NCT04194957

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.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
1,440

participants targeted

Target at P75+ for not_applicable

Timeline
Completed

Started Jan 2020

Geographic Reach
1 country

1 active site

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

November 15, 2019

Completed
26 days until next milestone

First Posted

Study publicly available on registry

December 11, 2019

Completed
1 month until next milestone

Study Start

First participant enrolled

January 15, 2020

Completed
12 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

January 1, 2021

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

January 1, 2021

Completed
Last Updated

January 22, 2020

Status Verified

January 1, 2020

Enrollment Period

12 months

First QC Date

November 15, 2019

Last Update Submit

January 20, 2020

Conditions

Neoplasms

Keywords

FluoropyrimidinesPhenotypingGenotypingDose-individualizationCapecitabine5-Fluorouracil5-FU

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (5)

  • 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

Study Arms (3)

Wild type for DPYD

EXPERIMENTAL

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

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

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

EXPERIMENTAL

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

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Homozygous or compound heterozygous carrier of DPYD variants

EXPERIMENTAL

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

Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

Interventions

Fluoropyrimidine (capecitabine or 5-fluorouracil)DRUG

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.

Wild type for DPYD

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Pathologically confirmed malignancy for which treatment with a fluoropyrimidine is considered to be in the patient's best interest
  • Patient need to be of Western descent
  • Age ≥ 18
  • Able and willing to give written informed consent
  • WHO performance status of 0, 1 or 2
  • Able and willing to undergo extra blood sampling for study related analysis
  • 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)

You may not qualify if:

  • Prior treatment with fluoropyrimidines
  • 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
  • Patients treated with the combination of a fluoropyrimidine and irinotecan

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Netherlands Cancer Institute - Antoni van Leeuwenhoek

Amsterdam, Netherlands

RECRUITING

Related Publications (2)

  • Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Frederix GWJ, Kienhuis E, Creemers GJ, Baars A, Dezentje 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.

    PMID: 30348537BACKGROUND

  • Knikman JE, Gelderblom H, Beijnen JH, Cats A, Guchelaar HJ, Henricks LM. Individualized Dosing of Fluoropyrimidine-Based Chemotherapy to Prevent Severe Fluoropyrimidine-Related Toxicity: What Are the Options? Clin Pharmacol Ther. 2021 Mar;109(3):591-604. doi: 10.1002/cpt.2069. Epub 2020 Nov 12.

    PMID: 33020924DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

CapecitabineFluorouracil

Intervention Hierarchy (Ancestors)

DeoxycytidineCytidinePyrimidine NucleosidesPyrimidinesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsUracilPyrimidinonesDeoxyribonucleosidesNucleosidesNucleic Acids, Nucleotides, and Nucleosides

Study Officials

  • Annemieke Cats, MD, PhD

    Netherlands Cancer Institute - Antoni van Leeuwenhoek

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Jonathan Knikman, PharmD

CONTACT

+31 (0)20 512 9111j.knikman@nki.nl

Annemieke Cats, MD, PhD

CONTACT

a.cats@nki.nl

Study Design

Study Type
interventional
Phase
not applicable
Allocation
NON RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

November 15, 2019

First Posted

December 11, 2019

Study Start

January 15, 2020

Primary Completion

January 1, 2021

Study Completion

January 1, 2021

Last Updated

January 22, 2020

Record last verified: 2020-01

Data Sharing

IPD Sharing
Will not share

Locations

NL(1)