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

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.

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)

• Study Type: Interventional
• Enrollment (Actual): 1103
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: heterozygous carrier of DPYD variant; 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 one of these SNPs	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.; Other Names: 5-FU; Xeloda; 5-fluorouracil; Capecitabine; fluorouracil
Experimental: wild type for DPYD; 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); 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.; Other Names: 5-FU; Xeloda; 5-fluorouracil; Capecitabine; fluorouracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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)
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

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Investigators: Principal Investigator: JHM Schellens, MD, PhD, The Netherlands Cancer Institute

Publications and helpful links

General Publications

• 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.
• Jacobs BA, Deenen MJ, Pluim D, van Hasselt JG, Krahenbuhl MD, van Geel RM, de Vries N, Rosing H, Meulendijks D, Burylo AM, Cats A, Beijnen JH, Huitema AD, Schellens JH. Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers. Br J Clin Pharmacol. 2016 Sep;82(3):706-16. doi: 10.1111/bcp.13007. Epub 2016 Jun 3.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: December 9, 2014
• First Submitted That Met QC Criteria: December 18, 2014
• First Posted (Estimate): December 24, 2014

Study Record Updates

• Last Update Posted (Actual): May 11, 2018
• Last Update Submitted That Met QC Criteria: May 7, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil; Capecitabine
• Other Study ID Numbers: M14DPD; 2014-005064-15 (EudraCT Number)