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

Masaryk University

Status and phase: Active, not recruiting; Phase 2

Conditions: Withdrawal;Drug; Chronic Myeloid Leukemia, Chronic Phase

Treatments: Drug: Nilotinib; Drug: Imatinib withdrawal; Drug: Dasatinib

Study type: Interventional

Funder types: Other

Identifiers

NCT04147533

HALF2019

Details and patient eligibility

About

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

Full 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.

Enrollment: 150 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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150 participants in 1 patient group

initially treated patients

Experimental group

Description:

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.

Treatment:

Drug: Dasatinib

Drug: Imatinib withdrawal

Drug: Nilotinib