Stopping tyrosine kinase inhibitors a second or third time after unsuccesful treatment discontinuation in chronic myeloid leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Heidelberg University

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Not possible to specify, Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-11-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma GmbH

External identifiers

EU CT number

2024-519472-69-00

EudraCT number

2015-004998-33

ClinicalTrials.gov

NCT02917720

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Assessment of duration of MMR or better after stopping TKI therapy a second or third time in patients with at least three years prior TKI treatment comprising at least two years of nilotinib treatment and maintained stable MR4 for at least one year and MR4.5 for at least 6 months before stopping in patients
➢ who failed a first stop in the EURO-SKI study (standardized criteria)
➢ who failed a first or second stop outside the EURO-SKI study but would have had fulfilled same eligible criteria and were stopped according to EURO-SKI criteria
➢ who failed a first or second stop outside the EURO-SKI study without fulfilling EURO-SKI criteria

Secondary objectives 9

1. Assessment of patients who re-achieved stable MR4.5 and were proposed for a 2nd or 3rd stop; number of patients who accept/refuse 2nd or 3rd stop after study entry
2. Assessment of safety profile, tolerability and AEs under nilotinib treatment
3. Assessment of QoL profiles under nilotinib treatment and after stopping
4. Identification of clinical and biological factors correlating with the persistence of MMR or better after stopping TKI (e.g. risk score Sokal/Euro/EUTOS/ELTS), gender, duration of TKI treatment, immunological status; stop according to Euro-SKI criteria y/n, molecular level at first or second stop
5. Estimation of overall and progression-free survival and proportion with a restart of TKI treatment without prior molecular recurrence (MRec)
6. Time to re-achievement of MMR, MR4 and MR4.5 after restart of therapy within this trial
7. Assessment of incidence of any AEs (e.g. from musculoskeletal system) that arise after stopping TKI treatment a second or third time.
8. Explorative objective: of clinical and biological factors correlating with reaching MR4.5 or better on nilotinib treatment after 1st or 2nd unsuccessful stopping;
9. Explorative objective: Evaluation of medico-economic impact of stopping TKI a second or third time.

Conditions and MedDRA coding

CML-Patients in chronic phase having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not and are pretreated at least one year with any TKI after 1st stop

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age ≥ 18 years
2. Patients with Ph chromosome and/or the BCR-ABL (either b3a2 and /or b2a2) fusion gene positive CML
3. CML in CP having failed prior attempt(s) to stop imatinib or other TKIs therapy either within EURO-SKI or not
4. Pretreatment at least one year with any TKI after 1st or 2nd stop, respectively
5. Written informed consent

Exclusion criteria 12

1. Previous hematological relapse after first or second stop of TKI
2. Failure to any TKI at any time during CML treatment according to current ELN criteria
3. Previous planned or performed allo SCT
4. Previous AP/BC at any time in the history of the disease
5. High cardiac risk according to ESC score (≥ 10 points)
6. Impaired cardiac function including any of the following: • Use of a ventricular paced pacemaker; • congenital long QT syndrome or family history of; • history or presence of significant ventricular or atrial tachyarrhythmia; • clinically significant resting bradycardia (<50 bpm); • QTcF >450 msec at baseline, • myocardial infarction before baseline; • other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension).
7. Treatment with inhibitors of CYP3A4 or medications that have been well documented to prolong the QT interval is contraindicated
8. History of acute pancreatitis within one year of study entry or medical history of chronic pancreatitis
9. Positive hepatitis B virus serology test or HBV infection
10. Any other malignancy except if neither clinically significant nor requires active intervention
11. Severe or uncontrolled medical conditions (i.e., uncontrolled diabetes, acute or chronic liver disease, pancreatic, or severe renal disease unrelated to tumor, active or uncontrolled infection).
12. Women who are pregnant, breast feeding, or of childbearing potential without a negative serum pregnancy test at baseline. Male or female patients of childbearing potential unwilling to use an effective barrier contraceptive method.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is molecular relapse-free survival, measured at 12 months and 36 months after 2nd or 3rd stop.

Secondary endpoints 4

1. overall survival and progression-free survival probabilities
2. Estimation of the number of patients in MR4.5 who would be eligible for stopping TKI therapy
3. The number of patients who regain MR4 and MR4.5 and the time to MR4 recovery
4. Outcome of molecular relapse-free survival at 12, 18, 24 and 36 months after TKI discontinuation

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Heidelberg University

Sponsor organisation

Heidelberg University

Address

Seminarstrasse 2, Altstadt Altstadt

City

Heidelberg

Postcode

69117

Country

Germany

Scientific contact point

Organisation

Heidelberg University

Contact name

Susanne Saußele

Public contact point

Organisation

Heidelberg University

Contact name

Susanne Saußele

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Results and documents

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

Documents 5 files

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

Application history

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