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

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ClinicalTrials.gov Identifier: NCT02324452
Recruitment Status : Completed
First Posted : December 24, 2014
Last Update Posted : May 11, 2018
Sponsor:
Information provided by (Responsible Party):
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 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.


Condition or disease Intervention/treatment Phase
Neoplasms Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil) Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1103 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety, Feasibility and Cost-effectiveness of Genotype-directed Individualized Dosing of Fluoropyrimidines
Study Start Date : March 2015
Actual Primary Completion Date : January 2018
Actual Study Completion Date : March 2018

Resource links provided by the National Library of Medicine


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:
  • Xeloda
  • Capecitabine
  • 5-fluorouracil
  • fluorouracil
  • 5-FU

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:
  • Xeloda
  • Capecitabine
  • 5-fluorouracil
  • fluorouracil
  • 5-FU




Primary Outcome Measures :
  1. Safety: incidence of severe treatment-related toxicity (CTC grade 3 to 5) [ Time Frame: patients will be followed during fluoropyrimidine treatment, expected average of 1 year ]
    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


Secondary Outcome Measures :
  1. Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective [ Time Frame: patients will be followed during fluoropyrimidine treatment, expected average of 1 year ]
    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.

  2. DPD phenotype, defined as deficient or not deficient [ Time Frame: Prior to start of fluoropyrimidine treatment of the patient (pre dose) ]
    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

  3. Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life [ Time Frame: At first week of start of fluoropyrimidine treatment of the patient ]
    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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02324452


Locations
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Netherlands
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Amsterdam, Netherlands
Wilhelmina Hospital Assen
Assen, Netherlands
Amphia Hospital
Breda, Netherlands
Reinier de Graaf Hospital
Delft, Netherlands
Deventer Hospital
Deventer, Netherlands
Hospital Gelderse Vallei
Ede, Netherlands
Catharina Hospital
Eindhoven, Netherlands
Leiden University Medical Center
Leiden, Netherlands
Maastricht University Medical Center
Maastricht, Netherlands
Canisius-Wilhelmina Hospital
Nijmegen, Netherlands
Laurentius Hospital
Roermond, Netherlands
Bravis Hospital
Roosendaal, Netherlands
Erasmus MC
Rotterdam, Netherlands
Franciscus Gasthuis & Vlietland
Rotterdam, Netherlands
Haga Hospital
the Hague, Netherlands
Medical Center Haaglanden
the Hague, Netherlands
University Medical Center Utrecht
Utrecht, Netherlands
Sponsors and Collaborators
The Netherlands Cancer Institute
Investigators
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Principal Investigator: JHM Schellens, MD, PhD The Netherlands Cancer Institute

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT02324452     History of Changes
Other Study ID Numbers: M14DPD
2014-005064-15 ( EudraCT Number )
First Posted: December 24, 2014    Key Record Dates
Last Update Posted: May 11, 2018
Last Verified: May 2018

Additional relevant MeSH terms:
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Capecitabine
Fluorouracil
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs