Ignite Creation Date:
2024-05-05 @ 11:37 AM
Last Modification Date:
2024-10-26 @ 9:10 AM
Study NCT ID:
NCT00094978
Status:
TERMINATED
Last Update Posted:
2019-12-12
First Post:
2004-10-28
Brief Title:
DepsipeptideFlavopiridol Infusion for Cancers of the Lungs Esophagus Pleura Thymus or Mediastinum
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Phase I Study of Sequential DepsipeptideFlavopiridol Infusion for Malignancies Involving Lungs Esophagus Pleura Thymus or Mediastinum
Status:
TERMINATED
Status Verified Date:
2013-05-20
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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
Detailed Description:
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 DPFLA mediates apoptosis in target tissues
Results of these studies may provide the rationale for phase II evaluation of sequential DPFLA infusion in thoracic oncology patients
ObjectivesTAB
Primary objectives
To define the maximum tolerated dose MTD and dose limiting toxicities DLT of sequential 4 hour DepsipeptideDP72 hour Flavopiridol FLA
To evaluate the pharmacokinetics of sequential DPFLA infusion
Secondary objectives
To analyze gene expression profiles in laser-captured tumor cells buccal mucosa and PBMC before and after sequential DPFLA exposure
To analyze mcl-1 protein expression and apoptosis in tumor biopsies before and after sequential DPFLA treatment
Tertiary objectives
The development of tissue and serum proteomic techniques to assess treatment response in patients receiving sequential DPFLA 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
DesignTABTAB
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 mgm2d or 50 mgm2d 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
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 DPFLA mediates apoptosis in target tissues
Results of these studies may provide the rationale for phase II evaluation of sequential DPFLA infusion in thoracic oncology patients
ObjectivesTAB
Primary objectives
To define the maximum tolerated dose MTD and dose limiting toxicities DLT of sequential 4 hour DepsipeptideDP72 hour Flavopiridol FLA
To evaluate the pharmacokinetics of sequential DPFLA infusion
Secondary objectives
To analyze gene expression profiles in laser-captured tumor cells buccal mucosa and PBMC before and after sequential DPFLA exposure
To analyze mcl-1 protein expression and apoptosis in tumor biopsies before and after sequential DPFLA treatment
Tertiary objectives
The development of tissue and serum proteomic techniques to assess treatment response in patients receiving sequential DPFLA 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
DesignTABTAB
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 mgm2d or 50 mgm2d 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 05-C-0010 | None | None | None |