Ignite Creation Date:
2024-05-05 @ 11:41 AM
Last Modification Date:
2024-10-26 @ 9:11 AM
Study NCT ID:
NCT00102622
Status:
TERMINATED
Last Update Posted:
2018-11-13
First Post:
2005-01-31
Brief Title:
Intraperitoneal tgDCC-E1 and Intravenous Paclitaxel in Women With Platinum-Resistant Ovarian Cancer
Sponsor:
MD Anderson Cancer Center
Organization:
MD Anderson Cancer Center
Study Overview
Official Title:
Phase I of Phase III Randomized Study of Intraperitoneal tgDCC-E1 and Intravenous Paclitaxel in Women With Platinum-Resistant Ovarian Cancer
Status:
TERMINATED
Status Verified Date:
2018-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Phase III study that did not progress to Phase II
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The goal of this clinical research study is to find the highest safe dose of intraperitoneal tgDCC-E1A that can be given in combination with paclitaxel as a treatment for patients with recurrent platinum-resistant ovarian cancer How the cancer responds to this treatment will also be studied Researchers will also ask the patients if they will allow additional tumor samples to be collected and extra blood samples to be drawn These samples will be used to learn about the biological response before and after treatment
Detailed Description:
Primary Objective
To evaluate toxicity and establish the maximum tolerated dose MTD of intraperitoneal tgDCC-E1A in combination with intravenous paclitaxel
To measure tumor response of intraperitoneal tgDCC-E1A in combination with intravenous paclitaxel and compare to intravenous paclitaxel
Secondary Objective
To measure time to progression and overall survival
To examine the biological effects of combined tgDCC- E1A and paclitaxel in ovarian cancer cells as measured by laboratory testing
Epithelial ovarian cancer is a significant public health problem It is the sixth most common cancer in women worldwide Globally it is estimated that 162000 new cases are diagnosed per year and that 106000 women die from the disease per year
Signs and symptoms of ovarian cancer are often subtle Seventy-five percent of subjects will present with advanced stage III and IV disease Standard treatment for stage IIIIV subjects consists of surgical debulking to the maximal extent possible and chemotherapy with paclitaxel plus a platinum compound cisplatin or carboplatin Despite high initial response rates the overall survival for this group is poor with only 20 of stage III and less than 5 of stage IV subjects surviving five years
Treatment of recurrent ovarian cancer varies depending upon the interval between prior treatment and recurrence Twenty percent of subjects are classified as platinum-refractory in that they fail to have even a partial response to a platinum-containing regimen Subjects with recurrent or progressive disease less than six months after initial therapy have a poor response rate to repeat treatment with a platinum-containing regimen and are generally considered to have platinum-resistant disease In contrast subjects with recurrent disease greater than six months after initial therapy have better response rates to repeat treatment with platinum-containing regimens and are generally considered to have platinum-sensitive disease
There is no consensus for the treatment of platinum-refractory or platinum-resistant ovarian cancer a class of individuals who are particularly challenging to treat Prognosis is poor and treatment is primarily palliative in nature Responses to a variety of single chemotherapeutic agents as well as to a combination of agents in largely phase II trials have been similar ranging from 10-35 Intravenous IV paclitaxel given alone or in combination with other agents is a standard treatment for subjects who have relapsed In an attempt to increase the dose intensity of paclitaxel therapy weekly IV paclitaxel has been recommended This treatment schedule is well tolerated but the response rate in heavily pretreated subjects is still only 289
Given that this group of subjects is poorly responsive to conventional chemotherapy and consequently has limited options an alternative approach to treatment is warranted The use of a gene therapy agent with anti-tumor effects and the ability to sensitize cancer cells to traditional chemotherapy is appealing
Overview of the Effect of E1A Gene Transfer on Cancer Cells
E1A a gene derived from Adenovirus type 5 has been shown to have potent anti-neoplastic activity through a variety of mechanisms including down-regulation of HER-2neu overexpression induction of apoptosis inhibition of metastasis and reversion of tumor cells toward a differentiated epithelial phenotype The E1A gene has also been shown to have an additive effect in vitro and in vivo on the apoptosis induced by chemotherapy and radiotherapy The E1A gene has been successfully transfected into human cells both in vitro and in vivo using tgDCC-E1A E1A-Lipid Complex which consists of the E1A plasmid pE1A-K2 complexed to the cationic lipid gene delivery system comprised of DC-Cholesterol 3bN-NN-dimethylaminoethane-carbamoyl cholesterol hydrochloride and DOPE 12-dioleoyl-sn-glycero-3-phosphoethanolamine
Rationale for Use of Cationic Lipids to Deliver DNA
Cationic lipids can form complexes with negatively charged DNA plasmids and facilitate the transfer of genes to target cells They are useful agents for delivery of gene therapy because they are synthesized chemically are simple to manufacture and pose no infectious risk The cationic derivative of cholesterol 3bN-NN-dimethylaminoethane-carbamoyl cholesterol hydrochloride DC-Chol is an ideal cationic lipid for therapeutic use as the cationic charge is provided by a non-toxic tertiary amine with a biodegradable carbamoyl bond DC-Chol can be used to prepare liposomes in combination with the neutral 12-dioleoyl-sn-glycero-3-phosphoethanolamine DOPE with a DC-Chol to DOPE ratio of 64 This liposome combination can be mixed with a plasmid encoding E1A to form tgDCC-E1A
The final preparation of tgDCC-E1A can be made within a range of lipidDNA ratios all of which have been shown in cell culture and in animal models to result in expression of E1A Clinical trials of tgDCC-E1A for injection into solid tumors have used a final preparation with a lipidDNA ratio of 1 nmol lipid to 1 microgram DNA tgDCC-E1A 11 Early clinical trials evaluating intracavitary administration eg intraperitoneal infusion for ovarian cancer used a preparation with a lipidDNA ratio of 10 nmol lipid to 1 microgram DNA tgDCC-E1A 101 More recent protocols of intraperitoneal delivery for ovarian cancer have used a preparation with a lipidDNA ratio of 3 nmol lipid to 1 microgram DNA tgDCC-E1A 31 as will this protocol
Rationale for Intraperitoneal Delivery of tgDCC-E1A
The peritoneal cavity is a common site of tumor recurrence after initial radical surgical treatment of ovarian malignancies Dissemination in this cavity is often widespread Because of the unusual natural course of ovarian cancer characterized by its tendency to be confined to the peritoneal cavity control of metastatic disease in the peritoneal cavity is an important and challenging problem which can be improved by direct delivery of drug into the peritoneal cavity
To evaluate toxicity and establish the maximum tolerated dose MTD of intraperitoneal tgDCC-E1A in combination with intravenous paclitaxel
To measure tumor response of intraperitoneal tgDCC-E1A in combination with intravenous paclitaxel and compare to intravenous paclitaxel
Secondary Objective
To measure time to progression and overall survival
To examine the biological effects of combined tgDCC- E1A and paclitaxel in ovarian cancer cells as measured by laboratory testing
Epithelial ovarian cancer is a significant public health problem It is the sixth most common cancer in women worldwide Globally it is estimated that 162000 new cases are diagnosed per year and that 106000 women die from the disease per year
Signs and symptoms of ovarian cancer are often subtle Seventy-five percent of subjects will present with advanced stage III and IV disease Standard treatment for stage IIIIV subjects consists of surgical debulking to the maximal extent possible and chemotherapy with paclitaxel plus a platinum compound cisplatin or carboplatin Despite high initial response rates the overall survival for this group is poor with only 20 of stage III and less than 5 of stage IV subjects surviving five years
Treatment of recurrent ovarian cancer varies depending upon the interval between prior treatment and recurrence Twenty percent of subjects are classified as platinum-refractory in that they fail to have even a partial response to a platinum-containing regimen Subjects with recurrent or progressive disease less than six months after initial therapy have a poor response rate to repeat treatment with a platinum-containing regimen and are generally considered to have platinum-resistant disease In contrast subjects with recurrent disease greater than six months after initial therapy have better response rates to repeat treatment with platinum-containing regimens and are generally considered to have platinum-sensitive disease
