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

NCT04147533 | Active Not Recruiting Phase 2

• 1 other identifier: HALF2019
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 8

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

Conditions

Chronic Myeloid Leukemia, Chronic Phase; Withdrawal;Drug

Keywords

tyrosine kinase inhibitors; drug withdrawal; chronic myeloid leukemia, chronic phase

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (13)

• 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 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

  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

  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

  months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36

Other Outcomes (124)

• failure-free survival

  months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36

• progression-free survival

  months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36

• overall survival

  months 2,4,6,8,10,12,13,14,15,16,17,18,19.5,21,22.5,24,27,30,33,36

Study Arms (1)

initially treated patients

EXPERIMENTAL

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; Drug: Dasatinib; Drug: Nilotinib

Interventions

Imatinib withdrawal DRUG

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

Also known as: Glivec withdrawal

initially treated patients

Dasatinib DRUG

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

Also known as: Sprycel withdrawal

initially treated patients

Nilotinib DRUG

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

Also known as: Tasigna withdrawal

initially treated patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Masaryk University: lead

Study Sites (8)

University Hospital Brno

Brno, 62500, Czechia

Location

University Hospital Hradec Kralove

Hradec Králové, 50005, Czechia

Location

University Hospital Olomouc

Olomouc, 77900, Czechia

Location

University Hospital Ostrava

Ostrava, 70852, Czechia

Location

University Hospital Plzen

Pilsen, 30599, Czechia

Location

University Hospital Kralovske Vinohrady

Prague, 10034, Czechia

Location

Insitute of Hematology and Blood Transfusion

Prague, 12800, Czechia

Location

General University Hospital in Prague

Prague, 12808, Czechia

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Chronic-Phase; Substance Withdrawal Syndrome

Interventions

Dasatinib; nilotinib

Condition Hierarchy (Ancestors)

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Daniela Zackova

  University Hospital Brno

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2019
• First Posted: November 1, 2019
• Study Start: June 16, 2020
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: November 26, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (8)