Efficacy and Safety of TKIs' Withdrawal After a Two-step Dose Reduction in Patients With Chronic Myeloid Leukemia

Study Overview
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Brief Summary
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Evaluation of the efficacy and safety of withdrawal of tyrosine kinase inhibitors after previous two-step dose reduction in patients with chronic myeloid leukemia in deep molecular remission

Detailed Description
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In the first phase of the study (first 6 months after the study enrollment), 50% reduction of standard TKI dose follows.Physical and clinical examinations (focused on adverse effects and possible withdrawal syndrome manifestation) will be performed in predefined time intervals, pharmacological history of the subject will be taken, mandatory biochemical, hematological, and molecular-biological examinations will be performed. In the following 6 months, the dose will be reduced by 50% i.e. medication will be administered every other day. Twelve months after enrollment, the medication will be stoped. The subject is followed in predefined time intervals.

Official Title
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A Prospective Phase II Clinical Trial Evaluating the Efficacy and the Safety of Tyrosine Kinase Inhibitors Withdrawal After a Previous Two-step Dose Reduction in Patients With Chronic Myeloid Leukemia in Deep Molecular Remission

Conditions
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Chronic Myeloid Leukemia, Chronic Phase, Withdrawal;Drug

Intervention / Treatment
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* Drug: Imatinib withdrawal
* Drug: Dasatinib
* Drug: Nilotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with documented Ph1-positive and / or BCR-ABL1-positive CML in a documented first chronic phase, the criteria of which are as follows: <15% blasts in peripheral blood (PB) or bone marrow (BM) <30% blasts + promyelocytes in PB or BM <20% of basophils in PB >= 100 billion / l platelets Absence of extramedullary involvement except hepato- and / or splenomegaly Age >= 18 years Signed informed consent to study participation Typical [e13a2 (b2a2) or e14a2 (b3a2)] or atypical quantifiable type of BCR-ABL1 transcript on an international scale Treatment of TKI either in the first line or in the second or other lines for intolerance only TKI treatment> 4 years Previous interferon-α treatment allowed with any treatment effect (intolerance / failure) Deep molecular response >= MR4.0 lasting > 2 years Participants in a fertile clinical trial must agree to use prescribed contraceptive methods from entry to study until one year after the last dose of study medication: Women - Proper use of a highly reliable contraceptive method, ie combined hormonal contraceptives (in oral, vaginal or transdermal dosage form), gestagen hormonal contraceptives associated with ovulation inhibition (in oral or injectable dosage form), non-hormonal IUDs (intrauterine device) or IUDs , ev. presence of bilateral tubular occlusion, partner vasectomy, or adherence to sexual abstinence Men - Observance of sexual abstinence or use of adequate contraceptive method (ie condom) in the case of sexual intercourse for the period from enrollment to 1 year after the last dose of the drug Exclusion Criteria: Patients with Ph1-positive and / or BCR-ABL1-positive CML in the second chronic phase, in the accelerated phase or blast crisis (AP/BC) at any time in the history of the disease Non-quantifiable type of BCR-ABL1 transcript on an international scale Treatment of TKI in the second or subsequent lines due to treatment failure according to ELN (European LeukemiaNet) criteria in 2006, 2009 or 2013 Previous failure of TKI treatment according to ELN criteria of 2006, 2009 or 2013 Previous allogeneic hematopoietic stem cell transplantation Previous participation in a TKI withdrawal study with a real withdrawal history Previous discontinuation of TKI outside the study for other reasons (eg intolerance or pregnancy) lasting more than 9 months and / or if a treatment response was lost during less than 12 months prior to screening Life expectancy of less than 36 months due to severe concurrent disease Severe concurrent disease that could limit adherence to study protocol or study completion Pregnancy and breastfeeding Disagreement or impossibility to comply with the contraceptive measures described in point 9 of the inclusion criteria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: initially treated patients<br>The dose of tyrosin kinase inhibitors (imatinib, or nilotinib, or dasatinib) in patients meeting all of the inclusion criteria and none of the exclusion criteria will be reduced in two consequent steps, during the first 6 months after study entry by 50%, during the second 6 months by 50% again; the medication is discontinued then and the patients are followed each month in the first 6 months after withdrawal, each 1,5 month in the next 6 months, and each 3 months in the next 12 months. | Drug: Imatinib withdrawal<br>* withdrawal of imatinib after previous two-step dose reduction: during the first 6 months after study entry, the dose of imatinib is 50% of the standard dose (200 mg daily), during the second 6 months after study entry, the dose of imatinib is 200 mg every other day; 12 months after study entry, imatinib is discontinued, the patient is followed in line with the aims of the trial<br>* Other names: Glivec withdrawal;Drug: Dasatinib<br>* withdrawal of dasatinib after previous two-step dose reduction: during the first 6 months after study entry, the dose of dasatinib is 50% of the standard dose (40 mg daily; tablets containing 50 mg are not available on the market), during the second 6 months after study entry, the dose of dasatinib is 40 mg every other day; 12 months after study entry, dasatinib is discontinued, the patient is followed in line with the aims of the trial<br>* Other names: Sprycel withdrawal;Drug: Nilotinib<br>* withdrawal of nilotinib after previous two-step dose reduction: during the first 6 months after study entry, the dose of nilotinib is 50% of the standard dose (200 mg every 12 hours), during the second 6 months after study entry, the dose of nilotinib is 400 mg every other day; 12 months after study entry, nilotinib is discontinued, the patient is followed in line with the aims of the trial<br>* Other names: Tasigna withdrawal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of patients in major molecular response, and MRFS at month 6 | Proportion of patients in major molecular response (MMR) ie BCR-ABL1 (oncogenic BCR-ABL gene fusion) transcript levels <= 0.1%) and Molecular Recurrence-Free Survival (MRFS, ie time from study entry to MMR loss, ie BCR-ABL1 transcript levels > 0.1% in 2 consecutive samples, or death from any cause) at month 6 after study entry | 6 months after entry | 
