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ID
Source
Brief title
Health condition
Colorectal or pancreas cancer
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the correlation between the baseline endogenous DPD substrate plasma ratios of DHU/U and DHT/T with the pharmacokinetics of 5-FU in patients with pancreas or colorectal cancer treated with intravenous 5-FU-based chemotherapy.
Secondary outcome
- To determine the potential changes in U, DHU, T and DHT concentrations over time during the prolonged 5-FU infusion
- To determine the DHU/U, DHT/T and DHFU/FU ratios over time during 5-FU prolonged infusion
- To establish a cut-off concentration in a daily Dutch patient population for all measured analytes, their metabolites and ratios, including 5-FU, DHFU, U, DHU, T and DHT
- To determine the effect of DPYD genotype on the U, DHU, T and DHT concentrations and on the pharmacokinetics of 5-FU
- To determine the correlation between serious adverse events or 5-FU toxicity to AUC of 5-FU, DHU/U or DHT/T ratio
- To determine the effect of other genetic polymorphisms on the pharmacokinetics of 5-FU (if applicable)
Background summary
The anticancer drug 5-fluorouracil (5-FU) is widely used in the treatment of amongst others early and advanced colorectal, gastric, pancreas and breast cancer. 5-FU is mainly metabolized by the enzyme dihydropyrimidine dehydrogenase (DPD), an enzyme encoded by the DPYD gene. Genetic polymorphism in this gene may lead to DPD deficiency and thereby an increased risk of drug-induced severe toxicity. In the Caucasian population, 3 to 5% has a partial DPD-deficiency and 0.1 to 0.2% has a complete deficiency.(1,2) DPD deficiency can lead to severe toxicity (grade 3 to 5, according to CTC-AE version 4.03), such as myelosuppression, mucositis, diarrhoea and hand-foot syndrome. Measuring the DPYD genotype prior 5-FU-based chemotherapy has shown to be able to prevent drug-induced severe toxicity of 5-FU. The clinical utility has thus far been demonstrated for four polymorphisms, i.e. DPYD*2A; *13; 2846A>T; 1236G>A, which are therefore routinely determined prior to start of chemotherapy. Despite the use of genotyping, a significant proportion of patients still develop 5-FU-related severe toxicity. Since both endogenous uracil (U) and thymine (T) are being converted by DPD into dihydrouracil (DHU) and dihydrothymine (DHT), respectively, patients with a low DHU/U and/or a low DHT/T plasma ratio before start of 5-FU based therapy have higher risk of 5-FU induced severe toxicity. In this study we will investigate the correlation between the endogenous DPD substrates uracil and thymine with the pharmacokinetics and toxicity of 5-FU in patients with colorectal or pancreas cancer treated with prolonged infusions of 5-FU. The ultimate goal is to develop an easy to measure additional predictive marker besides DPYD genotype in order to prevent 5-FU induced severe toxicity.
Study objective
A low ratio of U/DHU and/or T/DHT can cause serious adverse events in patients treated with 5-FU continous infusion.
Study design
T= 0, 1/2, 2 and 46 hours.
Inclusion criteria
1. Pathologically confirmed malignancy for which treatment with 5-FU is indicated in the FOLFOX, FOLFIRI or FOLFIRINOX regimen.
2. Age ≥ 18 years
3. Able and willing to give written informed consent
4. WHO performance status 0-2
5. Minimal acceptable safety laboratory values defined as
a. ANC of ≥ 1.5 x 109 /L
b. Platelet count of ≥ 100 x 109 /L
c. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 2.5 x ULN; in case of liver metastases ALAT and ASAT ≤ 5 x ULN.
d. Renal function as defined by MDRD >30 mL/min
Exclusion criteria
1. Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient’s safety
2. Women who are pregnant or breast feeding
3. Patients in whom the bolus injection will be skipped due to e.g. toxicity of previous chemo therapy regimen.
Design
Recruitment
IPD sharing statement
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL7539 |
| Other | MEC-U : R19.002/FUUT |