Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Thiopurine EnhAnced Maintenance Therapy (TEAM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02912676
Recruitment Status : Completed
First Posted : September 23, 2016
Last Update Posted : April 15, 2020
Sponsor:
Collaborators:
Danish Child Cancer Foundation
Nordic Society for Pediatric Hematology and Oncology
Information provided by (Responsible Party):
Kjeld Schmiegelow, Rigshospitalet, Denmark

Brief 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. 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).

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.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma Drug: Thioguanine (oral) Phase 1 Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 2016
Actual Primary Completion Date : March 2020
Actual Study Completion Date : April 2020


Arm Intervention/treatment
Experimental: 6TG/6MP/MTX
Single 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.
Drug: Thioguanine (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.
Other Names:
  • 6-mercaptopurine (oral)
  • Methotrexate (oral)




Primary Outcome Measures :
  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.). [ Time Frame: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy ]
    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


Secondary Outcome Measures :
  1. Erythrocyte 6MP cytosol metabolite levels [ Time Frame: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy ]
    Erythrocyte levels are measured at 2 weeks intervals from initiation of 6-thioguanine therapy until completion of ALL/LBL therapy

  2. Myelotoxicity [ Time Frame: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy ]
    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),

  3. Severe hepatotoxicity including sinusoidal obstruction syndrome [ Time Frame: From initiation of 6-thioguanine therapy until completion of ALL/LBL therapy ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   6 Months to 45 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Male and female patients of all ethnicities meeting all of the following criteria will be considered eligible for study participation:

  1. Meet just one of the following:

    1. Confirmed diagnosis with non-HR-ALL and in first remission at inclusion into this investigation. Patients aged 1-45 years at diagnosis are eligible or
    2. Confirmed diagnosis with T-LBL or pB-LBL, and in first remission at inclusion into this investigation. Patients aged 0.6-45 years at the time of inclusion are eligible.
  2. Have reached maintenance II therapy phase at inclusion.
  3. Scheduled to receive 6MP/MTX maintenance therapy without any other concomitant myelosuppressive agents.
  4. Patients must have a minimum of 3 months of 6MP/MTX maintenance therapy remaining at the time of inclusion.
  5. Bilirubin < UNL according to age, factor 2-7-10 > 0.5 or INR < 1.5 within 1 week prior to inclusion.
  6. WBC > 1.5 x109/L, ANC > 0.5 x109/L and TBC > 50 x109/L within 1 week prior to inclusion.
  7. Subject, if female of child-bearing potential (defined as postmenarche), must present with a negative pregnancy test and must be nonlactating.
  8. Sexually active females and males must use accepted safe contraception (OCPs, IUD, transdermal hormonal patch, vaginal hormonal ring or subdermal hormonal implants for women and condom for men) during therapy and until three months after study exit/early termination.
  9. No live vaccines given within 2 months prior to inclusion.
  10. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
  11. Whenever appropriate, the child should participate in the oral and written informed consent process together with the parents. Involving the child in discussions and the decision-making process respects their emerging maturity. This process will be conducted with enough time and at the same time as obtaining the consent from the parents or the legal representative, so that the informed consent reflects the presumed will of the minor, in accordance with Article 4(a) of the Clinical Trial Directive.
  12. If the study participant is unable to provide legally binding consent subject's legally authorized representative (e.g., both parent, legal guardian) must voluntarily sign and date a parental permission/ Informed Consent that is approved by the Danish Ethical Committee(EC), and the subject must sign an EC approved assent, before undergoing any protocol specific procedures or assessments according to Ethical considerations for clinical trials on medicinal products conducted with the paediatric population Directive 2001/20/EC1, ICH/GCP guidelines, and the Helsinki II Declaration.

Exclusion Criteria

  1. 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. 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.
  3. Any clinical suspicion of relapse or disease progression on routine imaging or in laboratory results.
  4. Previous sinusoidal obstruction syndrome (SOS) / veno-occlusive disease (VOD).
  5. Allergic hypersensitivity towards any ingredients in the three medicinal products used in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02912676


Locations
Layout table for location information
Denmark
Aarhus University Hospital Skejby
Skejby, Aarhus, Denmark, 8200
Odense University Hospital, Dept. Pediatric Oncology
Odense, Odense C, Denmark, 5000
Department of Pediatrics, Rigshospitalet
Copenhagen, Denmark, 2100
Rigshospitalet, Department of Hematology
Copenhagen, Denmark, 2100
Sponsors and Collaborators
Kjeld Schmiegelow
Danish Child Cancer Foundation
Nordic Society for Pediatric Hematology and Oncology
Investigators
Layout table for investigator information
Study Chair: Kjeld Schmiegelow, Professor Department of Pediatrics and Adolescent Medicine. University Hospital Rigshospitalet, Copenhagen
Publications:

Layout table for additonal information
Responsible Party: Kjeld Schmiegelow, Professor, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT02912676    
Other Study ID Numbers: Rigshospitalet - TEAM
First Posted: September 23, 2016    Key Record Dates
Last Update Posted: April 15, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data will be entered into the Leukemia Registry of the Nordic Society of Pediatric Hematology/Oncology
Keywords provided by Kjeld Schmiegelow, Rigshospitalet, Denmark:
Cancer
Thioguanine
Acute Lymphoblastic Leukemia
6 Mercaptopurine
Maintenance Therapy of Leukemia
Denmark
Lymphoblastic Lymphoma
Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Methotrexate
Mercaptopurine
Thioguanine
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors