Thiopurine EnhAnced Maintenance Therapy (TEAM)
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|ClinicalTrials.gov Identifier: NCT02912676|
Recruitment Status : Unknown
Verified April 2017 by Kjeld Schmiegelow, Rigshospitalet, Denmark.
Recruitment status was: Recruiting
First Posted : September 23, 2016
Last Update Posted : April 25, 2017
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 nuclotide 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.
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, methylated 6MP metabolites, and MTX polyglutamates (the latter two metabolites inhibit 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 Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Study Start Date :||October 2016|
|Estimated Primary Completion Date :||December 2018|
|Estimated Study Completion Date :||December 2018|
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. 6-mercaptopurine is reduced by 33% two weeks before addition of 6-thioguanine, while dose of methotrexate is unchanged. Oral 6-thioguanine is then 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.
- 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: 2-4 weeks after maximum dose of 6-thioguanine ]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
- Erythrocyte 6MP cytosol metabolite levels [ Time Frame: From initiation of 6-thioguanine therapy until 4 weeks after maximum dose of 6-thioguanine ]Erythrocyte levels are measured at 2 weeks intervals during the dose increment period (approximately 12 weeks)
- Myelotoxicity [ Time Frame: From initiation of 6-thioguanine therapy until 4 weeks after maximum dose of 6-thioguanine ]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),
- Severe hepatotoxicity including sinusoidal obstruction syndrome [ Time Frame: From initiation of 6-thioguanine therapy until 4 weeks after maximum dose of 6-thioguanine ]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.
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
|Contact: Kjeld Schmiegelow, Professor||+45 email@example.com|
|Contact: Rikke Hebo Larsen, MD||+45 firstname.lastname@example.org|
|Department of Pediatrics, Rigshospitalet||Recruiting|
|Copenhagen, Denmark, 2100|
|Contact: Kjeld Schmiegelow, MD +45 3545 1357 email@example.com|
|Contact: Rikke H Larsen, MD +45 35457093 firstname.lastname@example.org|
|Sub-Investigator: Rikke H Larsen, MD|
|Rigshospitalet, Department of Hematology||Recruiting|
|Copenhagen, Denmark, 2100|
|Contact: Cecilie U Rank, M.D. +45 35454534 email@example.com|
|Contact: Ove J Nielsen, M.D. +45 35451144 firstname.lastname@example.org|
|Study Chair:||Kjeld Schmiegelow, Professor||Department of Pediatrics and Adolescent Medicine. University Hospital Rigshospitalet, Copenhagen|