Lymphoblastic Leukemia, Acute, ChildhoodNCT01896752
Renal and Hepatic Clearance Following High-Dose Methotrexate in Childhood ALL
An observational study of Lymphoblastic Leukemia, Acute, Childhood, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.
Trial summary
High-dose methotrexate therapy (HDMTX) is an important part of treatment of childhood acute lymphoblastic leukemia (ALL). HDMTX would be improved substantially if it were possible to predict the clearance of MTX for each patient and use this to tailor an individualized dosing of the drug. Read more about this study
- Who is it for?
- Ages Up to 19 years
- Conditions the study is for
- Lymphoblastic Leukemia, Acute, Childhood
- How many people
- 43 participants
- Where
- 1 siteDenmark
- Study dates
- Mar 2011to Jan 2013
- Phase
- Observational
- 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 Up to 19 years
- All sexes
- No healthy volunteers
- Child, Adult
Study population: All children diagnosed and treated for Acute Lymphoblastic Leukemia, ALL, at Rigshospitalet during the last two years, i.e. 43 children, and who will receive HD-MTX during the study period.
Who may be able to join
- Admitted to Rigshospitalet
- Diagnosed with ALL
- Receiving high dose MTX
Who cannot join
- Using diaper (only exclusion criteria for the study part concerning urine collection)
- Above 19 years of age
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Pharmacokinetics: Renal and Hepatic Clearance Following High-Dose Methotrexate in Children With Acute Lymphoblastic Leukemia
High-dose methotrexate therapy (HDMTX) is an important part of treatment of childhood acute lymphoblastic leukemia (ALL). HDMTX would be improved substantially if it were possible to predict the clearance of MTX for each patient and use this to tailor an individualized dosing of the drug. However, only about 3.7, 0.2, and 2% of the inter-individual variation in MTX clearance is explained by age, gender and ancestry, respectively. Genetic variation seems to explain about 10% of this difference, and SNPs in genes encoding transporter proteins (e.g. organic anion transporter 1B1 (OATP1B1) and reduced folate carrier (RFC)) are suggested to have a particular large impact. A serious limitation to the applicability of SNPs in prediction of MTX pharmacokinetics, however, is the substantial intra-individual variation in MTX clearance.
The intra-individual variation in MTX clearance is related to renal function but a large amount of a HDMTX dose also enters the liver, where it is metabolized to 7-hydroxy MTX and probably also undergoes enterohepatic circulation. Thus, the aim of this study is to determine the role of the liver and renal function in MTX pharmacokinetics, and evaluate the predictive potential of pharmacogenetic (e.g. the rfc SNP) and pharmacokinetic parameters of MTX elimination during HDMTX.
Read the detailed description
Due to optimization of dosing and intensity of conventional anticancer drugs combined with early risk group classification and clinical trials the cure rates of childhood acute lymphoblastic leukemia (ALL) is now beyond 80%.
Methotrexate (MTX) is one of the most important drugs in the treatment of ALL and is a key component in all treatment phases. Infusions with high-dose methotrexate (HDMTX) are used in many treatment protocols for ALL but the optimal dose and infusion time remain undefined. The systemic clearance of MTX exhibits a large inter- and intra-individual variability and this cause several clinical problems. Fast MTX clearance has been associated with increased risk of relapse, whereas patients with slow MTX clearance have more side effects. In situations with extremely low MTX clearance it is necessary to administer very high doses of leucovorin in order to minimize toxicity; unfortunately treatment with this antidote can potentially rescue some of the cancer cells and thereby increase the risk of relapse.
Therapy with high-dose MTX would be improved substantially if it were possible to predict the clearance of MTX for each patient and use this to tailor an individualized dosing of the drug. However, only about 3.7, 0.2, and 2% of the inter-individual variation in MTX clearance is explained by age, gender and ancestry, respectively. Genetic variation seems to explain about 10% of this difference, and SNPs in genes encoding transporter proteins (e.g. reduced folate carrier and the anion transporter 1B1, OATP1B1) are suggested to have a particularly large impact. A serious limitation, however, is that SNPs are difficult to use in the prediction of MTX pharmacokinetics when the intra-individual variation in MTX clearance has been shown to be up to six fold. In order to use genetic variation in a clinically setting it is necessary to reduce the large intra-individual clearance of MTX.
The intra-individual variation in MTX clearance is related to renal function but a large amount of a HDMTX dose also enters the liver, where it is metabolized to 7-hydroxy MTX and probably also undergoes enterohepatic circulation. Additionally, an insignificant amount of MTX is degraded to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA). In order to determine whether the renal or hepatic function is responsible for the large intra-individual variation in MTX clearance the urinary excretion of MTX and the liver metabolite 7-hydroxy MTX have been studied, and modelling was applied to predict the individual time span for complete MTX excretion and to reveal early pharmacogenetic/kinetic patterns predictive of elimination of MTX during HDMTX courses in children with ALL.
- Conditions
- Lymphoblastic Leukemia, Acute, Childhood
- Medical subject headings
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
What is being measured
The primary outcome is the main question the study is designed to answer.
clearance
Measured: within the first 6 months after recruitment has been completed
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jul 2013 (estimated)
- Study startMar 2011
- Primary completionJan 2013
- Study completionJan 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Lymphoblastic Leukemia, Acute, ChildhoodStudies of the same condition, open and under way.
