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

Phase 2Active Not RecruitingNCT04147533

Masaryk University150 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Masking

NONE

Enrollment

150

Conditions

Chronic Myeloid Leukemia, Chronic Phase Withdrawal;Drug

Interventions

Imatinib withdrawalDRUG

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

DasatinibDRUG

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

Nilotinib

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. 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 2. Age \>= 18 years 3. Signed informed consent to study participation 4. Typical \[e13a2 (b2a2) or e14a2 (b3a2)\] or atypical quantifiable type of BCR-ABL1 transcript on an international scale 5. Treatment of TKI either in the first line or in the second or other lines for intolerance only 6. TKI treatment\> 4 years 7. Previous interferon-α treatment allowed with any treatment effect (intolerance / failure) 8. Deep molecular response \>= MR4.0 lasting \> 2 years 9. 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: 1. 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 2. Non-quantifiable type of BCR-ABL1 transcript on an international scale 3. Treatment of TKI in the second or subsequent lines due to treatment failure according to ELN (European LeukemiaNet) criteria in 2006, 2009 or 2013 4. Previous failure of TKI treatment according to ELN criteria of 2006, 2009 or 2013 5. Previous allogeneic hematopoietic stem cell transplantation 6. Previous participation in a TKI withdrawal study with a real withdrawal history 7. 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 8. Life expectancy of less than 36 months due to severe concurrent disease 9. Severe concurrent disease that could limit adherence to study protocol or study completion 10. Pregnancy and breastfeeding 11. Disagreement or impossibility to comply with the contraceptive measures described in point 9 of the inclusion criteria

Locations (8)

University Hospital Brno

Brno, Czechia

University Hospital Hradec Kralove

Hradec Králové, Czechia

University Hospital Olomouc

Olomouc, Czechia

University Hospital Ostrava

Ostrava, Czechia

Outcomes

Primary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Data from ClinicalTrials.gov

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Secondary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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)