Non-Hodgkin LymphomaPhase 1/2NCT02141100
Study of 6-Thioguanine in Combination With 6-Mercaptopurine During Maintenance Therapy of Childhood Lymphoma
A Phase 1/2 study testing 6-thioguanine in people with Non-Hodgkin Lymphoma, run by Kjeld Schmiegelow at 1 site in Denmark.
Trial summary
The purpose of this phase 1-2 study is to explore the applicability of supplementing standard methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy of children with non-Hodgkin lymphoma with 6-thioguanine (6TG). Read more about this study
- Who is it for?
- Ages 2 to 18 years
- Conditions the study is for
- Non-Hodgkin Lymphoma
- What is being tested?
- 6-thioguanine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteDenmark
- Study dates
- Jul 2014to Oct 2016
- Phase
- Phase 1/2
- 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 2 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Confirmed histomorphological or cytomorphological diagnosis of NHL or ALL.
- Meets just one of the following:
- Patient with NHL treated after the EURO-LB 02 protocol with at least 3.5 months of 6MP/MTX maintenance therapy remaining or
- Patient with ALL or NHL not achieving the target WBC (patients with a WBC > 3.0 x10^9/L) and/or experience elevated liver enzymes (ALAT > UNL) attributed to a simultaneous high Ery-MeMP level on standard MTX/6MP maintenance therapy.
- TPMT wild-type genotype or TPMT high activity phenotype (TPMT activity above 14 IU/mL or during maintenance therapy TPMT above 8 IU/mL measured in erythrocytes).
- Bilirubin < 35 micromol/L, factor 2-7-10 > 0.5 or INR < 1.5 and normal hepatic blood flow (verified by ultrasound) within 1 week prior to inclusion.
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- WBC > 1.5 x10^9/L, ANC > 0.5 x10^9/L and TBC > 50 x10^9/L within 1 week prior to inclusion.
- Pubertal females, Tanner stage B3/PH3 or higher, must present with a negative pregnancy test.
- Sexually active females must use accepted safe contraception (OCPs, IUD, transdermal hormonal patch, vaginal hormonal ring or subdermal hormonal implants) during therapy and until a month after completion of therapy.
- Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
- Oral and written informed consent to participate have been provided by both the parents (and when appropriate by the patient) according to the ICH/GCP guidelines and the Helsinki II Declaration.
- Patients with acute lymphoblastic lymphoma (0-17.9 yrs) not achieving the target WBC (patients with a WBC > 3.0 x10^9/L) and/or experience elevated liver enzymes (ALAT > UNL) attributed to a simultaneous high Ery-MeMP level on standard MTX/6MP maintenance therapy.
Who cannot join
- Any clinical suspicion of relapse or disease progression on routine imaging or in laboratory results.
- Previous veno-occlusive disease (VOD).
- Allergy towards any of the ingredients in the three medicinal products used in the study.
Trial locations and contacts
1 site in 1 country.
Denmark1 site
Dept. of Pediatric Oncology, JMC, Rigshospitalet
Copenhagen, 2100
About this study
Official title: A Phase 1-2 Study of 6-Thioguanine in Combination With Methotrexate and 6-Mercaptopurine During Maintenance Therapy of Childhood Non-Hodgkin's Lymphoma
The purpose of this phase 1-2 study is to explore the applicability of supplementing standard methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy of children with non-Hodgkin lymphoma with 6-thioguanine (6TG).
The investigators hypothesize that addition of 6TG to 6MP-based maintenance therapy of patients with high TPMT activity will mimic the more favourable thiopurine metabolism of patients with low TPMT activity and ultimately reduce relapse rates.
Read the detailed description
MTX/6MP maintenance therapy is challenged by treatment related liver toxicity, failure to achieve the target treatment parameter in all patients, and lack of direct parameters for monitoring treatment efficacy or even intensity. Patients with low activity of thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of 6MP, have lower levels of liver toxic metabolites (MeMPs), higher levels of the major active metabolites (TGNs), and reduced relapse rates. Most patients (90%) have high TPMT activity. Nearly all patients with high TPMT activity and high MeMP levels experience elevated liver enzymes. Increasing the 6MP dose in patients with high TPMT activity, to intensify therapy, will mainly lead to further increase in the MeMP level. A novel approach compensating the adverse thiopurine metabolism of the majority of patients is warranted.
