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Acute Lymphoblastic LeukemiaPhase 1/2TEAMNCT02912676

Thiopurine EnhAnced Maintenance Therapy

A Phase 1/2 study testing Thioguanine (oral) in people with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma, run by Kjeld Schmiegelow at 4 sites in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Acute Lymphoblastic Leukaemia (ALL) is the most frequent cancer in children. The survival rate has improved significantly during the last decades, but the treatment still fails to cure 15 % of the patients. Within the Nordic/Baltic countries, children are treated according to the same protocol, i.e. Read more about this study

Who is it for?
Ages 6 months to 45 years
What is being tested?
Thioguanine (oral)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
4 sitesDenmark
Study dates
Oct 2016to Apr 2020
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 6 months to 45 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

None listed.

Who cannot join

  • Patients with ALL and a minimal residual disease (MRD)-negative bone-marrow at treatment day 29 (counted from diagnosis)-since these patients have an excellent prognosis on current therapy, and DNA-TG has not been associated with risk of relapse for these patients
  • 2. DNA-TG > 1,500 fmol/μg DNA due to (i) a potential association with toxicity (although not shown so far), and (ii) the lack of evidence regarding an association between reduced relapse rates and such high DNA-TG levels. If DNA-TG subsequently fell below 1,500 fmol/μg DNA, the patient would be eligible for TEAM.
  • Any clinical suspicion of relapse or disease progression on routine imaging or in laboratory results.
  • Previous sinusoidal obstruction syndrome (SOS) / veno-occlusive disease (VOD).
  • Allergic hypersensitivity towards any ingredients in the three medicinal products used in the study.

Trial locations and contacts

4 sites in 1 country.

Denmark4 sites

  • Department of Pediatrics, Rigshospitalet

    Copenhagen, 2100

  • Rigshospitalet, Department of Hematology

    Copenhagen, 2100

  • Odense University Hospital, Dept. Pediatric Oncology

    Odense, Odense C, 5000

  • Aarhus University Hospital Skejby

    Skejby, Aarhus, 8200

Other trials in Denmark

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, Adolescent, and Adult Lymphoblastic Non-Hodgkin's Lymphoma and Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukaemia (ALL) is the most frequent cancer in children. The survival rate has improved significantly during the last decades, but the treatment still fails to cure 15 % of the patients. Within the Nordic/Baltic countries, children are treated according to the same protocol, i.e. NOPHO ALL-2008 protocol. Children and adolescents with Lymphoblastic Non-Hodgkin's Lymphoma (LBL) are treated in accordance with the EURO-LB 02 protocol, whereas adults with Lymphoblastic Non-Hodgkin's Lymphoma in Denmark are commonly treated in accordance with the NOPHO ALL-2008 protocol.

The longest treatment phase in both protocols is maintenance therapy, which is composed of 6-Mercaptopurine (6MP) and Methotrexate (MTX).

Read more

The cytotoxic property of 6MP relies upon conversion of 6MP into thioguanine nucleotides (TGN), which can be incorporated into DNA instead of guanine or adenine. This incorporation can cause nucleotide mismatching and cause cell death second to repetitive activation of the mismatch repair system. At Rigshospitalet investigators have developed pharmacological methods able to measure the incorporation of TGN into DNA (DNA-TGN). In a Nordic/Baltic study the investigators have demonstrated higher levels of DNA-TGN during maintenance therapy in children with ALL that do not develop relapse (Nielsen et al. Lancet Oncol. 2017 Apr;18(4)).

Preliminary studies indicate that the best approach to obtain DNA-TGN within a target range could be a combination of 6MP, MTX and 6-thioguanine (6TG), as 6TG more readily can be converted into TGN.

This study aims to explore if individual dose titration of 6TG added to 6MP/MTX therapy can achieve DNA-TGN levels above a set target above 500 fmol/µg DNA, and thus can be integrated into future ALL and LBL treatment strategies to reduce relapse rates in ALL and LBL.

The investigators plan to include 30 patients, and A) give incremental doses of 6TG until a mean DNA-TGN level above 500 fmol/µg DNA is obtained; and B) analyze the changes in DNA-TGN as well as cytosol levels of TGN and methylated 6MP metabolites (the latter inhibits purine de novo synthesis and thus enhance DNA-TGN incorporation), and C) occurrence of bone-marrow and liver toxicities during 6TG/6MP/MTX therapy.

Read the detailed description

Acute Lymphoblastic Leukaemia (ALL) is the most frequent cancer in children. Each year approximately 220 children are diagnosed with ALL within the Nordic and Baltic countries.

The survival rate has improved significantly during the last decades, but the treatment still fails to cure approximately 15 % of the patients. A significant proportion of these relapses are likely to reflect adverse drug disposition rather than resistence to antileukemic agents. This emphazises the importance of developing new dosing strategies for reduction of relapse rates.

Most ALL relapses occur during or after maintenance therapy, and recent studies have indicated that almost 50% of these relapses are caused by insuffient exposure of DNA to the cytotoxic metabolites of 6MP.

Childhood Non-Hodgkin's Lymphoma (NHL) constitutes approximately 5% of all childhood malignancies in the Nordic countries and one out of four children with NHL has lymphoblastic lymphoma (LBL), the majority being T cell lymphoblastic lymphoma (T-LBL). Nordic children are treated in accordance with the EURO-LB 02 protocol, and every year 12-15 children are diagnosed with T-LBL within the Nordic countries. During the last 25 years, the cure rate for childhood T-LBL has increased from 25% to 75%, however, among patients failing first line therapy almost none survive.

The treatment of childhood and adolescent T-LBL and pre B cell lymphoblastic lymphoma (pB-LBL) resembles that of ALL and consists of an induction phase, a re-induction phase and a maintenance phase with oral 6MP/MTX, which is continued until 2 years from diagnosis to eliminate residual disease.

Adult LBL accounts for approximately 2% of all NHL, the majority being T-LBL (85-90%). LBL occurs more commonly in children than in adults, mostly in males, and has a highly aggressive nature. The prognosis in adults has dramatically improved with the introduction of pediatric intensive chemotherapy regimens for ALL, in concert with the prognosis of childhood NHL, with a disease-free survival reaching 45-72% in adults. However, a broadly accepted standard treatment for adult T- and pB-LBL has not yet been defined. Patients with T-LBL and pB-LBL, classified as non-HR, and in first remission will be eligible for inclusion into this study.

The cytotoxic property of 6MP relies upon conversion of 6MP into thioguanine nucleotides (TGN). TGN is a substrate for the DNA polymerase, and can be incorporated into DNA instead of guanosine or adenine (DNA-TGN). Incorporated TGN is hereafter occasionally mismatched to thymidine, which causes cell death second to activation of the mismatch repair system. During thiopurine-based therapy patients vary widely in their DNA-TGN levels and patients with low DNA-TGN levels may have an increased risk of relapse.

The investigators will explore

  1. If individualized addition of 6TG to maintenance therapy can obtain a stable mean DNA-TGN level > 500 fmol/microgram DNA after addition of 6TG. DNA-TGN calculated as a 4 weeks mean.
  2. The toxicities encountered during 6TG/6MP/MTX therapy.

The investigators hypothesize that 6TG/6MP/MTX combination therapy will achieve significantly higher DNA-TGN levels, and they will describe toxicities and thiopurine metabolite levels during MTX/6MP/6TG combination therapy.

The TEAM Study is designed as a prospective, multicentre, non-randomised, phase 1-2 clinical trial. This trial is a "proof of principle" and feasibility study planned with a modified crossover design, where participants serve as their own (historical) controls.

Additionally, data from the maintenance therapy substudy by Nielsen et. al (Lancet Oncol. 2017 Apr;18(4)) will be used in order to compare DNA-TG levels in patients receiving MTX/6MP based maintenance therapy, and DNA-TG levels in patients treated according to TEAM strategy (i.e. maintenance therapy with MTX/6MP/6TG).

Pharmacological target:

The investigators will include 30 participants. Upon inclusion in the TEAM study; 6MP dose is reduced to 2/3rd, if the current 6MP dose is > 50 mg/m2/day. However, if 6MP dose reduction is indicated, 6MP dose is not reduced below 50 mg/m2/day. If the current 6MP dose is < 50 mg/m2/day, the patient continues on this 6MP dose without dose reduction. 6TG treatment is initiated concomitantly. MTX dose is not changed. The investigators give A) incremental doses of 6TG (steps of 2.5 mg/meter square, max 12.5 mg/meter square) until a mean DNA-TGN of at least 500 fmol/µg DNA is obtained; and B) analyze the changes in DNA-TGN as well as Ery-TGN and MeMP. The dose increments of 6TG in steps of 2.5 mg/square metre will be spaced by intervals of at least two weeks, and DNA-TGN measurements will be measured weekly during 6TG dose increments. 6TG dose increments will continue until a mean DNA-TGN level > 500 fmol/µg or a maximum dose of 6TG of 12.5 mg/square metre is reached. If tolerated, the participant can then continue on that 6TG dose until the end of ALL/LBL therapy. Participants can at any time point drop out of TEAM by their own decision or by that of the treating physician. 6TG is provided as a liquid formulation to ease precise dose titration.

Being tested
Thioguanine (oral)
Keywords
Cancer, Thioguanine, Acute Lymphoblastic Leukemia, 6 Mercaptopurine, Maintenance Therapy of Leukemia, Denmark, Lymphoblastic Lymphoma
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Thioguanine (oral)Drug

    Also called 6-mercaptopurine (oral), Methotrexate (oral)

    Addition of incremental doses of oral Thioguanine to oral daily 6-mercaptopurine and oral weekly methotrexate maintenance therapy of Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Oral 6-thioguanine is added at a starting dose of 2.5 mg/m.sq. with dose increments of 2.5 mg/m.sq. at two weeks intervals until a maximum dose of 12.5 mg/m.sq. of 6-thioguanine is given or dose-limiting toxicity occurs.

Study groups in NCT02912676
Study groupRoleWhat they receive
6TG/6MP/MTXExperimentalSingle arm feasibility study aiming to demonstrate the applicability of combining incremental doses of oral 6-Thioguanine with oral daily 6-Mercaptopurine and oral weekly Methotrexate in order to achieve mean levels of DNA-TG above 500 fmol/mikrogram DNA.
Receives: Drug: Thioguanine (oral)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Obtaining a stable mean DNA-TGN level > 500 fmol/microgram DNA after addition of 6TG. DNA-TGN calculated as a 4 weeks mean (maximum 6TG dose 12.5 mg/m.xq.).

    After incremental doses in steps of 2.5 mg/m.sq. of 6-thioguanine at 2 weeks intervals up to a maximum dose of 12.5 mg/m.sq. or a dose-limiting toxicity occur or a mean DNA-TGN level above 500 fmol/microgram DNA is obtained. Maximum dose is expected to be reached within 10-12 weeks

    Measured: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy

Secondary outcomes (3)

  1. Erythrocyte 6MP cytosol metabolite levels

    Erythrocyte levels are measured at 2 weeks intervals from initiation of 6-thioguanine therapy until completion of ALL/LBL therapy

    Measured: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy

  2. Myelotoxicity

    The dose-limiting toxicities are white blood cell count < 1.5x109/L and/or absolute neutrophil count < 0.5 x109/L and/or thrombocyte count < 50 x109/L),

    Measured: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy

  3. Severe hepatotoxicity including sinusoidal obstruction syndrome

    Dose-limiting severe hepatotoxicities include alanine aminotransferase > 20 x upper normal limit (UNL) and/or bilirubin > 3x UNL (according to age) and/or coagulation factors 2-7-10 < 0.50 (or INR > 1.5), and or clinical signs of sinusoidal obstruction syndrome (with at least 3 of 5 criteria: i) hepatomegaly, ii) hyperbilirubinaemia >UNL), iii) ascites, iv) weight gain of at least 5%, and v) thrombocytopenia (transfusion-resistant and/or otherwise unexplained by treatment induced myelosuppression.

    Measured: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Sep 2016 (estimated)
  2. Study startOct 2016
  3. Primary completionMar 2020
  4. Study completionApr 2020

Resources

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
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02912676
Sponsor's protocol ID
Rigshospitalet - TEAM
Acronym
TEAM
Status last verified
Apr 2020
First submitted
12 Sep 2016
Last updated
15 Apr 2020
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Yes: Individual participant data will be entered into the Leukemia Registry of the Nordic Society of Pediatric Hematology/Oncology

Publications

  • Gustafsson G, Schmiegelow K, Forestier E, Clausen N, Glomstein A, Jonmundsson G, Mellander L, Makipernaa A, Nygaard R, Saarinen-Pihkala UM. Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation. Nordic Society of Pediatric Haematology and Oncology (NOPHO). Leukemia. 2000 Dec;14(12):2267-75. doi: 10.1038/sj.leu.2401961.

