Improving the Safety of Fluoropyrimidine-based Chemotherapy

Not Applicable

• Conditions: Neoplasms
• Interventions: Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

• Registration Number: NCT04194957
• Lead Sponsor: The Netherlands Cancer Institute

Brief 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 phenotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

Detailed Description

In this study a phenotypic approach will be studied to determine the additional value of pretreatment uracil level-guided dose individualization in wildtype patients. Patients with a pretreatment serum uracil concentration above 16 ng/ml will be treated with a 50% reduced fluoropyrimidine starting dose. The pretreatment serum uracil levels in DPYD variant carriers will be assessed retrospectively and non-interventional. Additionally, the effect of a higher dose reduction in c.1236G\>A and c.2846A\>T DPYD variants carriers (50% instead of 25%) will be studied.

Study Timeline

• Study First Submitted: 2019-11-15
• Study First Submitted QC: 2019-12-09
• Study First Posted: 2019-12-11
• Status Verified: 2020-01
• Study Start: 2020-01-15
• Last Update Submitted: 2020-01-20
• Last Update Posted: 2020-01-22
• Primary Completion: 2021-01
• Study Completion: 2021-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 1440

Inclusion Criteria

1. Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest
2. Patient need to be of Western descent
3. Age ≥ 18
4. Able and willing to give written informed consent
5. WHO performance status of 0, 1 or 2
6. Able and willing to undergo extra blood sampling for study related analysis
7. Adequate baseline patient characteristics, in the opinion of the treating physician (complete blood count, hepatic function which involves serum bilirubin, AST, ALT, and renal function)

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 in the opinion of the treating physician
3. Patients treated with the combination of a fluoropyrimidine and irinotecan

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Wild type for DPYD	Fluoropyrimidine (capecitabine or 5-fluorouracil)	Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be wild type for these SNPs
heterozygous carrier of c.1236G>A or c.2846A>T DPYD variant	Fluoropyrimidine (capecitabine or 5-fluorouracil)	Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be heterozygous for c.1236G\>A or c.2846A\>T of these SNPs
Homozygous or compound heterozygous carrier of DPYD variants	Fluoropyrimidine (capecitabine or 5-fluorouracil)	Patients screened for four single nucleotide polymorphisms (SNPs) in DPYD (DPYD\*2A, c.2846A\>T, c.1236G\>A/HapB3 and DPYD\*13) that are found to be homozygous or compound heterozygous for these SNPs

Primary Outcome Measures

Name	Time	Method
Safety: incidence of severe fluoropyrimidine-related toxicity (CTCAE grade 3 to 5) in wild type patients	Patients with a pre-treatment uracil concentration above 16 ng/ml will be followed until end of treatment (expected average of 1 year). Otherwise, patients will be followed for the first 2 cycles (each cycle is 28 days).

Secondary Outcome Measures

Name	Time	Method
Safety: incidence of severe treatment-related toxicity (CTCAE grade 3 to 5) in heterozygous carriers of c.1236G>A or c.2846A>T DPYD variants	Patients will be followed during fluoropyrimidine treatment, expected average of 1 year
Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life	During the first administration of fluoropyrimidine treatment
Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective	Patients will be followed during fluoropyrimidine treatment, expected average of 1 year
Assessment of feasibility of dose titration following an initial dose reduction	During fluoropyrimidine treatment, expected average of 1 year
Assessment of geriatric parameters for grade 3-5 toxicity and/or treatment discontinuation	During fluoropyrimidine treatment, expected average of 1 year

Trial Locations

Locations (1)

Netherlands Cancer Institute - Antoni van Leeuwenhoek; 🇳🇱 Amsterdam, Netherlands