A Phase 1-2 Study of 6-Thioguanine in Combination With Methotrexate and 6-Mercaptopurine During Maintenance Therapy of Childhood, Adolescent, and Adult ... View Homepage


Ontology type: schema:MedicalStudy     


Clinical Trial Info

YEARS

2016-2018

ABSTRACT

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. 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-controlled (except for historical controls), 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. Pharmacological target: The investigators will include 30 participants. Two weeks prior to the first addition of 6TG, the 6MP dose will be reduced to 2/3rd of the 6MP dose the patient on average has received and tolerated prior to inclusion in order to reduce levels of methylated metabolites, and thus the degree of inhibition of purine de novo synthesis. The investigators will then A) give 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/MeMP/MTXpg. 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. More... »

URL

https://clinicaltrials.gov/show/NCT02912676

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2 schema:description 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. 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-controlled (except for historical controls), 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. Pharmacological target: The investigators will include 30 participants. Two weeks prior to the first addition of 6TG, the 6MP dose will be reduced to 2/3rd of the 6MP dose the patient on average has received and tolerated prior to inclusion in order to reduce levels of methylated metabolites, and thus the degree of inhibition of purine de novo synthesis. The investigators will then A) give 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/MeMP/MTXpg. 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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