Ignite Creation Date:
2024-05-05 @ 11:47 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00130936
Status:
TERMINATED
Last Update Posted:
2016-02-15
First Post:
2005-08-15
Brief Title:
Study of Epirubicin Pharmorubicin Carboplatin Paraplatin and Capecitabine Xeloda ECC in the Treatment of Unresectable Locally Advanced or Metastatic GastricGastroesophageal Junction Cancer With Pharmacogenetic Correlates
Sponsor:
AHS Cancer Control Alberta
Organization:
AHS Cancer Control Alberta
Study Overview
Official Title:
Combined Phase III Study of Epirubicin Pharmorubicin Carboplatin Paraplatin and Capecitabine Xeloda ECC in the Treatment of Unresectable Locally Advanced or Metastatic GastricGastroesophageal Junction Cancer With Pharmacogenetic Correlates
Status:
TERMINATED
Status Verified Date:
2009-09
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:
Although declining in incidence gastricgastroesophageal cancer is still a commonly diagnosed malignancy in Canada Patients who have undergone surgical resection for early disease have a high rate of local recurrence and distant spread More than 50 of patients present with either locally advanced or metastatic disease Patients with advanced disease have an extremely poor prognosis with average survival times ranging from 3 - 9 months Development of new therapeutic approaches for locally advanced or metastatic gastricgastroesophageal cancer is clearly needed
Despite its proven efficacy ECF epirubicin cisplatin and infusional 5-fluorouracil 5-FU has not been widely adopted in North America and is likely due to the technical difficulties and inconvenience associated with infusional chemotherapy This study will substitute the oral chemotherapy drug capecitabine for infusional 5-FU in addition to substituting intravenous cisplatin with carboplatin ECC - epirubicin carboplatin and capecitabine It is hoped that these substitutions will not only reduce the typical ECF related adverse effects but also allow for a more convenient administration of outpatient chemotherapy It is also hoped that the genetic correlates of this study may also identify specific populations that preferentially benefit from ECC treatment
Despite its proven efficacy ECF epirubicin cisplatin and infusional 5-fluorouracil 5-FU has not been widely adopted in North America and is likely due to the technical difficulties and inconvenience associated with infusional chemotherapy This study will substitute the oral chemotherapy drug capecitabine for infusional 5-FU in addition to substituting intravenous cisplatin with carboplatin ECC - epirubicin carboplatin and capecitabine It is hoped that these substitutions will not only reduce the typical ECF related adverse effects but also allow for a more convenient administration of outpatient chemotherapy It is also hoped that the genetic correlates of this study may also identify specific populations that preferentially benefit from ECC treatment
Detailed Description:
Background Information
Capecitabine is an orally administered systemic prodrug of 5-deoxy-5-fluorouridine which is converted to 5-fluorouracil Capecitabine is readily absorbed from the gastrointestinal tract and then hydrolyzed in the liver Capecitabine has been studied in the treatment of gastricgastroesophageal cancer in addition to a wide variety of other malignancies eg GI breast
Objectives
Phase I
Primary Objective
To define the maximum tolerated dose MTD of capecitabine with combined fixed doses of epirubicin and carboplatin in patients with advanced solid cancers With the identification of the MTD determination of the recommended phase II dose will be made and used to further evaluate the specific anti-tumor activity of ECC in unresectable locally advanced andor metastatic gastricgastroesophageal cancer
Secondary Objectives
To describe the safety toxicity profile principle and dose-limiting toxicities DLT of ECC when given on this schedule and
To determine the pharmacokinetic behavior of capecitabine when given in combination with epirubicin and carboplatin as part of the ECC regimen
Phase II
Primary Objective
To determine the anti-tumor activity of ECC when given at the RPTD in patients who have unresectable locally advanced andor metastatic gastricgastroesophageal cancer who have not received prior palliative chemotherapy
Secondary Objectives
To further characterize the toxicity profile of the ECC regimen
To determine time to progression duration of response and overall survival of patients on this study
To determine the effects of thymidylate synthase TS polymorphisms on both toxicities and efficacy of ECC in prospectively genotyped patients
