Neoplasms

Digestive System Diseases

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Respiratory Tract (Lung and Bronchial) Diseases

Symptoms and General Pathology

Rare Diseases

Esophageal Neoplasms

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Non-Small-Cell Lung

Neoplasm Metastasis

Lung Neoplasms

Mesothelioma

Mesothelioma, Malignant

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

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Small Cell Lung Cancer

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Antineoplastic Agents

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Anti-Inflammatory Agents

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Anti-Infective Agents

Decitabine

Celecoxib

Romidepsin

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Enzyme Inhibitors

Antimetabolites

Anti-Bacterial Agents

Antibiotics, Antitubercular

Histone Deacetylase Inhibitors

assigned dose level on day 4 and day 10 of each 34 day cycle

Depsipeptide

400mg PO BID on days 4 through 34 of each cycle

David S Schrump, M.D.

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.

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

National Cancer Institute (NCI)

Carcinoma, Small Cell

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Alvocidib

Growth Inhibitors

Protein Kinase Inhibitors

Flavopiridol (alvocidib)

This study will test the safety and effectiveness of two experimental medicines - depsipeptide and flavopiridol - given together to treat cancers of the lung, esophagus, and pleura. It will determine the highest dose that these drugs can safely be given together and will test whether giving them together works better at shrinking tumors than giving either one alone.

Patients 18 years of age and older with cancer of the lung, esophagus, or pleura, or other cancers that have spread to the lungs or pleura may be eligible for this study. Candidates are screened with a medical history and physical examination, blood tests, electrocardiogram (EKG), x-rays and scans, pulmonary function tests, and a tumor biopsy (removal of a small piece of tumor tissue for microscopic examination).

Participants are admitted to the hospital for treatment for approximately 10 days during each 28-day treatment cycle. Depsipeptide is infused through an arm vein or central venous catheter (tube placed in a large vein in the neck or chest) for 4 hours. When this infusion is complete, flavopiridol is infused over 72 hours. The dose of depsipeptide is increased four times over the period of the study with successive groups of patients, and flavopiridol is increased once to determine the maximum safe dose of giving these drugs together.

Blood tests are done before and after each depsipeptide infusion and 3 more times for the next 24 hours, and at various times over 4 days during the flavopiridol infusion to evaluate the effects of the medicines. Samples are also drawn periodically throughout the treatment cycle to evaluate safety. Heart function is monitored with several EKGs before and during the depsipeptide doses. The drug has shown effects on EKG tracings, but does not appear to injure the heart muscle.

Tumor biopsies are done before treatment begins and on the fifth day of the first treatment cycle. The biopsies may be done either in the operating room by passing a tube (bronchoscope) down the throat and into the lungs or in the Radiology Department using a thin needle put through the chest wall into the tumor. For the bronchoscopy, numbing medicine is sprayed into the back of the throat to reduce discomfort, and for the needle biopsy, the skin over the biopsy area is numbed. Optional repeat biopsies may be requested before the start of the second treatment cycle and on day 5 of that cycle. (The repeat biopsies are not required for participation in the study.) At the time of each tumor biopsy, a buccal mucosal biopsy is also done. This involves scraping a tongue depressor along the inside of the mouth to collect cells for examination.

At the end of the first treatment cycle, patients return to NIH for evaluation with a physical examination, blood work, x-rays, and scans of the chest, abdomen, pelvis, and brain. Patients who are not experiencing significant drug side effects are offered a second cycle, exactly like the first. The two cycles complete one course of treatment, after which patients once again return to NIH for evaluation. Additional treatment cycles may be offered to patients whose tumors have shrunk or remained stable with therapy. Patients whose tumors have not responded to therapy or who have developed severe drug side effects are taken off the study.

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.

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

Phase I Study of Sequential Depsipeptide/Flavopiridol Infusion for Malignancies Involving Lungs, Esophagus, Pleura, Thymus or Mediastinum

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I Study of Gene Induction Mediated by Sequential Decitabine/Depsipeptide Infusion With or Without Concurrent Celecoxib in Subjects With Pulmonary and Pleural Malignancies	NCT00037817	Advanced Esopha... Primary Small C... Non-Small-Cell ... Pleural Mesothe... Cancers of Non-...	Decitabine Depsipeptide Celecoxib	18 Years - 65 Years	National Institutes of Health Clinical Center (CC)
Depsipeptide/Flavopiridol Infusion for Cancers of the Lungs, Esophagus, Pleura, Thymus or Mediastinum	NCT00094978	Carcinoma, Smal... Carcinoma, Non-... Esophageal Neop... Mesothelioma	Depsipeptide Flavopiridol (a...	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for gene induction