive medications at time vaccinations commence. Design: * Following recovery from surgery, chemotherapy, or chemo/radiotherapy (XRT), patients with NED or MRD will be vaccinated via IM injection with H1299 cell lysates and Iscomatrix(TM) adjuvant monthly for 6 months. * Vaccines will be administered with or without with metronomic oral cyclophosphamide and celecoxib. * Systemic toxicities and immunologic response to therapy will be recorded. Pre and post vaccination serologic and cell mediated responses to a standard panel of CT antigens as well as autologous tumor cells (if available) and EBV-transformed lymphocytes will be assessed before and after vaccination. * Numbers/percentages and function of T regulatory cells in peripheral blood will be assessed before, during, and after vaccinations. * Patients will be followed in the clinic with routine staging scans until disease recurrence. * The trial will randomize 28 evaluable patients per arm to either receive vaccine alone or vaccine plus chemotherapy in order to have 80% power to determine if the frequency of immune responses on the combination arm exceeds that of the vaccine alone arm, if the expected frequencies of immune responses on the two arms were 20% and 50%, using a one-sided 0.10 alpha level Fisher's exact test. * Approximately 60 patients will be accrued to this trial.
Background: * Chromatin is is the structural building block of a chromosome. It is found inside the nucleus of the cell and consists of a complex of DNA and protein. * Cancers of the lung, pleura (lung lining) and esophagus show profound changes in chromatin structure that may affect the course of disease in patients. * A better understanding of these diseases and the genetic changes associated with them may be helpful in developing new treatments for them. Objectives: * To evaluate people with cancer of the lung, pleura or esophagus for participation in NCI clinical trials. * To obtain biopsies (small pieces of tissue) from tumor, normal tissue and blood samples to learn more about the cellular changes in blood and tissue in tumors of the lung, esophagus and pleura and surrounding structures in the chest. Eligibility: Patients 2 years of age and older with cancer of the lung, esophagus, pleura, mediastinum or chest wall, or cancers of other origin that have invaded the lung. Note: Patients \>= 2 years of age and under 18 years of age may only participate in research sample collection. Design: * Up to 1310 patients may be included in this study. * Patients undergo standard tests for evaluating the stage of their disease and for determining eligibility for an NCI investigational treatment study. * All patients undergo bronchoscopy and bronchoalveolar lavage ("washing" with salt water) to assess their tumor and collect a sample of normal tissue. Patients whose tumor is located on the outside portion of the lung may also undergo thoracoscopy to obtain a tumor sample. For bronchoscopy and bronchoalveolar lavage a tube with a light is passed through the nose or mouth into the lungs to examine the airways. Salt water is injected through the tube and then withdrawn to obtain cells for laboratory studies. For the thoracoscopy a small tube with a light is put through a small hole in the chest to obtain the tumor sample. Both procedures are usually done under general anesthesia. The tissue is examined to identify cell characteristics of people who respond to certain therapies and to identify markers on the surface of the tissue that may be useful in future research and treatment. * Blood and urine samples are collected from patients. * Patients who are eligible for a treatment study at NCI are offered participation in the study. * Patients for whom standard surgery, radiation or chemotherapy is more appropriate may receive treatment at NCI or with their own physician. * Patients who receive treatment at NCI return for follow-up examinations 4 weeks after discharge and then every 2 to 4 months depending on the nature of their cancer.
Background: Previously we have demonstrated induction of tumor antigen and tumor suppressor gene expression in lung cancer cells following exposure to the DNA demethylating agent, Decitabine (DAC). We have also demonstrated that DAC mediated target gene expression and apoptosis can be significantly enhanced in cancer cells by subsequent exposure to the histone deacetylase (HDAC) inhibitor Depsipeptide FK228 (DP). Furthermore, we have demonstrated that following DAC, or DAC/DP exposure, cancer cells can be recognized by cytolytic T cells specific for the cancer testis antigen, NY-FSO-1. This Phase I study will evaluate gene induction in thoracic oncology patients mediated by sequential DAC/DP treatment with or without the selective COX-2 inhibitor, celecoxib. Objectives: Evaluation of the pharmacokinetics and toxicity of continuous 72-hour intravenous Decitabine (DAC) infusion followed by 4-hour intravenous infusion of Depsipeptide FK228 (DP) with or without oral celecoxib in patients with unresectable cancers involving the lungs or pleura. Analysis of NY-ESO-1, p16 and p21 expression in cancer specimens before and after sequential Decitabine/Depsipeptide treatment. Analysis of serologic response to NY-ESO-1 before and after sequential drug treatment. Analysis of apoptosis in tumor biopsies before and after sequential Decitabine/Depsipeptide treatment. Refinement of laser capture microdissection and micro-array techniques for analysis of gene expression profiles in tumor tissues. Eligibility: Patients with histologically or cytologically proven primary small cell or non-small cell lung cancers, advanced esophageal cancers, pleural mesotheliomas, or non-thoracic cancers with metastases to the lungs or pleura. Patients must be 18 years or older with an ECOG performance status of 0-2 and have adequate pulmonary reserve evidenced by FEV1 and DLCO greater than the 30% predicted, and less than 50 mm Hg and p02 greater than 60 mm Hg on room air ABG. 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). Design: Patients with inoperable malignancies involving lungs or pleura will receive two cycles of 72-hour intravenous infusion of Decitabine followed by 4-hour Depsipeptide infusion using a Phase I study design. Decitabine will be administered by continuous infusion on days 1-4, and patient cohorts will receive escalating doses of Depsipeptide administered on day 4 and day 10 of a 34 day cycle. Once the MTD and toxicities for sequential DAC/DP have been identified, additional cohorts of 6 lung cancer patients and 6 mesothelioma patients will receive sequential DAC/DP administered at the MTD as outlined above with celecoxib (400mg bid) administered on days 4-34 of each treatment cycle, as a means to enhance target cell apoptosis and facilitate anti-tumor immune recognition/response. Pharmacokinetics, systemic toxicity, and response to therapy will be recorded. Tumor biopsies will be obtained prior to, and after therapy to evaluate expression of NY-ESO-1 tumor antigen, as well as p16 and p21 tumor suppressor genes, which are known to be modulated by chromatin structure. Additional analysis will be undertaken to evaluate the extent of apoptosis in tumor tissues, and to determine if immune recognition of NY-ESO-1 can be demonstrated following sequential DAC?DP +/- celecoxib treatment. As the exact set of comparisons and analyses to be performed will be determined following completion of the trial and will be based on limited numbers of patients, the analyses will be considered exploratory and hypothesis generating rather than definitive. A total of 40 patients will be enrolled.