Acute Lymphoblastic LeukemiaNCT01886651
The Influence of Thiopurine Methyltransferase Activity on Toxicity After High-dose Methotrexate in Childhood Acute Lymphoblastic Leukemia
An observational study of Acute Lymphoblastic Leukemia, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.
Trial summary
The purpose of this study is to explore the impact of thiopurine methyltransferase (TPMT) activity on the risk of HDM-related bone marrow- and hepatotoxicity and treatment interruptions during maintenance therapy for children with ALL. Read more about this study
- Who is it for?
- Ages 1 year to 15 years
- Conditions the study is for
- Acute Lymphoblastic Leukemia
- How many people
- 411 participants
- Where
- 1 siteDenmark
- Study dates
- Jul 2011to Feb 2012
- 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 1 year to 15 years
- All sexes
- No healthy volunteers
- Child
Study population: The study cohort was based on patients enrolled in the NOPHO ALL92 protocol, where 97% of all eligible patients were included. Participation in this study was on the basis of TPMT status that was randomly missing.
Who may be able to join
- included in the NOPHO ALL92 protocol
- available TPMT phenotype
- treated at least once with HD-MTX 5.0 g/m2 (+- 10%) during maintenance therapy
- at least one available measurement on blood counts or alanine aminotransferase levels 28 days after HD-MTX
Who cannot join
- HR ALL
- children with Down Syndrome
- Events during maintenance therapy
- TPMT deficiency
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Influence of Thiopurine Methyltransferase Activity on Bone Marrow- and Hepato-toxicity After High-dose Methotrexate in Childhood Acute Lymphoblastic Leukemia
The purpose of this study is to explore the impact of thiopurine methyltransferase (TPMT) activity on the risk of HDM-related bone marrow- and hepatotoxicity and treatment interruptions during maintenance therapy for children with ALL.
Hypothesis of the study: Patients with TPMT activity compatible with TPMT low activity polymorphisms have an increased risk of toxicity following high-dose methotrexate (HDM) compared to children with normal TPMT activity.
Read the detailed description
High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood ALL. Several studies have indicated that MTX and 6MP act synergistically. It has previously been reported that the risk of significant bone-marrow suppression is increased if oral 6MP is coadministered with HDM during maintenance therapy and that reductions of the dose of concurrently given oral 6MP can reduce the risk of significant myelotoxicity following HDM. MTX may increase the bioavailability of 6MP through inhibition of xanthine oxidase, which catabolizes 6MP. In addition, MTX may through inhibition of de novo purine synthesis enhance the availability of 6-thioguanine nucleotides (6TGN) that primarily exert the cytotoxic effect of 6MP.
The enzyme TPMT competes with the formation of 6TGN, as it methylates 6MP and thus create relatively non-toxic metabolites. TPMT heterozygous patients with one wild type and one low-activity allele have a higher risk of myelosuppression and treatment interruption compared to patients with TPMT wild type. Furthermore, TPMT heterozygous patients have a reduced risk of relapse and a higher risk of secondary malignancy compared to patients with TPMT wild type.
Little has been published on the influence of both TPMT activity and 6MP dosage on myelo- and hepatotoxicity following HDM.
- Conditions
- Acute Lymphoblastic Leukemia
- Keywords
- acute lymphoblastic leukemia, child, 6-mercaptopurine, methotrexate
- 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.
Toxicity of treatment, degree of myelo- and hepatotoxicity
Measured: 7-28 days after high-dose methotrexate
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jun 2013 (estimated)
- Study startJul 2011
- Primary completionFeb 2012
- Study completionFeb 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Lymphoblastic LeukemiaStudies 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
- Retrospective
- Enrolment
- 411 participants (actual)
Sponsor and investigators
- Lead sponsor
- Copenhagen University Hospital, Rigshospitalet
- Sponsor type
- University, hospital or other
- Collaborators
- Nordic Society for Pediatric Hematology and Oncology
- Responsible party
- Principal investigator, Kjeld Schmiegelow, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Kjeld Schmiegelow, M.D., Principal investigator, Copenhagen University Hospital, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01886651
- Sponsor's protocol ID
- NOPHO ALL92 study HDM TPMT
- Status last verified
- Jun 2013
- First submitted
- 21 Jun 2013
- Last updated
- 26 Jun 2013
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Jun 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Influence of Thiopurine Methyltransferase Activity on Bone Marrow- and Hepato-toxicity After High-dose Methotrexate in Childhood Acute Lymphoblastic Leukemia
- ClinicalTrials.gov ID
- NCT01886651
- Acronym / sponsor ID
- NOPHO ALL92 study HDM TPMT
- Conditions
- Acute Lymphoblastic Leukemia
- Keywords
- acute lymphoblastic leukemia, child, 6-mercaptopurine, methotrexate
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 411 participants (actual)
- Lead sponsor
- Copenhagen University Hospital, RigshospitaletUniversity, hospital or other
- Collaborators
- Nordic Society for Pediatric Hematology and Oncology
- Study start
- Jul 2011
- Primary completion
- Feb 2012 (actual)
- Study completion
- Feb 2012 (actual)
- First posted
- 26 Jun 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.
