- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01896752
Renal and Hepatic Clearance Following High-Dose Methotrexate in Childhood ALL
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.
Study Overview
Status
Conditions
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 Type
Enrollment (Actual)
Contacts and Locations
Study Locations
-
-
-
Copenhagen, Denmark, 2100
- Department of Pediatrics, Rigshospitalet
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
Inclusion Criteria:
- Admitted to Rigshospitalet
- Diagnosed with ALL
- Receiving high dose MTX
Exclusion Criteria:
- Using diaper (only exclusion criteria for the study part concerning urine collection)
- Above 19 years of age
Study Plan
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Prospective
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
clearance
Time Frame: within the first 6 months after recruitment has been completed
|
within the first 6 months after recruitment has been completed
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Chair: Kjeld Schmiegelow, MD, Rigshospitalet, Denmark
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- R35-A1642-10S7
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.
Clinical Trials on Lymphoblastic Leukemia, Acute, Childhood
-
National Cancer Institute (NCI)CompletedRecurrent Childhood Acute Lymphoblastic Leukemia | L1 Childhood Acute Lymphoblastic Leukemia | L2 Childhood Acute Lymphoblastic Leukemia | T-cell Childhood Acute Lymphoblastic Leukemia | Non-T, Non-B Childhood Acute Lymphoblastic LeukemiaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedChildhood Acute Lymphoblastic Leukemia in Remission | Graft Versus Host Disease | B-cell Childhood Acute Lymphoblastic Leukemia | L1 Childhood Acute Lymphoblastic Leukemia | L2 Childhood Acute Lymphoblastic Leukemia | T-cell Childhood Acute Lymphoblastic LeukemiaUnited States, Canada, Australia
-
National Cancer Institute (NCI)CompletedB-cell Adult Acute Lymphoblastic Leukemia | Acute Undifferentiated Leukemia | Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia | B-cell Childhood Acute Lymphoblastic Leukemia | L1 Childhood Acute Lymphoblastic Leukemia | L2 Childhood Acute Lymphoblastic Leukemia | T-cell... and other conditionsUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedChildhood Acute Lymphoblastic Leukemia in Remission | Recurrent Childhood Acute Lymphoblastic Leukemia | B-cell Childhood Acute Lymphoblastic Leukemia | T-cell Childhood Acute Lymphoblastic LeukemiaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedRecurrent Childhood Acute Lymphoblastic Leukemia | B-cell Childhood Acute Lymphoblastic Leukemia | Untreated Childhood Acute Lymphoblastic LeukemiaUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedB-cell Childhood Acute Lymphoblastic Leukemia | L1 Childhood Acute Lymphoblastic Leukemia | L2 Childhood Acute Lymphoblastic Leukemia | Intermediate Risk Recurrent Childhood Acute Lymphoblastic LeukemiaUnited States, Canada, Australia, Switzerland
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedChildhood Acute Lymphoblastic Leukemia in Remission | Recurrent Childhood Acute Lymphoblastic Leukemia | B-cell Childhood Acute Lymphoblastic LeukemiaUnited States
-
Autolus LimitedCompletedCD19 /22 CAR T Cells (AUTO3) for the Treatment of B Cell Acute Lymphoblastic Leukemia (ALL) (AMELIA)Recurrent Childhood Acute Lymphoblastic Leukemia | B Acute Lymphoblastic Leukemia | B-cell Acute Lymphoblastic Leukemia | Refractory Childhood Acute Lymphoblastic LeukemiaUnited Kingdom
-
National Cancer Institute (NCI)CompletedRecurrent Adult Lymphoblastic Lymphoma | Recurrent Adult Acute Lymphoblastic Leukemia | Recurrent Childhood Acute Lymphoblastic Leukemia | B-cell Adult Acute Lymphoblastic Leukemia | B-cell Childhood Acute Lymphoblastic Leukemia | T-cell Childhood Acute Lymphoblastic Leukemia | Recurrent Childhood... and other conditionsUnited States, Canada, Australia, Puerto Rico
-
National Cancer Institute (NCI)CompletedT-cell Childhood Acute Lymphoblastic Leukemia | Untreated Childhood Acute Lymphoblastic LeukemiaUnited States