Ignite Creation Date:
2024-05-05 @ 12:05 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00231829
Status:
TERMINATED
Last Update Posted:
2012-04-24
First Post:
2005-09-30
Brief Title:
A Pilot Study of Celecoxib in Patients With Grade 2 or 3 Uterine Cancers
Sponsor:
Mark H Einstein
Organization:
Montefiore Medical Center
Study Overview
Official Title:
A Pilot Phase II Trial of Celecoxib in Patients With Grade 2 or 3 Endometrioid-type Clear Cell and Papillary Serous Uterine Cancers
Status:
TERMINATED
Status Verified Date:
2012-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Due to reported toxicity of Celecoxib at high doses
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Expression of COX-II has been identified in many types of human cancers Uterine cancer is the most common gynecologic cancer in the US and there has been an increase in uterine cancer deaths over the past decade mainly due to the difficulty in treating recurrences in the more aggressive histologic types The study co-investigators have also identified COX-II expression in grade 2 and 3 endometrioid-type clear cell and papillary serous types of uterine cancers Upregulation of COX-II may control the cell cycle by regulating the proliferative capacity of neoplastic endometrial cells This is a Phase II pre-post intervention comparison study in eligible patients looking at the effects of a COX-II inhibitor on uterine cancer The patients whose endometrial biopsy shows grade 2 or 3 endometrioid-type clear cell and papillary serous types of uterine cancers will be put on a selective COX-II inhibitor Celebrex Celecoxib until the day of their surgery We hypothesize that Celecoxib will downregulate the expression of COX-II in these tumor types as it does in other similar tumors We also hypothesize that apoptosis as measured with the TUNEL assay will be increased in areas with less COX-II expression and should be inversely proportional to cellular p21 expression We hypothesize COX-related gene expression will be altered thus suggesting an up- or down-regulation of these genes in the end-organ tissue Documenting downregulation of COX-II enzyme and altered gene expression in endometrial carcinoma after treatment with Celecoxib may result in further prospective studies using selective COX-II inhibitors as effective well-tolerated chemotherapeutic agents in these uterine cancers that are resistant to many current therapies
Detailed Description:
Endometrial cancer is the most common gynecologic cancer in the United States The number of deaths from endometrial cancer has risen 128 since 1987 In 2001 an estimated 38300 women will develop endometrial cancer ACS Facts and Figures and an estimated 6600 women will die from endometrial cancer Preinvasive and well-differentiated endometrial cancers are hormonally driven and often cured with surgery alone Higher-grade tumors are usually not hormonally driven and proliferate via unknown mechanisms These tumors are largely responsible for the rising death rate Responses to toxic treatment protocols for recurrent endometrial cancer are dismal Unfortunately these post-menopausal women also often have comorbidities which limit their eligibility for current chemotherapy and radiotherapy treatments
Expression of COX-II has been identified in many human cancers including colon cancer gastric cancer esophogeal cancer bladder cancer head and neck cancer liver cancer pancreatic cancer prostate cancer and breast cancer COX-II expression is also strongly expressed in the primary tumor and metastasic site in human cervical cancer COX-II may influence cell cycle control by upregulating the proliferative capacity of neoplastic endometrial cells Furthermore COX-II inhibitors inhibit tumor proliferation even in cells that do not express COX This suggests an alternative mechanism of action not yet defined that may play a role in inhibiting the growth of cancer tissue
The enhanced expression of COX-II has led investigators to use COX-II inhibitors in the prevention andor treatment of colon and prostate cancers both in vivo and in vitro Celecoxib is now FDA approved for chemoprevention of colon cancer in familial adenomatous polyposis patients If it can be shown that COX-II is downregulated by COX-II inhibitors in endometrial cancer they may offer similar chemopreventative or chemotherapeutic potentials that have already been proven in colon cancer
COX-II enzyme activity may not always correlate with end organ gene expression Multiple genes have been implicated in apoptotic pathways and are affected by COX-II inhibitors NS-398 a selective COX-II inhibitor causes elevations in APC expression and downregulation of c-myc Prostate apoptosis response 4 Par-4 levels are increased in cells treated with COX inhibitors PTEN and hMLH1 are genes which are implicated in malignant transformation of endometrial tissue 5-Lipooxygenase 5-LOX is often correlated with COX-I and COX-II Thus in addition to COX-I and COX-II these are good candidate genes to study the effects of COX-II inhibitors on uterine cancers