To prospectively evaluate other potential pharmacogenetic correlates which may also play a role in augmenting toxicity including MTHFR and
To assess effects of uridine glucuronosyltransferase 2B7 UGT 2B7 polymorphisms on epirubicin metabolism
Study Design
This is a Phase III trial that will study the safety as well as the efficacy of the ECC combination chemotherapy regimen
Epirubicin will be administered as an IV push at a fixed dose of 50mgm2 on day 1 - repeated every 21 days
Carboplatin will be administered IV at a fixed dose with an AUC of 5 over a 1-hour infusion in 500ml of 5 dextrose on day 1 - repeated every 21 days
Capecitabine will be administered as a twice daily oral medication variable dose for phase I portion of the trial but fixed dose for phase II portion of the trial for 14 consecutive days days 1-14 - repeated every 21 days
For the phase I portion of the study cohorts of 3 patients will be treated at each of 3 pre-determined dose levels of capecitabine and monitored for toxicity
Dose level 1 750 mgm2 bid
Dose level 2 850 mgm2 bid
Dose level 3 1000 mgm2 bid
Dose level 4 25 dose escalation rounded to the nearest twice a day dosing
Statistical Analysis
Phase I
Summary statistics such as frequency and intensity of toxicity occurring at each dose level will be provided The percentage of patients developing DLT at each dose level will be computed The dose-toxicity curve can be estimated accordingly using either parametric or non-parametric methods
Phase II A Simons optimal two-stage phase II study will be conducted in patients with unresectable locally advanced or metastatic gastric or gastro-esophageal cancer at the RPTD of the ECC regimen A total sample size of 43 patients will be required 13 in the first stage and 30 in the second stage if criteria for second stage accrual are met If 313 patients respond this is deemed to correspond with the initial rejection limit and no further patients will be enrolled If 413 patients respond an additional 30 patients will be enrolled in the second stage total sample size 43 Further statistical details are specifically outlined in Section 8 of the protocol The response rate standard error and its 95 confidence intervals CI will be calculated under the binomial distribution model The efficacy of the regimen will then be evaluated by comparing the point estimates and 95 CI with historical data Potential covariates for response will also be identified and evaluated via the logistic regression model Kaplan-Meier estimates will be computed to estimate the secondary endpoints such as time to progression and survival Cox-regression model can be applied incorporating covariates in the model Fishers exact test will be applied to compare the response rates between the different genetic TS polymorphisms groupings
Stopping Rules
Treatment will be discontinued and the patient will come off the trial therapy due to severe intercurrent illness disease progression unacceptable toxicity patient request to stop andor if the physician deems it in the best interest of patient to discontinue
InclusionExclusion Criteria
Patient Population
Phase I - Histologically or cytologically confirmed solid tumor refractory to conventional cytotoxic anticancer therapy or for which there are no standard therapies with a reasonable therapeutic index
Phase II - Inoperableunresectable locally advanced andor metastatic histologically or cytologically confirmed adenocarcinoma or undifferentiated carcinoma of the stomach or gastro-esophageal junction presenting for first line palliative systemic treatment Prior adjuvant chemoradiotherapy for gastric or gastroesophageal junction adenocarcinoma is allowed as long as the patient has completed adjuvant therapy 6 months prior to study entry Patients need to have at least one site of measurable disease as defined by RECIST criteria
Inclusion
In general to participate in the study patients must be 18 years or older have an expected life expectancy of 12 weeks WHO performance status 0-2 LVEF by MUGA 50 adequate organ function hematological ANC 15X 109L platelets 100 x 109L hepatic bilirubin 15 x ULN ASTALT 3 x ULN renal calculated creatinine clearance 60 mlmin Negative pregnancy test for females with child-bearing potential Prior radiotherapy allowed but must be delivered to 25 of bone marrow must be completed 4 weeks before study entry and patients must have recovered from all side effects of the radiotherapy Radiation must not be delivered to the sole response indicator lesion unless there is documented evidence of disease progression in that site after completion of radiation Patients must be able to reliably tolerate and comply with oralfeeding tube administered medications patients are considered eligible if the investigator deems that there is no malabsorption syndrome and no GI obstruction that would impair the delivery of orally administered chemotherapy If patient has had prior anthracycline cumulative dose must be 300mgm2 of doxorubicin or its equivalent
