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

Completed · Phase 1

Conditions studied: Advanced Esophageal Cancers, Primary Small Cell Lung Cancers, Non-Small-Cell Lung Carcinoma, Pleural Mesotheliomas, Cancers of Non-thoracic Origin With Metastases to the Lungs or Pleura

In brief

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.

Key facts

Study ID: NCT00037817
Run by: National Cancer Institute (NCI)
People needed: 34
Starts: 2002-05-17
Expected to finish: 2009-11-09
Last updated by the study team: 2019-09-30

Who can join

Age: 18 and older, up to 65. Sex: any. Healthy volunteers: not accepted.

You may not qualify if…

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.

Where it is running

National Institutes of Health Clinical Center, 9000 Rockville Pike — Bethesda, Maryland, United States

Full record on ClinicalTrials.gov

Trial information comes from ClinicalTrials.gov and is refreshed daily. TrialsForMe does not provide medical care and does not run the studies it lists.