Improving the Safety of Fluoropyrimidine-based Chemotherapy

Neoplasms Clinical Trial

— Alpe2U  

Official title:

Improving the Safety of Fluoropyrimidine-based Chemotherapy by Combined DPYD Genotype-guided and DPD Phenotype-guided Dose Individualization: The ALPE2U Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04194957
• Other study ID #: M19ALP
• Status: Recruiting
• Phase: N/A
• Start date: January 15, 2020
• Est. completion date: January 2021

Study information

• Verified date: January 2020
• Source: The Netherlands Cancer Institute
• Contact: Jonathan Knikman, PharmD
• Phone: +31 (0)20 512 9111
• Email: j.knikman[@]nki.nl
• 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 phenotypic assessment of dihydropyrimidine dehydrogenase (DPD) deficiency.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1440
• Est. completion date: January 2021
• Est. primary completion date: January 2021
• 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. 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

Related Conditions & MeSH terms

• Neoplasms

Intervention

Drug:
• Fluoropyrimidine (capecitabine or 5-fluorouracil)
Patients that are found to be wild type and have a pre-treatment uracil concentration above 16 ng/mL will receive a reduced dosage of capecitabine or 5-fluorouracil (50% reduction). The dose will be titrated after 2 cycles , to achieve maximal safe exposure. Patients that are wildtype with a uracil concentration below 16 ng/mL will receive a normal (full) dose.
• Fluoropyrimidine (capecitabine or 5-fluorouracil)
Patients that are heterozygous carriers of c.1236G>A or c.2846A>T DPYD variant will receive a reduced dosage of capecitabine or 5-FU (50 % reduction). The dose will be titrated after 2 cycles, to achieve maximal safe exposure.
• Fluoropyrimidine (capecitabine or 5-fluorouracil)
Patients with homozygous or compound heterozygous DPYD variants will be treated with a reduced dose of capecitabine or 5-FU based on the DPD enzyme activity measured in peripheral blood mononuclear cells.

Locations

Country	Name	City	State
Netherlands	Netherlands Cancer Institute - Antoni van Leeuwenhoek	Amsterdam

Sponsors (2)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Leiden University Medical Center

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Frederix GWJ, Kienhuis E, Creemers GJ, Baars A, Dezentjé VO, Imholz ALT, Jeurissen FJF, Portielje JEA, Jansen RLH, Hamberg P, Ten Tije AJ, Droogendijk HJ, Koopman M, Nieboer P, van de Poel MHW, Mandigers CMPW, Rosing H, Beijnen JH, Werkhoven EV, van Kuilenburg ABP, van Schaik RHN, Mathijssen RHJ, Swen JJ, Gelderblom H, Cats A, Guchelaar HJ, Schellens JHM. DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol. 2018 Nov;19(11):1459-1467. doi: 10.1016/S1470-2045(18)30686-7. Epub 2018 Oct 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life		During the first administration of fluoropyrimidine treatment
Secondary	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
Secondary	Assessment of feasibility of dose titration following an initial dose reduction		During fluoropyrimidine treatment, expected average of 1 year
Secondary	Assessment of geriatric parameters for grade 3-5 toxicity and/or treatment discontinuation		During fluoropyrimidine treatment, expected average of 1 year