Exclusion
Patients currently enrolled in another clinical trial involving active cancer treatment Treatment with doxorubicin 300mgm2 or its equivalent Serious medical conditions including myocardial infarction within 6 months prior to entry unstable angina active cardiomyopathy unstable ventricular arrhythmia congestive heart failure uncontrolled hypertension uncontrolled psychotic disorders serious active infections uncontrolled diabetes or any other medical condition that might be aggravated by study treatment Pre-existing neuropathy grade 1 history of seizures or patients receiving anti-epileptic prophylaxis active and or progressive brain or leptomeningeal metastasis pregnant or lactating women patients with evidence or recent history of drug or alcohol abuse prior treatment with capecitabine or infusional 5-FU known hypersensitivity to carboplatin 5-FU anthracyclines or known DPD deficiency Patients that lack physical integrity of the GI tract leading to intestinal obstruction Patients taking warfarin Coumadin or other coumarin derivatives Presence of any mentally incapacitating psychological condition
Recruitment
The expected total number of patients to be enrolled phase I and II is 65
Capecitabine is an orally administered systemic prodrug of 5-deoxy-5-fluorouridine which is converted to 5-fluorouracil Capecitabine is readily absorbed from the gastrointestinal tract and then hydrolyzed in the liver Capecitabine has been studied in the treatment of gastricgastroesophageal cancer in addition to a wide variety of other malignancies eg GI breast
Objectives
Phase I
Primary Objective
To define the maximum tolerated dose MTD of capecitabine with combined fixed doses of epirubicin and carboplatin in patients with advanced solid cancers With the identification of the MTD determination of the recommended phase II dose will be made and used to further evaluate the specific anti-tumor activity of ECC in unresectable locally advanced andor metastatic gastricgastroesophageal cancer
Secondary Objectives
To describe the safety toxicity profile principle and dose-limiting toxicities DLT of ECC when given on this schedule and
To determine the pharmacokinetic behavior of capecitabine when given in combination with epirubicin and carboplatin as part of the ECC regimen
Phase II
Primary Objective
To determine the anti-tumor activity of ECC when given at the RPTD in patients who have unresectable locally advanced andor metastatic gastricgastroesophageal cancer who have not received prior palliative chemotherapy
Secondary Objectives
To further characterize the toxicity profile of the ECC regimen
To determine time to progression duration of response and overall survival of patients on this study
To determine the effects of thymidylate synthase TS polymorphisms on both toxicities and efficacy of ECC in prospectively genotyped patients
To prospectively evaluate other potential pharmacogenetic correlates which may also play a role in augmenting toxicity including MTHFR and
To assess effects of uridine glucuronosyltransferase 2B7 UGT 2B7 polymorphisms on epirubicin metabolism
Study Design
This is a Phase III trial that will study the safety as well as the efficacy of the ECC combination chemotherapy regimen
Epirubicin will be administered as an IV push at a fixed dose of 50mgm2 on day 1 - repeated every 21 days
Carboplatin will be administered IV at a fixed dose with an AUC of 5 over a 1-hour infusion in 500ml of 5 dextrose on day 1 - repeated every 21 days
Capecitabine will be administered as a twice daily oral medication variable dose for phase I portion of the trial but fixed dose for phase II portion of the trial for 14 consecutive days days 1-14 - repeated every 21 days
For the phase I portion of the study cohorts of 3 patients will be treated at each of 3 pre-determined dose levels of capecitabine and monitored for toxicity
Dose level 1 750 mgm2 bid
Dose level 2 850 mgm2 bid
Dose level 3 1000 mgm2 bid
Dose level 4 25 dose escalation rounded to the nearest twice a day dosing
Statistical Analysis
Phase I
Summary statistics such as frequency and intensity of toxicity occurring at each dose level will be provided The percentage of patients developing DLT at each dose level will be computed The dose-toxicity curve can be estimated accordingly using either parametric or non-parametric methods
