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

Phase 2

Active, not recruiting

• Conditions: Withdrawal;Drug; Chronic Myeloid Leukemia, Chronic Phase
• Interventions: Drug: Imatinib withdrawal; Drug: Dasatinib; Drug: Nilotinib

• Registration Number: NCT04147533
• Lead Sponsor: Masaryk University

Brief Summary

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

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 Timeline

• Study First Submitted: 2019-09-26
• Study First Submitted QC: 2019-10-29
• Study First Posted: 2019-11-01
• Study Start: 2020-06-16
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-22
• Last Update Posted: 2024-11-26
• Primary Completion: 2026-06
• Study Completion: 2026-06

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 150

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
initially treated patients	Imatinib withdrawal	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.
initially treated patients	Dasatinib	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.
initially treated patients	Nilotinib	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.

Primary Outcome Measures

Name	Time	Method
proportion of patients in major molecular response, and MRFS at month 6	6 months after entry	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
proportion of patients in major molecular response (MMR) and MRFS at month 12	12 months after study entry	Proportion of patients in major molecular response (MMR) and MRFS at month 12 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	18 months after study entry	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
proportion of patients in MMR without treatment (TFR) and treatment-free survival at month 24 after study entry, ie. 12 months after treatment withdrawal	24 months after study entry	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
proportion of patients in MMR without treatment (TFR) and treatment-free survival at month 36 after study entry, ie. 24 months after treatment withdrawal	36 months after study entry	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

Secondary Outcome Measures

Name	Time	Method
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	Proportion of patients who lose MMR after discontinuation of TKI and in whom MMR and MR4.0 will recover after TKI re-introduction
Time to re-establish MMR and MR4.0 after TKI restart	since TKI restart until MMR and MR4.0 recovered (only in case that restart is necessary)	Time to re-establish MMR and MR4.0 after TKI restart - evaluation every 3 months after TKI restart
Proportion of patients who lose MMR during de-escalation and in whom MMR and MR4.0 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 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
Assessment of the correlation between adverse effects on previous TKI treatment and possible withdrawal syndrome	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 (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades)
Correlation of BCR-ABL1 kinetics (number of BCR-ABL1 transcripts in time) 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 BCR-ABL1 kinetics during TKI therapy with potential molecular relapse after TKI discontinuation
Assessment of TKI's adverse effects dynamics during two-step reduction of their dose before withdrawal	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'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)
Assessment of TKI withdrawal syndrome - proportion of patients with development of withdrawal syndrome	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 - proportion of patients with development of withdrawal syndrome) (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades)
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 - time to first complaint
Assessment of TKI withdrawal syndrome - therapeutic intervention	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 (pharmacological history, dose changes)
Assessment of TKI withdrawal syndrome - severity of symptoms	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 (using Common Terminology Criteria for Adverse Events; CTCAE classification with 5 grades)
BCR-ABL1 kinetics 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	number of BCR-ABL1 transcripts during TKI therapy
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 - duration of complaints
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	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)

Trial Locations

Locations (8)

University Hospital Kralovske Vinohrady; 🇨🇿 Praha, Czechia

Insitute of Hematology and Blood Transfusion; 🇨🇿 Praha, Czechia

University Hospital Plzen; 🇨🇿 Plzen, Czechia

University Hospital Olomouc; 🇨🇿 Olomouc, Czechia

University Hospital Brno; 🇨🇿 Brno, Czechia

University Hospital Hradec Kralove; 🇨🇿 Hradec Králové, Czechia

University Hospital Ostrava; 🇨🇿 Ostrava, Czechia

General University Hospital in Prague; 🇨🇿 Praha, Czechia