| proportion of patients in major molecular response (MMR) and MRFS at month 12 | Proportion of patients in major molecular response (MMR) and MRFS at month 12 after study entry | 12 months after study entry | 
| proportion of patients in MMR without treatment (TFR) and treatment-free survival at month 18 after study entry, ie. 6 months after treatment withdrawal | The proportion of patients in MMR without treatment (TFR) and treatment-free survival (TFS, ie the time from withdrawal of TKI (tyrosin kinase inhibitors) to loss of MMR, reinitiation of TKI therapy from any cause, progression, or death from any cause) at month 18 after study entry, ie, 6 months after treatment discontinuation | 18 months after study entry | 
| proportion of patients in MMR without treatment (TFR) and treatment-free survival at month 24 after study entry, ie. 12 months after treatment withdrawal | The proportion of patients in MMR without treatment (TFR) and treatment-free survival (TFS, ie the time from withdrawal of TKI to loss of MMR, reinitiation of TKI therapy from any cause, progression, or death from any cause) at month 24 after study entry, ie 12 months after treatment discontinuation | 24 months after study entry | 
| proportion of patients in MMR without treatment (TFR) and treatment-free survival at month 36 after study entry, ie. 24 months after treatment withdrawal | The proportion of patients in MMR without treatment (TFR) and treatment-free survival (TFS, ie the time from withdrawal of TKI to loss of MMR, reinitiation of TKI therapy from any cause, progression, or death from any cause) at month 36 after study entry, ie 24 months after treatment discontinuation | 36 months after study entry | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who lose MMR during de-escalation and in whom MMR and MR4.0 will recover after TKI re-introduction | Proportion of patients who lose MMR during de-escalation and in whom MMR and MR4.0 (deep molecular response, level of BCR-ABL transcripts <0.01% related to the international scale) will recover after TKI re-introduction | every two months in the first 12 months, at early termination (due to pregnancy, investigator's,national competent authority's or sponsor's decision, poor adherence) | 
| Proportion of patients who lose MMR after discontinuation of TKI and in whom MMR and MR4.0 will recover after TKI re-introduction | Proportion of patients who lose MMR after discontinuation of TKI and in whom MMR and MR4.0 will recover after TKI re-introduction | every month between month 13 and 18, every 1.5 month between month 18 and 24, every 3 months between month 24 and 36, at time of early termination | 
| Time to re-establish MMR and MR4.0 after TKI restart | Time to re-establish MMR and MR4.0 after TKI restart - evaluation every 3 months after TKI restart | since TKI restart until MMR and MR4.0 recovered (only in case that restart is necessary) | 
| Assessment of TKI's adverse effects dynamics during two-step reduction of their dose before withdrawal | Assessment of TKI's adverse effects dynamics during two-step reduction of their dose before withdrawal (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades) | every two months in the first 12 months, at early termination (due to pregnancy, investigator's,national competent authority's or sponsor's decision, poor adherence) | 
| Assessment of TKI withdrawal syndrome - proportion of patients with development of withdrawal syndrome | Assessment of TKI withdrawal syndrome - proportion of patients with development of withdrawal syndrome) (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades) | months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36 | 
| Assessment of TKI withdrawal syndrome - severity of symptoms | Assessment of TKI withdrawal syndrome - severity of symptoms (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades) | months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36 | 
| Assessment of TKI withdrawal syndrome - time to first complaint | Assessment of TKI withdrawal syndrome - time to first complaint | months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36 | 
| Assessment of TKI withdrawal syndrome - duration of complaints | Assessment of TKI withdrawal syndrome - duration of complaints | months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36 | 
| Assessment of TKI withdrawal syndrome - therapeutic intervention | Assessment of TKI withdrawal syndrome - therapeutic intervention (pharmacological history, dose changes) | months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36 | 
| Assessment of the correlation between adverse effects on previous TKI treatment and possible withdrawal syndrome | Assessment of the correlation between adverse effects on previous TKI treatment and possible withdrawal syndrome (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades) | months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36 | 
| BCR-ABL1 kinetics during TKI therapy | number of BCR-ABL1 transcripts during TKI therapy | months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36 | 
| Correlation of BCR-ABL1 kinetics (number of BCR-ABL1 transcripts in time) during TKI therapy with potential molecular relapse after TKI discontinuation | Correlation of BCR-ABL1 kinetics during TKI therapy with potential molecular relapse after TKI discontinuation | months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36 | 
| Correlation of the effect of TKI dose reduction and subsequent discontinuation with lipid metabolism and glycemia (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades) | Correlation of the effect of TKI dose reduction and subsequent discontinuation with lipid metabolism and glycemia (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades) | months 2,4,6,8,10,12,15,18,21,24,30,36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tyrosine kinase inhibitors, drug withdrawal, chronic myeloid leukemia, chronic phase