There is no consensus for the treatment of platinum-refractory or platinum-resistant ovarian cancer a class of individuals who are particularly challenging to treat Prognosis is poor and treatment is primarily palliative in nature Responses to a variety of single chemotherapeutic agents as well as to a combination of agents in largely phase II trials have been similar ranging from 10-35 Intravenous IV paclitaxel given alone or in combination with other agents is a standard treatment for subjects who have relapsed In an attempt to increase the dose intensity of paclitaxel therapy weekly IV paclitaxel has been recommended This treatment schedule is well tolerated but the response rate in heavily pretreated subjects is still only 289
Given that this group of subjects is poorly responsive to conventional chemotherapy and consequently has limited options an alternative approach to treatment is warranted The use of a gene therapy agent with anti-tumor effects and the ability to sensitize cancer cells to traditional chemotherapy is appealing
Overview of the Effect of E1A Gene Transfer on Cancer Cells
E1A a gene derived from Adenovirus type 5 has been shown to have potent anti-neoplastic activity through a variety of mechanisms including down-regulation of HER-2neu overexpression induction of apoptosis inhibition of metastasis and reversion of tumor cells toward a differentiated epithelial phenotype The E1A gene has also been shown to have an additive effect in vitro and in vivo on the apoptosis induced by chemotherapy and radiotherapy The E1A gene has been successfully transfected into human cells both in vitro and in vivo using tgDCC-E1A E1A-Lipid Complex which consists of the E1A plasmid pE1A-K2 complexed to the cationic lipid gene delivery system comprised of DC-Cholesterol 3bN-NN-dimethylaminoethane-carbamoyl cholesterol hydrochloride and DOPE 12-dioleoyl-sn-glycero-3-phosphoethanolamine
Rationale for Use of Cationic Lipids to Deliver DNA
Cationic lipids can form complexes with negatively charged DNA plasmids and facilitate the transfer of genes to target cells They are useful agents for delivery of gene therapy because they are synthesized chemically are simple to manufacture and pose no infectious risk The cationic derivative of cholesterol 3bN-NN-dimethylaminoethane-carbamoyl cholesterol hydrochloride DC-Chol is an ideal cationic lipid for therapeutic use as the cationic charge is provided by a non-toxic tertiary amine with a biodegradable carbamoyl bond DC-Chol can be used to prepare liposomes in combination with the neutral 12-dioleoyl-sn-glycero-3-phosphoethanolamine DOPE with a DC-Chol to DOPE ratio of 64 This liposome combination can be mixed with a plasmid encoding E1A to form tgDCC-E1A
The final preparation of tgDCC-E1A can be made within a range of lipidDNA ratios all of which have been shown in cell culture and in animal models to result in expression of E1A Clinical trials of tgDCC-E1A for injection into solid tumors have used a final preparation with a lipidDNA ratio of 1 nmol lipid to 1 microgram DNA tgDCC-E1A 11 Early clinical trials evaluating intracavitary administration eg intraperitoneal infusion for ovarian cancer used a preparation with a lipidDNA ratio of 10 nmol lipid to 1 microgram DNA tgDCC-E1A 101 More recent protocols of intraperitoneal delivery for ovarian cancer have used a preparation with a lipidDNA ratio of 3 nmol lipid to 1 microgram DNA tgDCC-E1A 31 as will this protocol
Rationale for Intraperitoneal Delivery of tgDCC-E1A
The peritoneal cavity is a common site of tumor recurrence after initial radical surgical treatment of ovarian malignancies Dissemination in this cavity is often widespread Because of the unusual natural course of ovarian cancer characterized by its tendency to be confined to the peritoneal cavity control of metastatic disease in the peritoneal cavity is an important and challenging problem which can be improved by direct delivery of drug into the peritoneal cavity
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 |
|---|---|---|---|
| P50CA083639 | NIH | None | httpsreporternihgovquickSearchP50CA083639 |