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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.

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.

Thioguanine (oral)

Kjeld Schmiegelow, Professor

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.

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.

Thiopurine EnhAnced Maintenance Therapy

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

Individual participant data will be entered into the Leukemia Registry of the Nordic Society of Pediatric Hematology/Oncology

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 levels are measured at 2 weeks intervals 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),

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.

Danish Child Cancer Foundation

Nordic Society for Pediatric Hematology and Oncology

Kjeld Schmiegelow

Professor

Anti-Infective Agents

Anti-Inflammatory Agents

Cytarabine

Doxorubicin

Liposomal doxorubicin

Prednisone

Vincristine

Pegaspargase

Asparaginase

Clofarabine

Imatinib Mesylate

Anti-Bacterial Agents

Antibiotics, Antitubercular

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Antiviral Agents

Tubulin Modulators

Antimitotic Agents

Orally during Induction, Consolidation 1, CNS, Consolidation 2, and Continuation therapy.

Intravenously during Induction, CNS, Consolidation 2 and Continuation Therapy

Intravenously during Induction, CNS, and Consolidation 2 therapy

Intravenously during Induction, Consolidation 1, CNS, and Consolidation 2 therapy

PEG-asparaginase

Intrathecally during Induction and CNS therapy

Intrathecally during Induction, CNS, and Continuation Therapy

Orally during Induction, Consolidation 1, CNS, Consolidation 2 and Continuation Therapy

Imatinib

Intravenously during Consolidation 1 Therapy

Orally during CNS, Consolidation 2 and Continuation Therapy

6 Mercaptopurine

Amir Fathi, MD

The purpose of this study is to determine the safety and effectiveness of a multi-drug regimen (which includes prednisone, vincristine, cytarabine, doxorubicin, 6 mercaptopurine, and methotrexate) which is considered standard treatment for children and young adults with acute lymphoblastic leukemia (ALL), in combination with PEG-asparaginase and clofarabine to treat older adults with ALL. PEG-asparaginase has been used in chemotherapy treatment regimens for both children and adults with ALL. Clofarabine has been used in chemotherapy treatment regimens for children with ALL and has been shown to decrease the number of leukemia cells. Participants with leukemia that has an abnormal chromosome, called the Philadelphia chromosome, will also be given imatinib.

* This research study has stages of treatment as follows: 1) Induction 2) Consolidation 1 3) Stem cell of Bone Marrow Transplant (if the participant is eligible). If the participant does not have a transplant: 4) CNS Therapy 5) Consolidation 2 6) Continuation Therapy.
* During all phases of study treatment, participants will have additional tests and procedures to monitor their health and for research purposes. These tests will include: physical exams, blood tests, bone marrow aspirate/biopsy and EKGs (electrocardiogram) and/or ECHOs (echo-cardiogram).
* INDUCTION STAGE: This stage lasts for about one month. The study drugs and the way they are administered are as follows: Prednisone orally on days 1-21 for participants less than 60 and days 1-7 for participants 60 or greater; Vincristine intravenously on days 1, 8, 15 and 22; Doxorubicin intravenously on days 1 and 2; PEG-Asparaginase intravenously on days 7 and 21; Cytarabine intrathecally on day 1; Methotrexate intrathecally on day 29; Imatinib orally on days 14-29 if participant has the Philadelphia Chromosome.
* After induction, if there is evidence of ALL in the spinal fluid, participants may need to receive more intrathecal therapy.
* CONSOLIDATION 1 Therapy: This stage will last about one month. Participants will receive Consolidation 1 Therapy, regardless of whether or not their ALL is in full remission after Induction. The study drugs and the way they are administered are as follows: Prednisone orally days 1-5; Clofarabine intravenously days 1-5; PEG-Asparaginase intravenously days 1 and 15; Imatinib continues orally for participants with the Philadelphia Chromosome.
* After the participants blood counts return to normal, their bone marrow will be tested. If the bone marrow shows remission, participants will proceed to the next stage of the study. If the bone marrow does not show remission, the participants will no longer continue on this study.
* STEM CELL or BONE MARROW TRANSPLANTATION: The next stage is stem cell or bone marrow transplantation if the participant is eligible. If the participant receives a stem cell transplant, they will receive additional chemotherapy (separate from the study drugs) followed by an infusion of stem cells. If the participant receives a bone marrow transplant, they will have a bone marrow aspirate and biopsy 3 months after the transplant and 12 months from the start fo the induction to monitor the status of the ALL. If the participant receives a bone marrow or stem cell transplant, they will continue to be a part of the study, but will not proceed with CNS Therapy, Consolidation 2 Therapy, and Continuation Therapy.
* CENTRAL NERVOUS SYSTEM (CNS) THERAPY: CNS therapy will begin between 2 and 6 weeks following the end of Consolidation 1. This stage will last about one month. The study drugs and the way they are administered are as follows: vincristine intravenously on day 1; doxorubicin intravenously on day 1; 6 mercaptopurine orally on days 1-14; prednisone orally on days 1-5; PEG-asparaginase intravenously on days 1 and 15; methotrexate/cytarabine/prednisone intrathecally weekly for 3 weeks; imatinib orally continues daily if the participant has the Philadelphia Chromosome.
* Radiation therapy will also be given during this stage of the participant is under 60 years old. The purpose of radiation therapy is to prevent ALL from coming back in the brain. Radiation will be given in 8 treatments, given once a day, and will be scheduled with other study treatment.
* CONSOLIDATION 2 THERAPY: This stage begins as soon as CNS Therapy ends and lasts about 8 months. Participants will receive repeated cycles of the study drug treatment about every 4 weeks. The study drugs and the way they are administered are as follows: vincristine intravenously on day 1; doxorubicin intravenously on day 1; 6 mercaptopurine orally on days 1-14; prednisone orally days 1-5; PEG-asparaginase orally on days 1 and 15 (first cycle only); imatinib orally continues daily if the participant has Philadelphia chromosome.
* CONTINUATION THERAPY: This stage begins at the end of Consolidation 2 Therapy. The goal of this stage is to get rid of all of the ALL in the body. Participants will receive repeated cycles of the study drug treatment every 4 weeks. It will last until the participant has been in remission for 2 years. The study drugs and the way they are administered are as follows: vincristine intravenously on day 1; mercaptopurine orally on days 1-14; prednisone orally on days 1-5; methotrexate intravenously on day 15; imatinib orally continues daily if the participant has Philadelphia chromosome.

Treatment of Older Adults With Acute Lymphoblastic Leukemia

The number of participants alive one year after baseline.

Dana-Farber Cancer Institute

Beth Israel Deaconess Medical Center

Enzon Pharmaceuticals, Inc.

Genzyme, a Sanofi Company

Massachusetts General Hospital

Principal Investigator

All patients treated on same arm

Prednisone: Orally during Induction, Consolidation 1, CNS, Consolidation 2, and Continuation therapy.

Vincristine: Intravenously during Induction, CNS, Consolidation 2 and Continuation Therapy

Doxorubicin: Intravenously during Induction, CNS, and Consolidation 2 therapy

PEG-asparaginase: Intravenously during Induction, Consolidation 1, CNS, and Consolidation 2 therapy

Cytarabine: Intrathecally during Induction and CNS therapy

Methotrexate: Intrathecally during Induction, CNS, and Continuation Therapy

Imatinib: Orally during Induction, Consolidation 1, CNS, Consolidation 2 and Continuation Therapy

Clofarabine: Intravenously during Consolidation 1 Therapy

6 Mercaptopurine: Orally during CNS, Consolidation 2 and Continuation Therapy

Experimental

Age, Continuous

Sex: Female, Male

Caucasian

Not Available

Race/Ethnicity, Customized

United States

Region of Enrollment

White blood cell count

ECOG 0

ECOG 1

ECOG 2

Eastern Cooperative Oncology Group Performance Status 0 Fully active, able to carry on all pre-disease performance without restriction

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature
2. Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3. Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4. Completely disabled; cannot carry on any self-care totally confined to bed or chair
5. Dead

Performance status

Philadelphia chromosome positive

Mixed lineage leukemia rearrangement

Chromosomal alterations

B-cell ALL

T-cell ALL

acute lymphoblastic leukemia (ALL) immunophenotype

Immunophenotype

Dr. Amir Fathi

Overall Survival at One Year

All patients treated on same arm

Prednisone: Orally during Induction, Consolidation 1, CNS (central nervous system), Consolidation 2, and Continuation therapy.

Vincristine: Intravenously during Induction, CNS, Consolidation 2 and Continuation Therapy

Doxorubicin: Intravenously during Induction, CNS, and Consolidation 2 therapy

PEG-asparaginase: Intravenously during Induction, Consolidation 1, CNS, and Consolidation 2 therapy

Cytarabine: Intrathecally during Induction and CNS therapy

Methotrexate: Intrathecally during Induction, CNS, and Continuation Therapy

Imatinib: Orally during Induction, Consolidation 1, CNS, Consolidation 2 and Continuation Therapy

Clofarabine: Intravenously during Consolidation 1 Therapy

6 Mercaptopurine: Orally during CNS, Consolidation 2 and Continuation Therapy

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Thiopurine EnhAnced Maintenance Therapy	NCT02912676	Acute Lymphobla... Lymphoblastic L...	Thioguanine (or...	6 Months - 45 Years	Rigshospitalet, Denmark
Treatment of Older Adults With Acute Lymphoblastic Leukemia	NCT00973752	Acute Lymphobla...	Prednisone Vincristine Doxorubicin PEG-asparaginas... Cytarabine Methotrexate Imatinib Clofarabine 6 Mercaptopurin...	51 Years - 75 Years	Massachusetts General Hospital

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