Ignite Creation Date:
2024-05-05 @ 11:47 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00131612
Status:
TERMINATED
Last Update Posted:
2016-02-26
First Post:
2005-08-17
Brief Title:
An Investigation of the Effect of the Promoter Polymorphism in the Glucuronosyltransferase 2B7 in Patients on Breast Cancer Treatment
Sponsor:
AHS Cancer Control Alberta
Organization:
AHS Cancer Control Alberta
Study Overview
Official Title:
An Investigation of the Effect of the Promoter Polymorphism in the Glucuronosyltransferase 2B7 Using Epirubicin Clearance and the Ratios of Epirubicin and Epirubicinol Glucuronide to Epirubicin
Status:
TERMINATED
Status Verified Date:
2012-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
did not apply for ethics renewal
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
For many years scientists and cancer researchers have been trying to find out why some people benefit more from anti-cancer medications than other people who receive the same amount and same kind of medications Current studies suggest that inherited characteristics might explain these differences Height and eye color are examples of characteristics that have been inherited from parents Studies suggest that people might also inherit genetic differences in how their bodies break down medications When a person receives an anti-cancer medication it is broken down by the liver into smaller parts or by-products To try to understand more about how peoples bodies break down anti-cancer medications the researchers are studying the by-products called metabolites of epirubicin in the blood of people who are taking this medication as part of their breast cancer treatment
Detailed Description:
Epirubicin is an anthracycline that is widely used in breast cancer stomach and esophageal cancer Despite epirubicin being the 4-epi-isomer of doxorubicin epirubicin undergoes substantially different metabolism compared to doxorubicin The majority of epirubicin is metabolized to glucuronides 780 to epirubicin glucuronide and 193 to epirubicinol glucuronide and only 02 epirubicin is metabolized to epirubicinol Doxorubicin is primarily metabolized to aglycones or doxorubicinol but not to glucuronides There is substantial variability in epirubicin metabolism with the mean clearance of 846 Lh and a standard deviation of 635 A study by Hu et al showed epirubicin metabolism correlated with response In this study they showed patients with nasopharyngeal cancer treated with epirubicin were more likely to relapse if they rapidly metabolized epirubicin A study by Robert et al raises the possibility that the differences in epirubicin metabolism are determined by genetic differences They showed a bimodal distribution in the ratio of epirubicin glucuronides to epirubicin As well this study showed that low glucuronidation were more likely to respond to epirubicin than patients who had a high ratio of epirubicin glucuronides to epirubicin Innocenti et al has shown that epirubicin is metabolized to its glucuronides by uridine glucuronosyltransferase 2B7 UGT2B7 The same study showed a strong correlation between the formation of morphine-6-glucuronide and the glucuronidation of epirubicin in human liver microsomes The researchers have recently discovered a single nucleotide polymorphism in the enhancer region of UGT 2B7 Patients who were homozygous for this polymorphism tended to have lower ratios of morphine-6-glucuronide to morphine The researchers suspect that this T to C polymorphism decreases the transcription of UGT 2B7 and this is the basis of the decreased glucuronidation Given the strong correlation between the metabolism of morphine and epirubicin in human liver microsomes the researchers suspect that this polymorphism may be responsible for the variability in epirubicin metabolism Previous work has documented an overlapping bimodal distribution in the ratio of epirubicin glucuronides but they did not examine whether genetic polymorphisms were responsible for this This study will examine the effect of this polymorphism on the metabolism of epirubicin If a relationship exists between this polymorphism and epirubicin metabolism this may allow more accurate dosing of this important chemotherapeutic agent
Objectives
To determine in patients receiving adjuvant intravenous FEC chemotherapy 5-Fluoruracil 500 mgm2 epirubicin 100 mgm2 Cyclophosphamide 500 mgm2 given every 3 weeks whether the newly discovered SNP at position -161 T to C is responsible for the variability in epirubicin metabolism
Participants
Patients receiving adjuvant FEC chemotherapy Patients can not have pre-existing liver disease other than Gilberts syndrome In patients with a history of liver disease liver transaminases must be less than 3 times the upper limit of normal and bilirubin less than the upper limit of normal Patients must be 18 years of age
Eligible patients will be enrolled into the study after written informed consent is obtained Baseline characteristics including age weight renal function liver function concurrent medications and ethnic origin will be obtained from the medical chart or patient The patient chart will be reviewed periodically for hematological and nonhematological toxicity Outcome data such as recurrence and time of recurrence will be obtained from the chart
Sample Size
Medical oncologists consider a significant difference in drug clearance to be 15 Epirubicins clearance is 846 Lh with a standard deviation of 635 The researchers have calculated a sample size to have an 80 power to detect a 15 difference Assuming epirubicins average clearance is comprised of three separate groups which is the hypothesis the researchers would need 29 patients from each genotype to show a 15 difference between the mean clearance of different genotypes assuming a coefficient of variation of 20 The known polymorphism at amino acid residue 268 has an allele frequency of 50 This allele was in complete linkage disequilibrium with the new SNP at position -160 in the previous study of morphine Therefore the researchers would need approximately 120 patients to produce 30 TT 60 TC and 30 CC
Objectives
To determine in patients receiving adjuvant intravenous FEC chemotherapy 5-Fluoruracil 500 mgm2 epirubicin 100 mgm2 Cyclophosphamide 500 mgm2 given every 3 weeks whether the newly discovered SNP at position -161 T to C is responsible for the variability in epirubicin metabolism
Participants
Patients receiving adjuvant FEC chemotherapy Patients can not have pre-existing liver disease other than Gilberts syndrome In patients with a history of liver disease liver transaminases must be less than 3 times the upper limit of normal and bilirubin less than the upper limit of normal Patients must be 18 years of age
Eligible patients will be enrolled into the study after written informed consent is obtained Baseline characteristics including age weight renal function liver function concurrent medications and ethnic origin will be obtained from the medical chart or patient The patient chart will be reviewed periodically for hematological and nonhematological toxicity Outcome data such as recurrence and time of recurrence will be obtained from the chart
Sample Size
Medical oncologists consider a significant difference in drug clearance to be 15 Epirubicins clearance is 846 Lh with a standard deviation of 635 The researchers have calculated a sample size to have an 80 power to detect a 15 difference Assuming epirubicins average clearance is comprised of three separate groups which is the hypothesis the researchers would need 29 patients from each genotype to show a 15 difference between the mean clearance of different genotypes assuming a coefficient of variation of 20 The known polymorphism at amino acid residue 268 has an allele frequency of 50 This allele was in complete linkage disequilibrium with the new SNP at position -160 in the previous study of morphine Therefore the researchers would need approximately 120 patients to produce 30 TT 60 TC and 30 CC
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