Preliminary Data Since COX-II expression is seen in the endometrium and in other hormonally-dependent tumors we have investigated the expression of COX-II in endometrial cancer Our preliminary studies on 41 fixed samples of benign and neoplastic endometrium revealed that COX-II was not expressed in benign endometrial tissue stains minimally 1 of tumor cells in well-differentiated endometrial carcinomas and stains most strongly in poorly-differentiated carcinomas 12 of tumor cells most staining strongly COX-II is expressed in all poorly differentiated uterine cancers Our study also demonstrated that COX-II was also strongly expressed in uterine papillary serous carcinomas UPSC as well as clear cell carcinomas of the uterus These findings were confirmed by Ferrandina et al A small percent of our patients as well as the patients in the Ferrandina study have only 1 or 1-5 staining These low-expressers only made up 113 77 of our patients
COX-II expression in endometrial carcinoma has a slight inverse correlation with apoptosis r-0534 However COX-II expression in endometrial carcinoma correlated with lymphovascular invasion r069 and depth of invasion r068 There was no correlation between COX-II expression and ER r003 or PR r-002 The presence of a poorly-differentiated tumor may imply a hormonally-independent pathway resulting in de-differentiation In summary our preliminary data reveals that COX-II expression is high in grade 2 and 3 endometrioid-type endometrial cancers as well as UPSC and clear cell subtypes and is correlated with known clinical prognostic factors
Expression of COX-II has been identified in many types of human cancers Uterine cancer is the most common gynecologic cancer in the US and there has been an increase in uterine cancer deaths over the past decade mainly due to the difficulty in treating recurrences in the more aggressive histologic types The study co-investigators have also identified COX-II expression in grade 2 and 3 endometrioid-type clear cell and papillary serous types of uterine cancers Upregulation of COX-II may control the cell cycle by regulating the proliferative capacity of neoplastic endometrial cells This is a Phase II pre-post intervention comparison study in eligible patients looking at the effects of a COX-II inhibitor on uterine cancer The patients whose endometrial biopsy shows grade 2 or 3 endometrioid-type clear cell and papillary serous types of uterine cancers will be put on a selective COX-II inhibitor Celebrex Celecoxib until the day of their surgery The expression of COX-II and p21 will be quantified after treatment with Celecoxib in eligible patients This expression will be evaluated by performing immunohistochemical staining on the endometrial biopsy pre-intervention and the hysterectomy specimen post-intervention Apoptosis evaluated by the terminal deoxynucleotidyl transferase TdT-mediated dUTP- digoxigenin nick end-labeling TUNEL assay will also be evaluated and compared to COX-II expression in endometrial cancer in the two specimens endometrial biopsy pre-intervention and uterus post-intervention In addition to IHC analysis and apoptosis gene expression of COX-related genes in the post-intervention uterine specimens will This gene expression will be compared to matched controls who were not treated with a COX-II inhibitor COX-II expression will be correlated with established clinical prognostic factors including lymphovascular invasion depth of myometrial invasion and lymph node involvement We hypothesize that Celecoxib will downregulate the expression of COX-II in these tumor types as it does in other similar tumors We also hypothesize that apoptosis as measured with the TUNEL assay will be increased in areas with less COX-II expression and should be inversely proportional to cellular p21 expression Additionally COX-II inhibitors affect apoptotic pathways even in cells that do not express COX-II For low expressing cells COX-II inhibitor activity may be better documented with apoptosis We hypothesize COX-related gene expression will be altered thus suggesting an up- or down-regulation of these genes in the end-organ tissue Documenting downregulation of COX-II enzyme and altered gene expression in endometrial carcinoma after treatment with Celecoxib may result in further prospective studies using selective COX-II inhibitors as effective well-tolerated chemotherapeutic agents in these uterine cancers that are resistant to many current therapies
Expression of COX-II has been identified in many human cancers including colon cancer gastric cancer esophogeal cancer bladder cancer head and neck cancer liver cancer pancreatic cancer prostate cancer and breast cancer COX-II expression is also strongly expressed in the primary tumor and metastasic site in human cervical cancer COX-II may influence cell cycle control by upregulating the proliferative capacity of neoplastic endometrial cells Furthermore COX-II inhibitors inhibit tumor proliferation even in cells that do not express COX This suggests an alternative mechanism of action not yet defined that may play a role in inhibiting the growth of cancer tissue
The enhanced expression of COX-II has led investigators to use COX-II inhibitors in the prevention andor treatment of colon and prostate cancers both in vivo and in vitro Celecoxib is now FDA approved for chemoprevention of colon cancer in familial adenomatous polyposis patients If it can be shown that COX-II is downregulated by COX-II inhibitors in endometrial cancer they may offer similar chemopreventative or chemotherapeutic potentials that have already been proven in colon cancer
