Improving the Safety of Fluoropyrimidine-based Chemotherapy (Alpe2U)

January 20, 2020 updated by: The Netherlands Cancer Institute

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Anticipated)

1440

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Jonathan Knikman, PharmD
  • Phone Number: +31 (0)20 512 9111
  • Email: j.knikman@nki.nl

Study Contact Backup

Study Locations

  • Netherlands
      • Amsterdam, Netherlands
        • Recruiting
        • Netherlands Cancer Institute - Antoni van Leeuwenhoek
        • Contact:
          • Annemieke Cats, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 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. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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)
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.
Drug: 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.
Drug: 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.
Experimental: heterozygous carrier of c.1236G>A or c.2846A>T 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 c.1236G>A or c.2846A>T of these SNPs
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.
Drug: 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.
Drug: 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.
Experimental: Homozygous or compound heterozygous carrier of DPYD variants
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)
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.
Drug: 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.
Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Safety: incidence of severe fluoropyrimidine-related toxicity (CTCAE grade 3 to 5) in wild type patients
Time Frame: 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).
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 Outcome Measures

Outcome Measure
Time Frame
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
Time Frame: Patients will be followed during fluoropyrimidine treatment, expected average of 1 year
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
Time Frame: During the first administration of fluoropyrimidine treatment
During the first administration of fluoropyrimidine treatment
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
Patients will be followed during fluoropyrimidine treatment, expected average of 1 year
Assessment of feasibility of dose titration following an initial dose reduction
Time Frame: During fluoropyrimidine treatment, expected average of 1 year
During fluoropyrimidine treatment, expected average of 1 year
Assessment of geriatric parameters for grade 3-5 toxicity and/or treatment discontinuation
Time Frame: During fluoropyrimidine treatment, expected average of 1 year
During fluoropyrimidine treatment, expected average of 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Netherlands Cancer Institute

Collaborators

Leiden University Medical Center

Investigators

  • Principal Investigator: Annemieke Cats, MD, PhD, Netherlands Cancer Institute - Antoni van Leeuwenhoek

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 15, 2020

Primary Completion (Anticipated)

January 1, 2021

Study Completion (Anticipated)

January 1, 2021

Study Registration Dates

First Submitted

November 15, 2019

First Submitted That Met QC Criteria

December 9, 2019

First Posted (Actual)

December 11, 2019

Study Record Updates

Last Update Posted (Actual)

January 22, 2020

Last Update Submitted That Met QC Criteria

January 20, 2020

Last Verified

January 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • M19ALP

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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