| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009015 |
| E.1.2 | Term | Chronic myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 compare 2 TKI discontinuation strategies on the probability of successful discontinuation in patients followed for CML treated with TKIs. |
|
| E.2.2 | Secondary objectives of the trial |
1.2-Comparison of TKI tolerability and quality of life in 2 arms
3.4-Comparison of the proportion to loose MMR and DMR in 2 arms
5-Comparison of the quantitative and qualitative evolution of CD8i LT in 2 arms
6-Evaluate residual plasma TKI concentration for 2 arms
7-Comparison of the proportion of loss DMR during the discontinuation phase in 2 arms
8-Evaluate quality of life in the discontinuation phase in 2 arms
9-Describe for patients losing their DMR in the TKI phase and for patients losing their MMR during the discontinuation phase
10-Evaluate the predictive value at the time of discontinuation of the quantitative and qualitative characteristics of CD8LTi on the successful discontinuation between in TFR 24M post discontinuation and those who lost their MMR and resumed their TKI during the same period in 2 arms
11-Analyse longitudinally the quantitative and qualitative evolution of CD8ILT after TKI discontinuation in patients in FIT 24M post discontinuation in 2 arms
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patient aged ≥ 18 years
- Diagnosed with chronic phase CML (CML-CP) according to WHO 2016 criteria with a typical BCR::ABL1 rearrangement (e13a2 or e14a2)
- Duration of TKI treatment ≥ 3 years and not having had a dose reduction in the last 6 months
- Duration of DMR (≥ 4-log reduction in peripheral blood BCR::ABL1 mRNA level from diagnosis) ≥ 1 year with at least 3 quantitative BCR::ABL1 mRNA RT-PCR results available in the 12 months prior to inclusion
- No contraindication to the continuation of the same TKI for 12 months at the same dosage according to international recommendations7 and the originator's CPR of each TKI i.e.:
Glivec® or generic: Imatinib (≥ 200 mg/d)
Sprycel® or generic: Dasatinib (≥ 50 mg/d)
Tasigna®: Nilotinib (≥ 300 mg/d)
Bosulif®: Bosutinib (≥ 200 mg/d)
- Sexually active men should use contraception while taking Dasatinib
- Must be affiliated to the social security system or have a third party who does so
- Patient not participating in another interventional study for the duration of the study
- Have signed the consent form after having read the information note
|
|
| E.4 | Principal exclusion criteria |
- Patients with a serious progressive disease with poor prognosis compromising participation in the entire study and/or with an uncontrolled chronic disease (cardiac, (recent myocardial infarction, congestive heart failure, unstable angina...), renal, respiratory...)
- ECOG > 3
- No previous resistance to a TKI
- Patients who have already participated in a study involving a TKI discontinuation strategy
- Persons benefiting from enhanced protection, i.e. minors, persons deprived of their liberty by a judicial or administrative decision, persons staying in a health or social establishment, adults under legal protection and finally patients in emergency situations
- Pregnant or breastfeeding women, women of childbearing age who do not have effective contraception (hormonal/mechanical: per os, injectable, transcutaneous, implantable, intrauterine device, or surgical: tubal ligation, hysterectomy, total oophorectomy)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion (%) of patients in TFR 24 months after discontinuation in the dose maintenance then discontinuation arm and in the dose de-escalation then discontinuation arm. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 months after discontinuation |
|
| E.5.2 | Secondary end point(s) |
1-Recording of adverse events and scoring according to CTCAE V5 grades
2.8-Collection of EQ-5D5 and FACT-Leu32
3-Proportion (%) of patients losing their MMR
4.7-Proportion (%) of patients losing their DMR
5-Quantitative analysis: difference in the proportions, at randomisation and 12 months post-randomisation, of innate CD8 LTs within total CD8 LTs
6-Evaluation of the residual plasma concentration of the TKI in ng/mL
9-After loss of DMR during the treatment phase: collection of the prescribed TKI and its daily dosage (mg per day) as well as the time (in months) between the loss of DMR and its re-obtainment; after loss of MMR during the discontinuation phase: collection of the time (in months) between the loss of MMR and its re-obtainment
10- Quantitative analysis: proportions of CD8i LTs in total CD8 LTs
11- Quantitative analysis: proportions of innate CD8 LTs in total CD8 LTs
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-At 6 months and 12 months post-randomisation
2.8-At randomisation, 6 months and 12 months post-randomisation and at 3 months and 6 months post-stop
3-Every 3 months in both arms during the ITK treatment phase
4.7-Every 3 months in the 2 arms during the ITK treatment phase then every month until the 6th month post-stop, then every 2 months between 6 months and 12 months, then every 3 months.
5-At randomisation and 12 months post-randomisation
6-At the time of randomisation and 12 months later
9-After loss of MMR and recording of the time (in months) between the loss of MMR and its re-obtainment after resumption of TKI treatment
10-At the time of arrest
11-At the time of arrest
|
|
| 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 | No |
| 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 | No |
| E.6.13 | Others | No |
| 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 | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
|
| LVLS+to finalise the monitoring, dosing and database locked |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 70 |
| E.8.9.1 | In the Member State concerned days | |
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