Ignite Creation Date:
2024-05-05 @ 11:45 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00126867
Status:
TERMINATED
Last Update Posted:
2019-07-05
First Post:
2005-08-03
Brief Title:
Thymidylate Synthase Polymorphisms as a Predictor of Toxicity to Capecitabine Chemotherapy in Colon Cancer Treatment
Sponsor:
AHS Cancer Control Alberta
Organization:
AHS Cancer Control Alberta
Study Overview
Official Title:
Thymidylate Synthase Polymorphisms as a Predictor of Toxicity to Capecitabine Based Adjuvant Chemotherapy in Colon Cancer Treatment
Status:
TERMINATED
Status Verified Date:
2019-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Insufficient accrual and no funding
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Cancers of the colon and rectum are the third most common cancers in Canadian males and females The initial therapy of colorectal cancer is surgery to remove the cancer and nearby lymph glands If the cancer has spread to the lymph glands there is a high chance that the cancer will come back To reduce the risk of the cancer recurring patients are treated with an anticancer drug capecitabine This study will determine if a simple blood test can predict which patients are at risk for developing side effects from this chemotherapy In addition participants of this study will be followed to determine if this same blood test will predict which patients will have their cancer relapse
Detailed Description:
Hypothesis
Recently the thymidylate synthase genes promoter has been found to be polymorphic with variable numbers of tandem repeats of 28 base pairs in length These polymorphisms have been associated with tumor response to treatment with fluoropyrimidines The investigators hypothesize that polymorphisms in thymidylate synthase TS genes promoter region are associated with toxicity from capecitabine treatment specifically development of myelosuppression and diarrhea The investigators hypothesize that a polymorphism in methylene tetrahydrofolate reductase MTHFR is also associated with toxicity and efficacy of capecitabine treatment The investigators speculate that the MTHFR polymorphism only becomes clinically significant by stratifying patients by TS promoter polymorphisms
Objectives
1 To determine if polymorphisms in thymidylate synthases promoter region are associated with development of overall toxicity diarrhea neutropenia or mucositis in patients treated with capecitabine
2 To determine if a polymorphism in methylene tetrahydrofolate reductase MTHFR is associated with development of overall toxicity diarrhea neutropenia or mucositis in patients treated with capecitabine
Background and Significance
Capecitabine is a potent antimetabolite that is the currently accepted adjuvant treatment for colorectal cancer As well capecitabine is used to treat head and neck cancers breast cancer and gastric cancer In 1985 Takeishi et al demonstrated that thymidylate synthases gene had a satellite in the 5 untranslated region which consisted of 3 tandem repeats of a 28 base pair sequence Horie et al demonstrated that these satellites were polymorphic in length due to different numbers of tandem repeats with 2 length polymorphism existing 2 tandem repeats of 28 base pairs 2R and 3 tandem repeats of 28 base pairs 3R Subsequent authors have demonstrated 4 repeats 4R five repeats 5R and nine repeats 9R
Kawakami et al demonstrated that the number of tandem repeats affected TS gene translation They showed those patients homozygous for 3R alleles had higher TS protein levels and 2R3R heterozygotes Using in vitro expression of 2R and 3R genes they demonstrated that the increased protein levels were due to increased translational efficiency of the 3R RNA and not due to increased 3R mRNA expression These tandem repeats are predictive of response rates of various cancers to fluoropyrimidine cancer chemotherapy Park et al showed in metastatic colorectal cancer patients treated with capecitabine the response rate was 14 in patients homozygous for 3R repeats and 80 in the patients homozygous for 2R repeats No prospective study has examined if a patients TS genotype predicts for 5-FU toxicity
A polymorphism in methylene tetrahydrofolate reductases MTHFR gene may also determine a patients risk for capecitabine toxicity A polymorphism in MTHFR exists at position 677 C to T producing a thermolabile and rapidly degraded enzyme TT homozygotes have increased levels of methylene tetrahydrofolate Methylene tetrahydrofolate stabilizes binding of 5FU to thymidylate synthase and the complex of TS 5FU and methylene tetrahydrofolate is referred to as the ternary complex I hypothesize that increased stabilization of TS and 5FU due to increased amounts of methylene tetrahydrofolate would lead to increased capecitabine toxicity and efficacy No study has examined if TT homozygotes have an increased response rate to fluoropyrimidines or increased toxicity
Dihydropyrimidine dehydrogenase DPD deficiency has been identified as the cause of rare severe life threatening reactions to fluoropyrimidines The first case was reported by Tuchman et al in a 27 year old woman who had undergone adjuvant chemotherapy with cyclophosphamide methotrexate and 5-fluoruracil and developed severe neurological complications Diasio et al reported the second case again in a women being treated with 5-fluoruracil for breast cancer
A study by Etienne et al has raised questions regarding the utility of DPD activity alone to predict patients at risk for fluoropyrimidine toxicity They prospectively studied 185 patients treated with 5FU containing chemotherapy regimens They found a normal distribution of DPD activity with a mean value of 0222 nmolminmg protein They did not find any correlation between DPD activity and 5FU toxicity
The investigators propose to study the effect of these two polymorphic enzymes on capecitabines toxicity in adjuvant colon cancer patients It is anticipated that patients homozygous for 2R2R will have higher rates of overall toxicity diarrhea neutropenia and mucositis than 3R3R homozygotes For MTHFR we anticipate that TT homozygotes will have higher rates overall toxicity diarrhea neutropenia and mucositis than CC homozygotes The effect of MTHFR polymorphism on capecitabines toxicity will be examined controlling for thymidylate synthase genotype
Methods
Patients who have been advised to have adjuvant chemotherapy for colorectal cancer will be enrolled Patients will be treated with standard doses of capecitabine according to the X-ACT study Toxicities during cycle one will be graded according to National Cancer Institute Common Toxicity Criteria Version 30 Dose reductions during cycle one will be recorded
Investigations
Prior to starting treatments patients will provide a 10 ml sample of blood which will be used to obtain DNA from white bloods Patients will be genotyped according to TS and MTHFR genotypes Plasma will be banked to determined DPD phenotype
Sample Size Calculation
The allele frequency of 3R tandem repeats is 06 and 2R tandem repeats is 0417 In 100 patients therefore I would expect 16 patients with 2R2R genotypes 48 with 2R3R genotypes and 36 with 3R3R genotypes It is interesting to note that the incidence of grade 34 palmar plantar erythrodysesthesia and diarrhea is on the order of 14 to 16 percent A sample of 104 patients we would have a power of 08 to show a statistically significant difference of 40 between 2R2R 60 and 3R3R 20
Statistical Analysis
Associations between TS genotype and development of grade 12 and 34 overall toxicity will be examined using the chi square test with a level of significance of 005 Other toxicities of interest diarrhea mucositis and neutropenia will be examined for association with TS genotype chi square test Similar exploratory analysis will be done for MTHFR phenotypes
Recently the thymidylate synthase genes promoter has been found to be polymorphic with variable numbers of tandem repeats of 28 base pairs in length These polymorphisms have been associated with tumor response to treatment with fluoropyrimidines The investigators hypothesize that polymorphisms in thymidylate synthase TS genes promoter region are associated with toxicity from capecitabine treatment specifically development of myelosuppression and diarrhea The investigators hypothesize that a polymorphism in methylene tetrahydrofolate reductase MTHFR is also associated with toxicity and efficacy of capecitabine treatment The investigators speculate that the MTHFR polymorphism only becomes clinically significant by stratifying patients by TS promoter polymorphisms
Objectives
1 To determine if polymorphisms in thymidylate synthases promoter region are associated with development of overall toxicity diarrhea neutropenia or mucositis in patients treated with capecitabine
2 To determine if a polymorphism in methylene tetrahydrofolate reductase MTHFR is associated with development of overall toxicity diarrhea neutropenia or mucositis in patients treated with capecitabine
Background and Significance
Capecitabine is a potent antimetabolite that is the currently accepted adjuvant treatment for colorectal cancer As well capecitabine is used to treat head and neck cancers breast cancer and gastric cancer In 1985 Takeishi et al demonstrated that thymidylate synthases gene had a satellite in the 5 untranslated region which consisted of 3 tandem repeats of a 28 base pair sequence Horie et al demonstrated that these satellites were polymorphic in length due to different numbers of tandem repeats with 2 length polymorphism existing 2 tandem repeats of 28 base pairs 2R and 3 tandem repeats of 28 base pairs 3R Subsequent authors have demonstrated 4 repeats 4R five repeats 5R and nine repeats 9R
