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 |
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Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma | Drug: Thioguanine (oral) | Phase 1 Phase 2 |
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 |
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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.
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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:
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Ages Eligible for Study: | 6 Months to 45 Years (Child, Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Male and female patients of all ethnicities meeting all of the following criteria will be considered eligible for study participation:
Meet just one of the following:
Exclusion Criteria
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 |
Study Chair: | Kjeld Schmiegelow, Professor | Department of Pediatrics and Adolescent Medicine. University Hospital Rigshospitalet, Copenhagen |
Tracking Information | |||||
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First Submitted Date ICMJE | September 12, 2016 | ||||
First Posted Date ICMJE | September 23, 2016 | ||||
Last Update Posted Date | April 15, 2020 | ||||
Actual Study Start Date ICMJE | October 2016 | ||||
Actual Primary Completion Date | March 2020 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
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
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Original Primary Outcome Measures ICMJE |
DNA-TGN >500 fmol/microgram DNA after intervention with 6-thioguanine (maximum 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 DNA-TGN above 500 fmol/microgram DNA is obtained. Maxumum dose is expected to be reached within 10-12 weeks
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Change History | |||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE |
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Current Other Pre-specified Outcome Measures | Not Provided | ||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||
Descriptive Information | |||||
Brief Title ICMJE | Thiopurine EnhAnced Maintenance Therapy | ||||
Official Title ICMJE | 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 | ||||
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. |
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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
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. |
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Study Type ICMJE | Interventional | ||||
Study Phase ICMJE | Phase 1 Phase 2 |
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Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment |
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Condition ICMJE |
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Intervention ICMJE | 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:
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Study Arms ICMJE | 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.
Intervention: Drug: Thioguanine (oral)
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Publications * |
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||
Recruitment Status ICMJE | Completed | ||||
Actual Enrollment ICMJE |
30 | ||||
Original Estimated Enrollment ICMJE | Same as current | ||||
Actual Study Completion Date ICMJE | April 2020 | ||||
Actual Primary Completion Date | March 2020 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE |
Male and female patients of all ethnicities meeting all of the following criteria will be considered eligible for study participation:
Exclusion Criteria
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Sex/Gender ICMJE |
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Ages ICMJE | 6 Months to 45 Years (Child, Adult) | ||||
Accepts Healthy Volunteers ICMJE | No | ||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
Listed Location Countries ICMJE | Denmark | ||||
Removed Location Countries | |||||
Administrative Information | |||||
NCT Number ICMJE | NCT02912676 | ||||
Other Study ID Numbers ICMJE | Rigshospitalet - TEAM | ||||
Has Data Monitoring Committee | Yes | ||||
U.S. FDA-regulated Product | Not Provided | ||||
IPD Sharing Statement ICMJE |
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Responsible Party | Kjeld Schmiegelow, Rigshospitalet, Denmark | ||||
Study Sponsor ICMJE | Kjeld Schmiegelow | ||||
Collaborators ICMJE |
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Investigators ICMJE |
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PRS Account | Rigshospitalet, Denmark | ||||
Verification Date | April 2020 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |