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
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Not specified
- Sponsor
- Masarykova Univerzita
- Enrollment
- 221
- Locations
- 8
- Primary Endpoint
- 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
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
The primary objective of the study is to evaluate the efficacy of tyrosine kinase inhibitor discontinuation during and after a two-step dose reduction in patients with chronic myeloid leukemia in deep 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.
Investigators
Žáčková
Scientific
Masarykova Univerzita
Eligibility Criteria
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
- •Pregnancy and breastfeeding
- •Disagreement or impossibility to comply with the contraceptive measures described in point 9 of the inclusion criteria
- •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
Outcomes
Primary Outcomes
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) 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 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 (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, 24 and 36 after study entry, ie, 6, 12 and 24 months after treatment discontinuation
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, 24 and 36 after study entry, ie, 6, 12 and 24 months after treatment discontinuation
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 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
- Assessment of TKI's adverse effects dynamics during two-step reduction of their dose before withdrawal
- Assessment of TKI withdrawal syndrome (proportion of patients with development of withdrawal syndrome, severity of symptoms, time to first complaint, duration of complaints, therapeutic intervention)
- Assessment of the correlation between adverse effects on previous TKI treatment and possible withdrawal syndrome
- Correlation of BCR-ABL1 kinetics (number of BCR-ABL1 transcripts in time) during TKI therapy with potential molecular relapse after TKI discontinuation
- Correlation of the effect of TKI dose reduction and subsequent discontinuation with lipid metabolism and glycemia