E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with chronic myeloid leukemia with complete molecular response can stop tyrosine kinase inhibitors under close monitoring |
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E.1.1.1 | Medical condition in easily understood language |
Trial estimating the impact of stopping tyrosine kinase inhibitors in chronic myeloid leukemia; patients in complete molecular response with CML are requested to stop therapy under close monitoring |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009016 |
E.1.2 | Term | Chronic myeloid leukemia in remission |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Assessment of the duration of MMR or better after stopping of TKI therapy |
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E.2.2 | Secondary objectives of the trial |
1- Identification of clinical and biological factors affecting the persistence of complete molecular remission after stopping TKI (e.g. level of CMR, risk score, duration of TKI treatment, type of TKI pretreatment)
2- Evaluation of QoL in patients stopping TKI
3- Evaluation of medico-economic impact of stopping TKI
4- Estimating the number of patients in CMR who would be eligible for stopping TKI therapy by setting up a screening log
5- Time to recovery of CMR4
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) Role of telomere shortening in normal hematopoiesis for disease recurrence upon cessation of TKI treatment (substudy 4 in protocol)
Objective is to investigate the prognostic role of telomere shortening in patients with CML and molecular response to TKI treatment for disease recurrence upon cessation of TKI treatment
2) Nordic immunology substudy (lymphocyte subclasses, functional tests, T-cell receptor clonality assay, cytokine assay) (substudy 5 in protocol.)
The cytotoxicity of NK-cells will be analyzed. T-cell activation will be determined with IFN-γ production from CD4+ and CD8+ cells after OKT-3 and CD28 antibody stimulation. Granzyme B staining will be used for evaluating the cytotoxic potential of T-cells. Furthermore, as immunosuppressive mechanisms are exhibited by many tumors (including CML), the role of suppressor cells (myeloid-derived suppressor cells and regulatory T-cells) will be analyzed. |
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E.3 | Principal inclusion criteria |
• CML in CP under treatment with TKI in first line or in second line because of toxicity to first line TKI or with TKI in combination
• Duration of TKI treatment before enrolment at least 3 years
• Complete molecular remission (CMR4 (≤ 0.01% on IS) for at least one year; at least three PCR-results with CMR4 within the last year (± 2 months) before study entry
• Before inclusion confirmation of CMR through a EUTOS-CMR laboratory
• Both sexes but fertile women only if using effective contraceptive
• Health insurance coverage
• 18 years or older
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E.4 | Principal exclusion criteria |
• Under 18 years old
• Hospitalized patients without ability to give informed consent
• Adults under law protection or without ability to assent
• Previous or planned allogeneic stem cell transplantation
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E.5 End points |
E.5.1 | Primary end point(s) |
Evaluation of molecular relapse-free survival after stopping TKI (survival without molecular relapse defined by BCR-ABL1 ratio > 0.1% on the IS at one time point (loss of major molecular response, MMR)) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 200 patients with follow-up of at least 6 months |
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E.5.2 | Secondary end point(s) |
1-Identification of clinical and biological factors affecting the persistence of MMR and CMR (MR4) after stopping TKI (level of CMR before treatment discontinuation, predicting factors like risk score, duration, dosage and type of TKI pretreatment)
2-Estimation of OS and PFS
3-Estimation of probabilities of a restart of TKI therapy without prior molecular relapse
4-Patient reported QoL and symptom burden over time
5-Evaluation of medico-economic impact of TKI discontinuation
6-Time to recovery of CMR (MR4) after restart of TKI due to relapse (loss of MMR).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At interim analysis as described above |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
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 |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | No |
E.8.1.7 | Other | No |
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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Russian Federation |
Switzerland |
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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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In case of hematological relapse or progression to accelerated or blastic phase, the sponsor must be contacted within 24h and the Data Safety Monitoring Board (DSMB) will decide on continuation of the study. Inclusion of patients in the trial will be stopped until then. Criteria to stop the study at interim analysis: According to published study results, if the number of progressions exceeds 2%, the study will be stopped (2). |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |