NeoplasmsAlpe2UNCT04194957
Improving the Safety of Fluoropyrimidine-based Chemotherapy
A study testing Fluoropyrimidine (capecitabine or 5-fluorouracil) in people with Neoplasms, run by The Netherlands Cancer Institute at 1 site in Netherlands.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Neoplasms
- What is being tested?
- Fluoropyrimidine (capecitabine or 5-fluorouracil)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,440 participants
- Where
- 1 siteNetherlands
- Study dates
- 15 Jan 2020to Jan 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Annemieke Cats, MD, PhD contact
Netherlands1 site, 1 recruiting
- Recruiting
Netherlands Cancer Institute - Antoni van Leeuwenhoek
Amsterdam
Annemieke Cats, MD, PhD
About this study
Official title: 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.
Read the 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.
- Conditions
- Neoplasms
- Being tested
- Fluoropyrimidine (capecitabine or 5-fluorouracil)
- Keywords
- Fluoropyrimidines, Phenotyping, Genotyping, Dose-individualization, Capecitabine, 5-Fluorouracil, 5-FU
- Medical subject headings
- Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
Fluoropyrimidine (capecitabine or 5-fluorouracil)Drug
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)Drug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 Receives: Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety: incidence of severe fluoropyrimidine-related toxicity (CTCAE grade 3 to 5) in wild type patients
Measured: 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
Measured: 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
Measured: During the first administration of fluoropyrimidine treatment
Cost-effectiveness: medical costs that are made during fluoropyrimidine treatment seen from a health care perspective
Measured: Patients will be followed during fluoropyrimidine treatment, expected average of 1 year
Assessment of feasibility of dose titration following an initial dose reduction
Measured: During fluoropyrimidine treatment, expected average of 1 year
Assessment of geriatric parameters for grade 3-5 toxicity and/or treatment discontinuation
Measured: During fluoropyrimidine treatment, expected average of 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Dec 2019
- Study start15 Jan 2020
- Primary completionJan 2021 (estimated)
- Study completionJan 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for NeoplasmsStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 1,440 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Leiden University Medical Center
- Responsible party
- Sponsor
- Investigators
- Annemieke Cats, MD, PhD, Principal investigator, Netherlands Cancer Institute - Antoni van Leeuwenhoek
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04194957
- Sponsor's protocol ID
- M19ALP
- Acronym
- Alpe2U
- Status last verified
- Jan 2020
- First submitted
- 15 Nov 2019
- Last updated
- 22 Jan 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 30348537Knikman 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.
PubMed 33020924
Study at a glance
From the registry record, last updated by the sponsor on 22 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Improving the Safety of Fluoropyrimidine-based Chemotherapy by Combined DPYD Genotype-guided and DPD Phenotype-guided Dose Individualization: The ALPE2U Study
- ClinicalTrials.gov ID
- NCT04194957
- Acronym / sponsor ID
- Alpe2U / M19ALP
- Conditions
- Neoplasms
- Keywords
- Fluoropyrimidines, Phenotyping, Genotyping, Dose-individualization, Capecitabine, 5-Fluorouracil, 5-FU
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 1,440 participants (estimated)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- Leiden University Medical Center
- Study start
- 15 Jan 2020 (actual)
- Primary completion
- Jan 2021 (estimated)
- Study completion
- Jan 2021 (estimated)
- First posted
- 11 Dec 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Wild type for DPYD | Experimental | Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)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 |
| heterozygous carrier of c.1236G>A or c.2846A>T DPYD variant | Experimental | Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)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 |
| Homozygous or compound heterozygous carrier of DPYD variants | Experimental | Drug: Fluoropyrimidine (capecitabine or 5-fluorouracil)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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (3 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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 | Wild type for DPYD |
| 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 | heterozygous carrier of c.1236G>A or c.2846A>T DPYD variant |
| 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. | Drug | Homozygous or compound heterozygous carrier of DPYD variants |
Primary outcome
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).
5 secondary outcomes
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
Assessment of pharmacokinetics: Such profile parameters will include Cmax, Tmax, AUC and elimination half-life
Time frame: 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
Assessment of feasibility of dose titration following an initial dose reduction
Time frame: 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
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jan 2020.
- Background: PubMed 30348537Henricks 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.
- Derived from this study: PubMed 33020924Knikman 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Annemieke Cats, MD, PhD contact
Annemieke Cats, MD, PhD principal investigator
Netherlands Cancer Institute - Antoni van Leeuwenhoek
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Fluoropyrimidine (capecitabine or 5-fluorouracil) in people with Neoplasms, run by The Netherlands Cancer Institute at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 22 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Jonathan Knikman, PharmD (+31 (0)20 512 9111, j.knikman@nki.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04194957, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jan 2020.