- Conditions
- Non-Hodgkin Lymphoma
- Being tested
- 6-thioguanine
- Keywords
- thioguanine, mercaptopurine, methotrexate
- Medical subject headings
- Lymphoma, Non-Hodgkin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
6-thioguanineDrug
All eligible patients will be supplemented with 6-thioguanine in addition to the standard therapy with 6-mercaptopurine and methotrexate.
In case of significant myelo-/hepatotoxicity all therapy will be paused. If patients develop VOD they will be excluded from further 6TG therapy.
| Study group | Role | What they receive |
|---|---|---|
| 6-thioguanine, 6-mercaptopurine and methotrexate | Experimental | This is the only treatment arm; all eligible patients will receive standard methotrexate/6-mercaptopurine (6MP/MTX) maintenance therapy supplemented with 6-thioguanine (6TG).
Patients are enrolled when they have 12 to 3.5 months remaining of their maintenance therapy. After dose reduction in 6MP to 2/3 of the current dose 6TG therapy is initiated with a starting dose of 2.5 mg/m2/day. The 6TG dose will hereafter be increased at 2.5 mg/m2/day every 14 days until a max. of 12.5 mg/m2/day is reached or until the thiopurine metabolite profile (Ery-TGN/Ery-MeMP) has been increased by at least a factor 5. Receives: Drug: 6-thioguanine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in median thiopurine metabolite index
Change in Ery-TGN/Ery-MeMP after addition of 6-thioguanine to therapy. The thiopurine metabolites will be measured every 2 weeks during the trial period. The trial period is max. 12 months.
Measured: Every 2 weeks up to the max. trial period of 12 months
Secondary outcomes (2)
Toxicities
Myelo- and hepatotoxicity. Blood samples (WBC, neutrophil count, thrombocyte count, ALAT, bilirubin, factors 2-7-10) will be taken every 2 weeks throughout the trial period and at additional time points in case of clinical signs/symptoms of toxicity.
Measured: Minimum every 2 weeks, up to 12 months
Change in median DNA-TG
Change in DNA-TG (incorporation of thioguanine nucleotides in to DNA) after addition of 6-thioguanine. This parameter will be measured every 2 weeks during the trial period. The max. trial period is 12 months.
Measured: Every 2 weeks, up to 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 May 2014 (estimated)
- Study startJul 2014
- Primary completionOct 2016 (estimated)
- Study completionOct 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-Hodgkin LymphomaStudies of the same condition, open and under way.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Kjeld Schmiegelow
- Sponsor type
- University, hospital or other
- Collaborators
- Aalborg University Hospital, Aarhus University Hospital Skejby, Odense University Hospital
- Responsible party
- Sponsor-investigator, Kjeld Schmiegelow, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Kjeld Schmiegelow, M.D., Study chair, Copenhagen University Hospital, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02141100
- Sponsor's protocol ID
- JMC-2014-6TG/6MP
- Status last verified
- Oct 2016
- First submitted
- 7 May 2014
- Last updated
- 7 Oct 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 7 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1-2 Study of 6-Thioguanine in Combination With Methotrexate and 6-Mercaptopurine During Maintenance Therapy of Childhood Non-Hodgkin's Lymphoma
- ClinicalTrials.gov ID
- NCT02141100
- Acronym / sponsor ID
- JMC-2014-6TG/6MP
- Conditions
- Non-Hodgkin Lymphoma
- Keywords
- thioguanine, mercaptopurine, methotrexate
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Kjeld SchmiegelowUniversity, hospital or other
- Collaborators
- Aalborg University Hospital, Aarhus University Hospital Skejby, Odense University Hospital
- Study start
- Jul 2014
- Primary completion
- Oct 2016 (estimated)
- Study completion
- Oct 2016 (estimated)
- First posted
- 19 May 2014 (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 phase 1-2 study is to explore the applicability of supplementing standard methotrexate/6-mercaptopurine (MTX/6MP) maintenance therapy of children with non-Hodgkin lymphoma with 6-thioguanine (6TG).