Phase II A Simons optimal two-stage phase II study will be conducted in patients with unresectable locally advanced or metastatic gastric or gastro-esophageal cancer at the RPTD of the ECC regimen A total sample size of 43 patients will be required 13 in the first stage and 30 in the second stage if criteria for second stage accrual are met If 313 patients respond this is deemed to correspond with the initial rejection limit and no further patients will be enrolled If 413 patients respond an additional 30 patients will be enrolled in the second stage total sample size 43 Further statistical details are specifically outlined in Section 8 of the protocol The response rate standard error and its 95 confidence intervals CI will be calculated under the binomial distribution model The efficacy of the regimen will then be evaluated by comparing the point estimates and 95 CI with historical data Potential covariates for response will also be identified and evaluated via the logistic regression model Kaplan-Meier estimates will be computed to estimate the secondary endpoints such as time to progression and survival Cox-regression model can be applied incorporating covariates in the model Fishers exact test will be applied to compare the response rates between the different genetic TS polymorphisms groupings
Stopping Rules
Treatment will be discontinued and the patient will come off the trial therapy due to severe intercurrent illness disease progression unacceptable toxicity patient request to stop andor if the physician deems it in the best interest of patient to discontinue
InclusionExclusion Criteria
Patient Population
Phase I - Histologically or cytologically confirmed solid tumor refractory to conventional cytotoxic anticancer therapy or for which there are no standard therapies with a reasonable therapeutic index
Phase II - Inoperableunresectable locally advanced andor metastatic histologically or cytologically confirmed adenocarcinoma or undifferentiated carcinoma of the stomach or gastro-esophageal junction presenting for first line palliative systemic treatment Prior adjuvant chemoradiotherapy for gastric or gastroesophageal junction adenocarcinoma is allowed as long as the patient has completed adjuvant therapy 6 months prior to study entry Patients need to have at least one site of measurable disease as defined by RECIST criteria
Inclusion
In general to participate in the study patients must be 18 years or older have an expected life expectancy of 12 weeks WHO performance status 0-2 LVEF by MUGA 50 adequate organ function hematological ANC 15X 109L platelets 100 x 109L hepatic bilirubin 15 x ULN ASTALT 3 x ULN renal calculated creatinine clearance 60 mlmin Negative pregnancy test for females with child-bearing potential Prior radiotherapy allowed but must be delivered to 25 of bone marrow must be completed 4 weeks before study entry and patients must have recovered from all side effects of the radiotherapy Radiation must not be delivered to the sole response indicator lesion unless there is documented evidence of disease progression in that site after completion of radiation Patients must be able to reliably tolerate and comply with oralfeeding tube administered medications patients are considered eligible if the investigator deems that there is no malabsorption syndrome and no GI obstruction that would impair the delivery of orally administered chemotherapy If patient has had prior anthracycline cumulative dose must be 300mgm2 of doxorubicin or its equivalent
Exclusion
Patients currently enrolled in another clinical trial involving active cancer treatment Treatment with doxorubicin 300mgm2 or its equivalent Serious medical conditions including myocardial infarction within 6 months prior to entry unstable angina active cardiomyopathy unstable ventricular arrhythmia congestive heart failure uncontrolled hypertension uncontrolled psychotic disorders serious active infections uncontrolled diabetes or any other medical condition that might be aggravated by study treatment Pre-existing neuropathy grade 1 history of seizures or patients receiving anti-epileptic prophylaxis active and or progressive brain or leptomeningeal metastasis pregnant or lactating women patients with evidence or recent history of drug or alcohol abuse prior treatment with capecitabine or infusional 5-FU known hypersensitivity to carboplatin 5-FU anthracyclines or known DPD deficiency Patients that lack physical integrity of the GI tract leading to intestinal obstruction Patients taking warfarin Coumadin or other coumarin derivatives Presence of any mentally incapacitating psychological condition
Recruitment
The expected total number of patients to be enrolled phase I and II is 65
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