Improving the Safety of Fluoropyrimidine-based Chemotherapy (Alpe2U)

Netherlands Cancer Institute (NKI)

Status: Unknown

Conditions: Neoplasms

Treatments: Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Study type: Interventional

Funder types: Other

Identifiers

NCT04194957

M19ALP

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,440 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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1,440 participants in 3 patient groups

Wild type for DPYD

Experimental group

Description:

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

Treatment:

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

heterozygous carrier of c.1236G>A or c.2846A>T DPYD variant

Experimental group

Description:

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

Treatment:

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Homozygous or compound heterozygous carrier of DPYD variants

Experimental group

Description:

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

Treatment:

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)