- More trials run by Copenhagen University Hospital, RigshospitaletThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 43 participants (actual)
Sponsor and investigators
- Lead sponsor
- Copenhagen University Hospital, Rigshospitalet
- Sponsor type
- University, hospital or other
- Collaborators
- Danish Cancer Society
- Responsible party
- Principal investigator, Kjeld Schmiegelow, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Kjeld Schmiegelow, MD, Study chair, Copenhagen University Hospital, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01896752
- Sponsor's protocol ID
- R35-A1642-10S7
- Status last verified
- Jul 2013
- First submitted
- 8 Jul 2013
- Last updated
- 16 Jul 2013
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Jul 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetics: Renal and Hepatic Clearance Following High-Dose Methotrexate in Children With Acute Lymphoblastic Leukemia
- ClinicalTrials.gov ID
- NCT01896752
- Acronym / sponsor ID
- R35-A1642-10S7
- Conditions
- Lymphoblastic Leukemia, Acute, Childhood
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 43 participants (actual)
- Lead sponsor
- Copenhagen University Hospital, RigshospitaletUniversity, hospital or other
- Collaborators
- Danish Cancer Society
- Study start
- Mar 2011
- Primary completion
- Jan 2013 (actual)
- Study completion
- Jan 2013 (actual)
- First posted
- 11 Jul 2013 (estimated)
- 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.
High-dose methotrexate therapy (HDMTX) is an important part of treatment of childhood acute lymphoblastic leukemia (ALL). HDMTX would be improved substantially if it were possible to predict the clearance of MTX for each patient and use this to tailor an individualized dosing of the drug. However, only about 3.7, 0.2, and 2% of the inter-individual variation in MTX clearance is explained by age, gender and ancestry, respectively. Genetic variation seems to explain about 10% of this difference, and SNPs in genes encoding transporter proteins (e.g. organic anion transporter 1B1 (OATP1B1) and reduced folate carrier (RFC)) are suggested to have a particular large impact. A serious limitation to the applicability of SNPs in prediction of MTX pharmacokinetics, however, is the substantial intra-individual variation in MTX clearance.
The intra-individual variation in MTX clearance is related to renal function but a large amount of a HDMTX dose also enters the liver, where it is metabolized to 7-hydroxy MTX and probably also undergoes enterohepatic circulation. Thus, the aim of this study is to determine the role of the liver and renal function in MTX pharmacokinetics, and evaluate the predictive potential of pharmacogenetic (e.g. the rfc SNP) and pharmacokinetic parameters of MTX elimination during HDMTX.
Detailed description
Due to optimization of dosing and intensity of conventional anticancer drugs combined with early risk group classification and clinical trials the cure rates of childhood acute lymphoblastic leukemia (ALL) is now beyond 80%.
Methotrexate (MTX) is one of the most important drugs in the treatment of ALL and is a key component in all treatment phases. Infusions with high-dose methotrexate (HDMTX) are used in many treatment protocols for ALL but the optimal dose and infusion time remain undefined. The systemic clearance of MTX exhibits a large inter- and intra-individual variability and this cause several clinical problems. Fast MTX clearance has been associated with increased risk of relapse, whereas patients with slow MTX clearance have more side effects. In situations with extremely low MTX clearance it is necessary to administer very high doses of leucovorin in order to minimize toxicity; unfortunately treatment with this antidote can potentially rescue some of the cancer cells and thereby increase the risk of relapse.
Therapy with high-dose MTX would be improved substantially if it were possible to predict the clearance of MTX for each patient and use this to tailor an individualized dosing of the drug. However, only about 3.7, 0.2, and 2% of the inter-individual variation in MTX clearance is explained by age, gender and ancestry, respectively. Genetic variation seems to explain about 10% of this difference, and SNPs in genes encoding transporter proteins (e.g. reduced folate carrier and the anion transporter 1B1, OATP1B1) are suggested to have a particularly large impact. A serious limitation, however, is that SNPs are difficult to use in the prediction of MTX pharmacokinetics when the intra-individual variation in MTX clearance has been shown to be up to six fold. In order to use genetic variation in a clinically setting it is necessary to reduce the large intra-individual clearance of MTX.
The intra-individual variation in MTX clearance is related to renal function but a large amount of a HDMTX dose also enters the liver, where it is metabolized to 7-hydroxy MTX and probably also undergoes enterohepatic circulation. Additionally, an insignificant amount of MTX is degraded to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA). In order to determine whether the renal or hepatic function is responsible for the large intra-individual variation in MTX clearance the urinary excretion of MTX and the liver metabolite 7-hydroxy MTX have been studied, and modelling was applied to predict the individual time span for complete MTX excretion and to reveal early pharmacogenetic/kinetic patterns predictive of elimination of MTX during HDMTX courses in children with ALL.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- Up to 19 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
- Study population
- All children diagnosed and treated for Acute Lymphoblastic Leukemia, ALL, at Rigshospitalet during the last two years, i.e. 43 children, and who will receive HD-MTX during the study period.
Key inclusion criteria (3 listed)
- Admitted to Rigshospitalet
- Diagnosed with ALL
- Receiving high dose MTX
Key exclusion criteria (2 listed)
- Using diaper (only exclusion criteria for the study part concerning urine collection)
- Above 19 years of age
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
clearance
Time frame: within the first 6 months after recruitment has been completed
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jul 2013.
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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.
Kjeld Schmiegelow, MD study chair
Copenhagen University Hospital, Rigshospitalet
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Lymphoblastic Leukemia, Acute, Childhood, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.
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 3 inclusion and 2 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: finished, as of the sponsor's last update on 16 Jul 2013. 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 Denmark. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
clearance (time frame: within the first 6 months after recruitment has been completed). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 16 Jul 2013.