The investigators hypothesize that addition of 6TG to 6MP-based maintenance therapy of patients with high TPMT activity will mimic the more favourable thiopurine metabolism of patients with low TPMT activity and ultimately reduce relapse rates.
Detailed description
MTX/6MP maintenance therapy is challenged by treatment related liver toxicity, failure to achieve the target treatment parameter in all patients, and lack of direct parameters for monitoring treatment efficacy or even intensity. Patients with low activity of thiopurine methyltransferase (TPMT), an enzyme involved in the metabolism of 6MP, have lower levels of liver toxic metabolites (MeMPs), higher levels of the major active metabolites (TGNs), and reduced relapse rates. Most patients (90%) have high TPMT activity. Nearly all patients with high TPMT activity and high MeMP levels experience elevated liver enzymes. Increasing the 6MP dose in patients with high TPMT activity, to intensify therapy, will mainly lead to further increase in the MeMP level. A novel approach compensating the adverse thiopurine metabolism of the majority of patients is warranted.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 6-thioguanine, 6-mercaptopurine and methotrexate | Experimental | Drug: 6-thioguanineThis is the only treatment arm; all eligible patients will receive standard methotrexate/6-mercaptopurine (6MP/MTX) maintenance therapy supplemented with 6-thioguanine (6TG). Patients are enrolled when they have 12 to 3.5 months remaining of their maintenance therapy. After dose reduction in 6MP to 2/3 of the current dose 6TG therapy is initiated with a starting dose of 2.5 mg/m2/day. The 6TG dose will hereafter be increased at 2.5 mg/m2/day every 14 days until a max. of 12.5 mg/m2/day is reached or until the thiopurine metabolite profile (Ery-TGN/Ery-MeMP) has been increased by at least a factor 5. |
Who may qualify
- Ages
- 2 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (12 listed)
- Confirmed histomorphological or cytomorphological diagnosis of NHL or ALL.
- Meets just one of the following:
- TPMT wild-type genotype or TPMT high activity phenotype (TPMT activity above 14 IU/mL or during maintenance therapy TPMT above 8 IU/mL measured in erythrocytes).
- Bilirubin < 35 micromol/L, factor 2-7-10 > 0.5 or INR < 1.5 and normal hepatic blood flow (verified by ultrasound) within 1 week prior to inclusion.
- WBC > 1.5 x10^9/L, ANC > 0.5 x10^9/L and TBC > 50 x10^9/L within 1 week prior to inclusion.
Key exclusion criteria (3 listed)
- Any clinical suspicion of relapse or disease progression on routine imaging or in laboratory results.
- Previous veno-occlusive disease (VOD).
- Allergy towards any of the ingredients in the three medicinal products used in the study.
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 |
|---|---|---|
| 6-thioguanineAll eligible patients will be supplemented with 6-thioguanine in addition to the standard therapy with 6-mercaptopurine and methotrexate. In case of significant myelo-/hepatotoxicity all therapy will be paused. If patients develop VOD they will be excluded from further 6TG therapy. | Drug | 6-thioguanine, 6-mercaptopurine and methotrexate |
Primary outcome
Change in median thiopurine metabolite index
Time frame: Every 2 weeks up to the max. trial period of 12 months
Change in Ery-TGN/Ery-MeMP after addition of 6-thioguanine to therapy. The thiopurine metabolites will be measured every 2 weeks during the trial period. The trial period is max. 12 months.
2 secondary outcomes
Toxicities
Time frame: Minimum every 2 weeks, up to 12 months
Change in median DNA-TG
Time frame: Every 2 weeks, up to 12 months
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Oct 2016.
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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, M.D. 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?
A Phase 1/2 study testing 6-thioguanine in people with Non-Hodgkin Lymphoma, run by Kjeld Schmiegelow 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 12 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: withdrawn, as of the sponsor's last update on 7 Oct 2016. 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.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
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?
Change in median thiopurine metabolite index (time frame: Every 2 weeks up to the max. trial period of 12 months). 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 7 Oct 2016; AzTrials last refreshed its copy on 7 Nov 2026.