COX-II enzyme activity may not always correlate with end organ gene expression Multiple genes have been implicated in apoptotic pathways and are affected by COX-II inhibitors NS-398 a selective COX-II inhibitor causes elevations in APC expression and downregulation of c-myc Prostate apoptosis response 4 Par-4 levels are increased in cells treated with COX inhibitors PTEN and hMLH1 are genes which are implicated in malignant transformation of endometrial tissue 5-Lipooxygenase 5-LOX is often correlated with COX-I and COX-II Thus in addition to COX-I and COX-II these are good candidate genes to study the effects of COX-II inhibitors on uterine cancers
Preliminary Data Since COX-II expression is seen in the endometrium and in other hormonally-dependent tumors we have investigated the expression of COX-II in endometrial cancer Our preliminary studies on 41 fixed samples of benign and neoplastic endometrium revealed that COX-II was not expressed in benign endometrial tissue stains minimally 1 of tumor cells in well-differentiated endometrial carcinomas and stains most strongly in poorly-differentiated carcinomas 12 of tumor cells most staining strongly COX-II is expressed in all poorly differentiated uterine cancers Our study also demonstrated that COX-II was also strongly expressed in uterine papillary serous carcinomas UPSC as well as clear cell carcinomas of the uterus These findings were confirmed by Ferrandina et al A small percent of our patients as well as the patients in the Ferrandina study have only 1 or 1-5 staining These low-expressers only made up 113 77 of our patients
COX-II expression in endometrial carcinoma has a slight inverse correlation with apoptosis r-0534 However COX-II expression in endometrial carcinoma correlated with lymphovascular invasion r069 and depth of invasion r068 There was no correlation between COX-II expression and ER r003 or PR r-002 The presence of a poorly-differentiated tumor may imply a hormonally-independent pathway resulting in de-differentiation In summary our preliminary data reveals that COX-II expression is high in grade 2 and 3 endometrioid-type endometrial cancers as well as UPSC and clear cell subtypes and is correlated with known clinical prognostic factors
Expression of COX-II has been identified in many types of human cancers Uterine cancer is the most common gynecologic cancer in the US and there has been an increase in uterine cancer deaths over the past decade mainly due to the difficulty in treating recurrences in the more aggressive histologic types The study co-investigators have also identified COX-II expression in grade 2 and 3 endometrioid-type clear cell and papillary serous types of uterine cancers Upregulation of COX-II may control the cell cycle by regulating the proliferative capacity of neoplastic endometrial cells This is a Phase II pre-post intervention comparison study in eligible patients looking at the effects of a COX-II inhibitor on uterine cancer The patients whose endometrial biopsy shows grade 2 or 3 endometrioid-type clear cell and papillary serous types of uterine cancers will be put on a selective COX-II inhibitor Celebrex Celecoxib until the day of their surgery The expression of COX-II and p21 will be quantified after treatment with Celecoxib in eligible patients This expression will be evaluated by performing immunohistochemical staining on the endometrial biopsy pre-intervention and the hysterectomy specimen post-intervention Apoptosis evaluated by the terminal deoxynucleotidyl transferase TdT-mediated dUTP- digoxigenin nick end-labeling TUNEL assay will also be evaluated and compared to COX-II expression in endometrial cancer in the two specimens endometrial biopsy pre-intervention and uterus post-intervention In addition to IHC analysis and apoptosis gene expression of COX-related genes in the post-intervention uterine specimens will This gene expression will be compared to matched controls who were not treated with a COX-II inhibitor COX-II expression will be correlated with established clinical prognostic factors including lymphovascular invasion depth of myometrial invasion and lymph node involvement We hypothesize that Celecoxib will downregulate the expression of COX-II in these tumor types as it does in other similar tumors We also hypothesize that apoptosis as measured with the TUNEL assay will be increased in areas with less COX-II expression and should be inversely proportional to cellular p21 expression Additionally COX-II inhibitors affect apoptotic pathways even in cells that do not express COX-II For low expressing cells COX-II inhibitor activity may be better documented with apoptosis We hypothesize COX-related gene expression will be altered thus suggesting an up- or down-regulation of these genes in the end-organ tissue Documenting downregulation of COX-II enzyme and altered gene expression in endometrial carcinoma after treatment with Celecoxib may result in further prospective studies using selective COX-II inhibitors as effective well-tolerated chemotherapeutic agents in these uterine cancers that are resistant to many current therapies
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