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

Sponsor-declared trial summary

Key facts

Sponsor

Masarykova Univerzita

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

16 Jun 2020 → ongoing

Decision date (initial)

2024-09-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Masaryk University

External identifiers

EU CT number

2024-514592-17-00

EudraCT number

2019-003221-16

ClinicalTrials.gov

NCT04147533

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacoeconomic, Dose response, Safety, Therapy, Efficacy, Pharmacokinetic

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

Secondary objectives 1

1. The secondary objective of the study is to evaluate the safety of discontinuing tyrosine kinase inhibitors during and after a two-step dose reduction in patients with chronic myeloid leukemia in deep remission

Conditions and MedDRA coding

chronic myeloid leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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 11

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 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
2. Proportion of patients in major molecular response (MMR) and MRFS at month 12 after study entry
3. 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 endpoints 8

1. Proportion of patients who lose MMR during de-escalation and in whom MMR and MR4.0 will recover after TKI re-introduction
2. Proportion of patients who lose MMR after discontinuation of TKI and in whom MMR and MR4.0 will recover after TKI re-introduction
3. Time to re-establish MMR and MR4.0 after TKI restart
4. Assessment of TKI's adverse effects dynamics during two-step reduction of their dose before withdrawal
5. 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)
6. Assessment of the correlation between adverse effects on previous TKI treatment and possible withdrawal syndrome
7. Correlation of BCR-ABL1 kinetics (number of BCR-ABL1 transcripts in time) during TKI therapy with potential molecular relapse after TKI discontinuation
8. Correlation of the effect of TKI dose reduction and subsequent discontinuation with lipid metabolism and glycemia

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Masarykova Univerzita

Sponsor organisation

Masarykova Univerzita

Address

Zerotinovo Namesti 617/9, Brno-Mesto Brno-Mesto

City

Brno

Postcode

602 00

Country

Czechia

Scientific contact point

Organisation

Masarykova Univerzita

Contact name

Žáčková

Public contact point

Organisation

Masarykova Univerzita

Contact name

Regina Demlová

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications