Phase I Study of Gene Induction Mediated by Sequential Decitabine/Depsipeptide Infusion With or Without Concurrent Celecoxib in Subjects With Pulmonary and Pleural Malignancies
Condition: 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
MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Mesothelioma; Mesothelioma, Malignant; Carcinoma, Non-Small-Cell Lung
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Decitabine; Depsipeptide; Celecoxib
Intervention type(s): Drug; Biological; Drug
Intervention description(s): assigned dose level on day 4 and day 10 of each 34 day cycle; assigned dose level on day 4 and day 10 of each 34 day cycle; 400mg PO BID on days 4 through 34 of each cycle
Intervention MeSH terms: Celecoxib; Decitabine; Romidepsin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Toxicity Evaluation; Pharmacokinetics; Apoptosis; Gene Induction; Gene Expression; Lung Cancer; Small Cell Lung Cancer; Non-Small Cell Lung Cancer; Pleural Mesothelioma