Advanced Esophageal CancersPhase 1NCT00037817
Phase I Study of Gene Induction Mediated by Sequential Decitabine/Depsipeptide Infusion With or Without Concurrent Celecoxib in Subjects With Pulmonary and Pleural Malignancies
A Phase 1 study testing Decitabine, Depsipeptide and Celecoxib in people with Advanced Esophageal Cancers and Primary Small Cell Lung Cancers, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Advanced Esophageal Cancers, Primary Small Cell Lung Cancers, Non-Small-Cell Lung Carcinoma
- What is being tested?
- Decitabine, Depsipeptide and Celecoxib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteUnited States
- Study dates
- 17 May 2002to 9 Nov 2009
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with histologically or cytologically proven primary small cell or non-small cell lung cancers, advanced esophageal cancer, or pleural mesotheliomas are eligible for evaluation. In addition, patients with cancers of nonthoracic origin with metastases to the lungs or pleura are eligible for evaluation.
- Patients with intracranial metastases which have been treated by surgery or radiation therapy may be eligible for study provided there is no evidence of active disease and no requirement for anticonvulsant therapy or steroids following treatment.
- Patients with prior Decitabine or Depsipeptide exposure are eligible for study provided they have not experienced dose limiting toxicity at the dose of DAC or DP that they are scheduled to receive.
- Patients with prior or current celecoxib exposure are eligible for study provided that it has been intermittent, or of short term duration (less than 1 month).
- Patients must have had no chemotherapy, biologic therapy, celecoxib exposure, or radiation therapy for their malignancy within 30 days prior to treatment. Patients may have received localized radiation therapy to non-target lesions provided that the radiotherapy is completed 14 days prior to commencing therapy, and the patients has recovered from any toxicity.
- Patients must have an ECOG performance status of 0-2.
Show all 11Show fewer
- Patients must have adequate pulmonary reserve evidenced by FEV1 and DLCO greater than the 30% 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 due to the unknown effects of demethylating agents and HDAC inhibitors during childhood and adolescent development.
- 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).
- All patients will have cardiology consultation. Subsequent evaluation will consist of stress/redistribution thallium, 24th ambulatory EKG monitoring, ECHO, cardiac MR, or coronary angiography as indicated.
- Patients must be aware of the neoplastic nature of his/her illness, the experimental nature of the therapy, alternative treatments, potential benefits, and risks. The patient must be willing to sign an informed consent, and undergo tumor biopsies to evaluate target gene expression prior to, and after, decitabine/depsipeptide treatment.
Who cannot join
- 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.
Show all 27Show fewer
- 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.
- Patients with HIV infection will be excluded due to the potential risk of opportunistic infection during DAC/DP-induced myelosuppression and potentially deleterious activation of viral gene expression.
- Patients should not be using hydrochlorothiazide diuretics if entered on this protocol. Therefore, patients who must use hydrochlorothiazide diuretics will be excluded.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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.
Read more
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.
Read the 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.
- Conditions
- 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
- Being tested
- Decitabine, Depsipeptide, Celecoxib
- Keywords
- Toxicity Evaluation, Pharmacokinetics, Apoptosis, Gene Induction, Gene Expression, Lung Cancer, Small Cell Lung Cancer, Non-Small Cell Lung Cancer, Pleural Mesothelioma
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Small Cell Lung Carcinoma, Mesothelioma, Malignant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DecitabineDrug
assigned dose level on day 4 and day 10 of each 34 day cycle
DepsipeptideBiological
assigned dose level on day 4 and day 10 of each 34 day cycle
CelecoxibDrug
400mg PO BID on days 4 through 34 of each cycle
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Dose escalation cohort Receives: Drug: Decitabine; Biological: Depsipeptide |
| 2 | Experimental | Molecular response cohort Receives: Drug: Decitabine; Biological: Depsipeptide |
| 3 | Experimental | Celecoxib combination cohort at MTD Receives: Drug: Decitabine; Biological: Depsipeptide; Drug: Celecoxib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetics and toxicity profile
Measured: Every cycle until approximately 70 days after first dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2002 (estimated)
- Study start17 May 2002
- Primary completion8 Oct 2008
- Study completion9 Nov 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Advanced Esophageal CancersStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Investigators
- David S Schrump, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00037817
- Sponsor's protocol ID
- 020205
- Other IDs
- 02-C-0205
- Status last verified
- 30 Nov 2016
- First submitted
- 21 May 2002
- Last updated
- 30 Sep 2019
- Results posted
- No
Publications
Schrump DS, Nguyen DM. Targets for molecular intervention in multistep pulmonary carcinogenesis. World J Surg. 2001 Feb;25(2):174-83. doi: 10.1007/s002680020016.