The purpose of this study is to explore the impact of thiopurine methyltransferase (TPMT) activity on the risk of HDM-related bone marrow- and hepatotoxicity and treatment interruptions during maintenance therapy for children with ALL.
Hypothesis of the study: Patients with TPMT activity compatible with TPMT low activity polymorphisms have an increased risk of toxicity following high-dose methotrexate (HDM) compared to children with normal TPMT activity.
Detailed description
High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood ALL. Several studies have indicated that MTX and 6MP act synergistically. It has previously been reported that the risk of significant bone-marrow suppression is increased if oral 6MP is coadministered with HDM during maintenance therapy and that reductions of the dose of concurrently given oral 6MP can reduce the risk of significant myelotoxicity following HDM. MTX may increase the bioavailability of 6MP through inhibition of xanthine oxidase, which catabolizes 6MP. In addition, MTX may through inhibition of de novo purine synthesis enhance the availability of 6-thioguanine nucleotides (6TGN) that primarily exert the cytotoxic effect of 6MP.
The enzyme TPMT competes with the formation of 6TGN, as it methylates 6MP and thus create relatively non-toxic metabolites. TPMT heterozygous patients with one wild type and one low-activity allele have a higher risk of myelosuppression and treatment interruption compared to patients with TPMT wild type. Furthermore, TPMT heterozygous patients have a reduced risk of relapse and a higher risk of secondary malignancy compared to patients with TPMT wild type.
Little has been published on the influence of both TPMT activity and 6MP dosage on myelo- and hepatotoxicity following HDM.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
Who may qualify
- Ages
- 1 year to 15 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
- Study population
- The study cohort was based on patients enrolled in the NOPHO ALL92 protocol, where 97% of all eligible patients were included. Participation in this study was on the basis of TPMT status that was randomly missing.
Key inclusion criteria (4 listed)
- included in the NOPHO ALL92 protocol
- available TPMT phenotype
- treated at least once with HD-MTX 5.0 g/m2 (+- 10%) during maintenance therapy
- at least one available measurement on blood counts or alanine aminotransferase levels 28 days after HD-MTX
Key exclusion criteria (4 listed)
- HR ALL
- children with Down Syndrome
- Events during maintenance therapy
- TPMT deficiency
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
Toxicity of treatment, degree of myelo- and hepatotoxicity
Time frame: 7-28 days after high-dose methotrexate
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 26 Jun 2013.
Related trials for Acute Lymphoblastic Leukemia
Active, not recruitingPhase 2
Brentuximab Vedotin and Combination Chemotherapy in Treating Patients With CD30-Positive Peripheral T-cell Lymphoma
Adult T-Cell Leukemia/Lymphoma, Anaplastic Large Cell Lymphoma, ALK-Negative
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Not yet recruitingPhase 2
Obesity Treatment With Phentermine-Topiramate ER in AYA Surviving Leukemia and Lymphoma
Acute Lymphoblastic Leukemia in Remission, Hodgkin Lymphoma in Remission
Recruiting
A Multicenter Study to Evaluate Next-Generation Sequencing (NGS) Testing and Monitoring of B-Cell Recovery to Guide Management Following Chimeric Antigen Receptor T-cell (CART) Induced Remission in Children and Young Adults With B Lineage Acute Lymph...
B-All, Acute Lymphoblastic Leukemia
Not yet recruitingPhase 1
A Study to Assess the Pharmacokinetics and Safety of Revumenib in Participants With Advanced Cancer and Hepatic or Renal Impairment
Relapsed/Refractory (R/R) Hematologic Malignancies, Acute Leukemia
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, M.D. principal investigator
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 Acute Lymphoblastic Leukemia, 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 4 inclusion and 4 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 26 Jun 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?
Toxicity of treatment, degree of myelo- and hepatotoxicity (time frame: 7-28 days after high-dose methotrexate). 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 26 Jun 2013.