E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Lymphoblastic Leukemia Lymphoblastic Non-Hodgkin’s Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Cancer: Leukemia, Lymphoblastic Non-Hodgkin’s Lymphoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To explore the feasibility of 6TG as a supplement to maintenance therapy of Acute Lymphoblastic Leukemia and Lymphoblastic Non-Hodgkin’s Lymphoma in order to improve the existing dose adjustment strategies. We hypothesize that MTX/6MP/6TG combination therapy will achieve a higher DNA-TGN level and enhance the effect of 6MP. We will describe toxicities, hematology and thiopurine metabolite levels during MTX/6MP/6TG combination therapy. This study will be the first to assess the applicability of 6TG in combination with standard MTX/6MP maintenance therapy.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion 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: a. 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 b. 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 and c. Scheduled to receive 6MP/MTX maintenance therapy without any other concomitant myelosuppressive agents. 2. Patients must have reached the maintenance II therapy phase upon inclusion. 3. Patients must have a minimum of 3 months of 6MP/MTX maintenance therapy remaining at the time of inclusion. 4. Bilirubin < UNL according to age, factor 2-7-10 > 0.5 or INR < 1.5 within 1 week prior to inclusion. 5. WBC > 1.5 x109/L, ANC > 0.5 x109/L and TBC > 50 x109/L within 1 week prior to inclusion. 6. Subject, if female of child-bearing potential (defined as postmenarche), must present with a negative pregnancy test and must be nonlactating. 7. 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. 8. No live vaccines given within 2 months prior to inclusion. 9. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. 10. 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. 11. 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. |
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E.4 | Principal exclusion criteria |
1. Patients with ALL with negative bone-marrow minimal residual disease at treatment day 29 (counted from diagnosis), since these patients have an excellent prognosis on current therapy. 2. Any clinical suspicion of relapse or disease progression on routine imaging or in laboratory results. 3. DNA-TGN > 1500 fmol/µg DNA, since the correlation between reduced risk of relapse and DNA-TGN levels of this magnitude has not been sufficiently clarified. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Obtaining a stable mean DNA-TGN level > 500 fmol/microgram DNA after addition of 6TG. DNA-TGN calculated as a 4 weeks mean.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Dynamic change in DNA-TGN levels every other week for the first 6 weeks, then every week during dosage escalation of 6TG to MP/MTX treatment, then every other week during the rest of trial period. Eligible patients are enrolled at individual time points during the standard oral MTX/6MP maintenance therapy for both lymphoblastic NHL patients and ALL patients. Patients must have a minimum of 3 months of maintenance therapy remaining at inclusion. |
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E.5.2 | Secondary end point(s) |
Change in median Ery-TGN/Ery-MeMP. 6TG doses and myelo-/hepatotoxicities encountered during MTX/6MP/6TG therapy (WBC, ANC, TBC, ALAT, bilirubin, factors 2-7-10, signs of SOS, second malignancy, mortality). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The thiopurine metabolites (Ery-TGN and Ery-MeMP), hematology and liver parameters are measured every week during dose escalation of 6TG, and every 2 weeks during rest of the trial period. 6TG doses noted in the CRF and in the patient's diary. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Pharmacokinetics and -dynamics, tolerability, toxicities |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Modified cross-over. Patients receive standard therapy first and are then supplemented with 6TG. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Patients are their own comporator |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |