Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines

Neoplasms Clinical Trial

Official title:

Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02324452
• Other study ID #: M14DPD
• Secondary ID: 2014-005064-15
• Status: Completed
• Phase: N/A
• Start date: March 2015
• Est. completion date: March 2018

Study information

• Verified date: May 2018
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In this study it will be determined whether the rate of severe toxicity associated with fluoropyrimidine treatment (capecitabine or 5-fluorouracil) can be significantly diminished by individualized dosing of fluoropyrimidines based on upfront genotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

In addition to the genotyping, the DPD phenotype of all patients will be determined by measuring the baseline dihydrouracil/uracil (DHU/U) ratio, in order to investigate whether phenotype-guided treatment can further improve patient safety. In a subgroup of patients, other phenotyping methods will be tested: measuring the plasma levels of uracil after a uracil test dose and a uracil breath test after a dose of [2-13C] -labeled uracil. To validate these tests, these phenotyping results will be compared with the results of a DPD activity assay (which measures DPD enzyme activity in peripheral blood mononuclear cells), which is considered the gold standard in measuring DPD phenotype.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1103
• Est. completion date: March 2018
• Est. primary completion date: January 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest

2. Age = 18 years

3. Able and willing to give written informed consent

4. WHO performance status of 0, 1 or 2

5. Life expectancy of at least 12 weeks

6. Able to swallow and retain oral medication

7. Able and willing to undergo blood sampling for pharmacogenetic and phenotyping analysis

8. Minimal acceptable safety laboratory values (ANC, platelet count, hepatic function, renal function)

Additional inclusion criteria for patients in subgroup of study:

1. Able and willing to undergo blood sampling and breath sampling at several time points

2. Able and willing to receive uracil for the test dose assay

3. Able and willing to receive [2-13C] -labeled uracil for the breath test

Exclusion Criteria:

1. Prior treatment with fluoropyrimidines

2. Patients with known substance abuse, psychotic disorders, and/or other diseases expected to interfere with study or the patient's safety

3. Women who are pregnant or breast feeding

4. Both men and women who refuse to use reliable contraceptive methods throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms)

5. Patients with a homozygous polymorphic genotype or compound heterozygous genotype for DPYD

Related Conditions & MeSH terms

• Neoplasms

Intervention

Drug:
• Fluoropyrimidine (capecitabine or 5-fluorouracil)
Patient that are a heterozygous carrier of a DPYD variant will receive a reduced dosage of capecitabine or 5-fluorouracil (25-50% reduction, depending on which SNP is identified). The dose will be titrated in subsequent cycles, to achieve maximal safe exposure. Patients that are wild type (not carrying any of the for DPYD variants) will receive a normal (full) dose.

Locations

Country	Name	City	State
Netherlands	Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital	Amsterdam
Netherlands	Wilhelmina Hospital Assen	Assen
Netherlands	Amphia Hospital	Breda
Netherlands	Reinier de Graaf Hospital	Delft
Netherlands	Deventer Hospital	Deventer
Netherlands	Hospital Gelderse Vallei	Ede
Netherlands	Catharina Hospital	Eindhoven
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	Canisius-Wilhelmina Hospital	Nijmegen
Netherlands	Laurentius Hospital	Roermond
Netherlands	Bravis Hospital	Roosendaal
Netherlands	Erasmus MC	Rotterdam
Netherlands	Franciscus Gasthuis & Vlietland	Rotterdam
Netherlands	Haga Hospital	the Hague
Netherlands	Medical Center Haaglanden	the Hague
Netherlands	University Medical Center Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5)	The incidence of severe treatment-related toxicity (CTC grade 3 to 5) in patients carrying DPYD variants compared to wild type patients and compared to a historical cohort of DPYD heterozygous patients treated with a full dose of fluoropyrimidines	patients will be followed during fluoropyrimidine treatment, expected average of 1 year
Secondary	Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective	Costs in the group where dose individualization of fluoropyrimidines based on upfront genotyping is performed is compared to a historic cohort without dose individualization. Costs include costs for genotyping, fluoropyrimidine drug therapy and costs related to adverse events.	patients will be followed during fluoropyrimidine treatment, expected average of 1 year
Secondary	DPD phenotype, defined as deficient or not deficient	Several phenotyping tests that assess DPD enzyme activity will be compared and clinical sensitivity, specificity, positive predictive value and negative predictive value of each test will be determined	Prior to start of fluoropyrimidine treatment of the patient (pre dose)
Secondary	Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life	In patients with heterozygous DPYD mutations the plasma levels of capecitabine, 5-FU and metabolites will be determined to assess the pharmacokinetic (PK) profile in these patients given reduced doses of capecitabine and 5-FU	At first week of start of fluoropyrimidine treatment of the patient