Phase I Study of Gene Induction Mediated by Sequential Decitabine/Depsipeptide Infusion With or Without Concurrent Celecoxib in Subjects With Pulmonary and Pleural Malignancies
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.
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
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
Refinement of laser capture microdissection and micro-array techniques for analysis of gene
expression profiles in tumor tissues.
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
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.
Primary Purpose: Treatment
David S Schrump, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|