Kawakami et al demonstrated that the number of tandem repeats affected TS gene translation They showed those patients homozygous for 3R alleles had higher TS protein levels and 2R3R heterozygotes Using in vitro expression of 2R and 3R genes they demonstrated that the increased protein levels were due to increased translational efficiency of the 3R RNA and not due to increased 3R mRNA expression These tandem repeats are predictive of response rates of various cancers to fluoropyrimidine cancer chemotherapy Park et al showed in metastatic colorectal cancer patients treated with capecitabine the response rate was 14 in patients homozygous for 3R repeats and 80 in the patients homozygous for 2R repeats No prospective study has examined if a patients TS genotype predicts for 5-FU toxicity
A polymorphism in methylene tetrahydrofolate reductases MTHFR gene may also determine a patients risk for capecitabine toxicity A polymorphism in MTHFR exists at position 677 C to T producing a thermolabile and rapidly degraded enzyme TT homozygotes have increased levels of methylene tetrahydrofolate Methylene tetrahydrofolate stabilizes binding of 5FU to thymidylate synthase and the complex of TS 5FU and methylene tetrahydrofolate is referred to as the ternary complex I hypothesize that increased stabilization of TS and 5FU due to increased amounts of methylene tetrahydrofolate would lead to increased capecitabine toxicity and efficacy No study has examined if TT homozygotes have an increased response rate to fluoropyrimidines or increased toxicity
Dihydropyrimidine dehydrogenase DPD deficiency has been identified as the cause of rare severe life threatening reactions to fluoropyrimidines The first case was reported by Tuchman et al in a 27 year old woman who had undergone adjuvant chemotherapy with cyclophosphamide methotrexate and 5-fluoruracil and developed severe neurological complications Diasio et al reported the second case again in a women being treated with 5-fluoruracil for breast cancer
A study by Etienne et al has raised questions regarding the utility of DPD activity alone to predict patients at risk for fluoropyrimidine toxicity They prospectively studied 185 patients treated with 5FU containing chemotherapy regimens They found a normal distribution of DPD activity with a mean value of 0222 nmolminmg protein They did not find any correlation between DPD activity and 5FU toxicity
The investigators propose to study the effect of these two polymorphic enzymes on capecitabines toxicity in adjuvant colon cancer patients It is anticipated that patients homozygous for 2R2R will have higher rates of overall toxicity diarrhea neutropenia and mucositis than 3R3R homozygotes For MTHFR we anticipate that TT homozygotes will have higher rates overall toxicity diarrhea neutropenia and mucositis than CC homozygotes The effect of MTHFR polymorphism on capecitabines toxicity will be examined controlling for thymidylate synthase genotype
Methods
Patients who have been advised to have adjuvant chemotherapy for colorectal cancer will be enrolled Patients will be treated with standard doses of capecitabine according to the X-ACT study Toxicities during cycle one will be graded according to National Cancer Institute Common Toxicity Criteria Version 30 Dose reductions during cycle one will be recorded
Investigations
Prior to starting treatments patients will provide a 10 ml sample of blood which will be used to obtain DNA from white bloods Patients will be genotyped according to TS and MTHFR genotypes Plasma will be banked to determined DPD phenotype
Sample Size Calculation
The allele frequency of 3R tandem repeats is 06 and 2R tandem repeats is 0417 In 100 patients therefore I would expect 16 patients with 2R2R genotypes 48 with 2R3R genotypes and 36 with 3R3R genotypes It is interesting to note that the incidence of grade 34 palmar plantar erythrodysesthesia and diarrhea is on the order of 14 to 16 percent A sample of 104 patients we would have a power of 08 to show a statistically significant difference of 40 between 2R2R 60 and 3R3R 20
Statistical Analysis
Associations between TS genotype and development of grade 12 and 34 overall toxicity will be examined using the chi square test with a level of significance of 005 Other toxicities of interest diarrhea mucositis and neutropenia will be examined for association with TS genotype chi square test Similar exploratory analysis will be done for MTHFR phenotypes
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