PubMed 11338019Schrump DS, Waheed I. Strategies to circumvent SV40 oncoprotein expression in malignant pleural mesotheliomas. Semin Cancer Biol. 2001 Feb;11(1):73-80. doi: 10.1006/scbi.2000.0348.
PubMed 11243901Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet. 2001 Apr;10(7):687-92. doi: 10.1093/hmg/10.7.687.
PubMed 11257100
Study at a glance
From the registry record, last updated by the sponsor on 30 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Gene Induction Mediated by Sequential Decitabine/Depsipeptide Infusion With or Without Concurrent Celecoxib in Subjects With Pulmonary and Pleural Malignancies
- ClinicalTrials.gov ID
- NCT00037817
- Acronym / sponsor ID
- 020205
- Conditions
- 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
- Keywords
- Toxicity Evaluation, Pharmacokinetics, Apoptosis, Gene Induction, Gene Expression, Lung Cancer, Small Cell Lung Cancer, Non-Small Cell Lung Cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 17 May 2002
- Primary completion
- 8 Oct 2008 (actual)
- Study completion
- 9 Nov 2009 (actual)
- First posted
- 22 May 2002 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Decitabine, Biological: DepsipeptideDose escalation cohort |
| 2 | Experimental | Drug: Decitabine, Biological: DepsipeptideMolecular response cohort |
| 3 | Experimental | Drug: Decitabine, Biological: Depsipeptide, Drug: CelecoxibCelecoxib combination cohort at MTD |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Patients with histologically or cytologically proven primary small cell or non-small cell lung cancers, advanced esophageal cancer, or pleural mesotheliomas are eligible for evaluation. In addition, patients with cancers of nonthoracic origin with metastases to the lungs or pleura are eligible for evaluation.
- Patients with intracranial metastases which have been treated by surgery or radiation therapy may be eligible for study provided there is no evidence of active disease and no requirement for anticonvulsant therapy or steroids following treatment.
- Patients with prior Decitabine or Depsipeptide exposure are eligible for study provided they have not experienced dose limiting toxicity at the dose of DAC or DP that they are scheduled to receive.
- Patients with prior or current celecoxib exposure are eligible for study provided that it has been intermittent, or of short term duration (less than 1 month).
- Patients must have had no chemotherapy, biologic therapy, celecoxib exposure, or radiation therapy for their malignancy within 30 days prior to treatment. Patients may have received localized radiation therapy to non-target lesions provided that the radiotherapy is completed 14 days prior to commencing therapy, and the patients has recovered from any toxicity.
Key exclusion criteria (27 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Decitabineassigned dose level on day 4 and day 10 of each 34 day cycle | Drug | 1, 2, 3 |
| Depsipeptideassigned dose level on day 4 and day 10 of each 34 day cycle | Biological | 1, 2, 3 |
| Celecoxib400mg PO BID on days 4 through 34 of each cycle | Drug | 3 |
Primary outcome
Pharmacokinetics and toxicity profile
Time frame: Every cycle until approximately 70 days after first dose
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Sep 2019.
- Background: PubMed 11338019Schrump DS, Nguyen DM. Targets for molecular intervention in multistep pulmonary carcinogenesis. World J Surg. 2001 Feb;25(2):174-83. doi: 10.1007/s002680020016.
- Background: PubMed 11243901Schrump DS, Waheed I. Strategies to circumvent SV40 oncoprotein expression in malignant pleural mesotheliomas. Semin Cancer Biol. 2001 Feb;11(1):73-80. doi: 10.1006/scbi.2000.0348.
- Background: PubMed 11257100Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet. 2001 Apr;10(7):687-92. doi: 10.1093/hmg/10.7.687.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David S Schrump, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Decitabine, Depsipeptide and Celecoxib in people with Advanced Esophageal Cancers and Primary Small Cell Lung Cancers, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetics and toxicity profile (time frame: Every cycle until approximately 70 days after first dose). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00037817, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Sep 2019.