    PubMed 11187918

  • Schmiegelow K, Forestier E, Hellebostad M, Heyman M, Kristinsson J, Soderhall S, Taskinen M; Nordic Society of Paediatric Haematology and Oncology. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia. 2010 Feb;24(2):345-54. doi: 10.1038/leu.2009.251. Epub 2009 Dec 10.

    PubMed 20010622

  • Pui CH, Campana D, Evans WE. Childhood acute lymphoblastic leukaemia--current status and future perspectives. Lancet Oncol. 2001 Oct;2(10):597-607. doi: 10.1016/S1470-2045(01)00516-2.

    PubMed 11902549

  • Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J. Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol. 2014 Oct;36(7):503-17. doi: 10.1097/MPH.0000000000000206.

    PubMed 24936744

  • Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood. 1999 May 1;93(9):2817-23.

    PubMed 10216075

  • Schmiegelow K, Schroder H, Gustafsson G, Kristinsson J, Glomstein A, Salmi T, Wranne L. Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology. J Clin Oncol. 1995 Feb;13(2):345-51. doi: 10.1200/JCO.1995.13.2.345.

    PubMed 7531219

  • Schmiegelow K, Forestier E, Kristinsson J, Soderhall S, Vettenranta K, Weinshilboum R, Wesenberg F; Nordic Society of Paediatric Haematology and Oncology. Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia. 2009 Mar;23(3):557-64. doi: 10.1038/leu.2008.316. Epub 2008 Nov 6.

    PubMed 18987654

  • Cooper SL, Brown PA. Treatment of pediatric acute lymphoblastic leukemia. Pediatr Clin North Am. 2015 Feb;62(1):61-73. doi: 10.1016/j.pcl.2014.09.006. Epub 2014 Oct 18.

    PubMed 25435112

  • Hunger SP, Winick NJ, Sather HN, Carroll WL. Therapy of low-risk subsets of childhood acute lymphoblastic leukemia: when do we say enough? Pediatr Blood Cancer. 2005 Dec;45(7):876-80. doi: 10.1002/pbc.20501. No abstract available.

    PubMed 16007585

  • Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008 Jan;8(1):24-36. doi: 10.1038/nrc2292.

    PubMed 18097462

  • Hedeland RL, Hvidt K, Nersting J, Rosthoj S, Dalhoff K, Lausen B, Schmiegelow K. DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma. Cancer Chemother Pharmacol. 2010 Aug;66(3):485-91. doi: 10.1007/s00280-009-1184-5. Epub 2009 Dec 3.

    PubMed 19956952

  • Ebbesen MS, Nersting J, Jacobsen JH, Frandsen TL, Vettenranta K, Abramsson J, Wesenberg F, Schmiegelow K. Incorporation of 6-thioguanine nucleotides into DNA during maintenance therapy of childhood acute lymphoblastic leukemia-the influence of thiopurine methyltransferase genotypes. J Clin Pharmacol. 2013 Jun;53(6):670-4. doi: 10.1002/jcph.81. Epub 2013 Apr 15. No abstract available.

    PubMed 23585236

  • Jacobsen JH, Schmiegelow K, Nersting J. Liquid chromatography-tandem mass spectrometry quantification of 6-thioguanine in DNA using endogenous guanine as internal standard. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Jan 15;881-882:115-8. doi: 10.1016/j.jchromb.2011.11.032. Epub 2011 Nov 28.

    PubMed 22178190

  • Erb N, Harms DO, Janka-Schaub G. Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol. 1998;42(4):266-72. doi: 10.1007/s002800050816.

    PubMed 9744770

  • Schmiegelow K, Bjork O, Glomstein A, Gustafsson G, Keiding N, Kristinsson J, Makipernaa A, Rosthoj S, Szumlanski C, Sorensen TM, Weinshilboum R. Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol. 2003 Apr 1;21(7):1332-9. doi: 10.1200/JCO.2003.04.039.

    PubMed 12663723

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Thioguanine (oral) in people with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma, run by Kjeld Schmiegelow at 4 sites 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 0 inclusion and 5 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 15 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites 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 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?

Obtaining a stable mean DNA-TGN level > 500 fmol/microgram DNA after addition of 6TG. DNA-TGN calculated as a 4 weeks mean (maximum 6TG dose 12.5 mg/m.xq.). (time frame: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy). 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 NCT02912676, which also lists 22 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 15 Apr 2020.

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