Ponatinib for Acute lymphoblastic leukaemia (Philadelphia chromosome-positive, BCR-ABL+)

Inclusion criteria

• {"criterion_text":"- Male or female patients > 55 years (biological age)\n- Women of non-childbearing potential defined as sexually mature women who have undergone a hysterectomy or surgical sterilization or who have been naturally postmenopausal for at least 12 consecutive months (i.e., absence of menses in the preceding 12 consecutive months)\n- Philadelphia chromosome- or BCR-ABL positive acute lymphoblastic leukemia\n- Not previously treated except with corticosteroids, single dose vincristine or up to three doses of cyclophosphamide (maximum cumulative dose 1g/m2) or intrathecal therapy to control meningeal leukaemia\n- No uncontrolled CNS involvement\n- WHO performance status <2\n- Normal serum levels > LLN (lower limit of normal) of potassium and magnesium, or corrected to within normal limits with supplements, prior to the first dose of study medication\n- Signed written informed consent\n- Molecular evaluation for BCR-ABL1 performed\n- Willingness of sexually active male subjects whose sexual partners are women of childbearing potential (WOCBP), to use an effective form of contraception (pearl index < 1%) during the study and at least 6 months thereafter. Effective forms of contraception are complete sexual abstinence (refraining from heterosexual intercourse during the entire period of risk associated with the study treatments), combined oral contraceptive, hormone IUCD, vaginal hormone ring, transdermal contraceptive patch, contraceptive implant or depot contraceptive injection in combination with a second method of contraception like a condom or a cervical cap/diaphragm with spermicide or surgical sterilisation (vasectomy) in male patients"}

Exclusion criteria

• {"criterion_text":"- Patient previously treated with tyrosine kinase inhibitors\n- Known impaired cardiac function (if uncontrolled), including any of the following: • LVEF < 40% • Complete left bundle branch block • Right bundle branch block plus left anterior hemiblock, bifascicular block • History of or presence of clinically significant ventricular or atrial tachyarrhythmias • Clinically significant resting bradycardia (< 50 beats per minute) • Congenital long QT syndrome or QTcF >470 msec on screening ECG. If QTc > 470 msec and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion. • Myocardial infarction within 12 months prior to starting study treatment • Other clinical significant heart disease (e.g. unstable angina, congestive heart failure, uncontrolled hypertension)\n- Symptomatic peripheral vascular disease\n- Any history of ischemic stroke or transient ischemic attacks (TIAs)\n- Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention\n- Active ALL in the CNS (confirmed by CSF analysis) or testes (by clinical assessment)\n- Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C\n- Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study\n- Inadequate hepatic functions defined as ASAT or ALAT > 2,5 times the institutional upper limit of normal or > 5 times ULN if considered due to leukemia\n- Total bilirubin > 1.5 fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert/M. Meulengracht\n- Concurrent severe diseases which exclude the administration of therapy\n- Chronic pancreatitis or acute pancreatitis within 6 months of study start\n- Pregnant or lactating females\n- Patients unwilling or unable to comply with the protocol\n- Patients with history of hypersensitivity to any of the experimental treatments"}

Primary endpoints

• {"endpoint_text":"- Achievement of a molecular response in treatment arms 1 and 2 defined by a BCR-ABL1/ABL1 (B/A) transcript ratio of ≤10-4 by the time point scheduled for MRD analysis after consolidation 2 (for arms 1 and 2) or within 5 months after start of study treatment, whichever is earlier.","definition_or_measurement_approach":"Molecular response defined by BCR-ABL1/ABL1 (B/A) transcript ratio ≤10^-4 measured by MRD molecular analysis at the scheduled time point after consolidation 2 or within 5 months after start of study treatment, whichever is earlier."}

Secondary endpoints

• {"endpoint_text":"- Event-free survival (EFS), with an event defined as failure to achieve a CR, progression, relapse or death\n- Confirmed undetectable BCR-ABL1 transcripts with an assay sensitivity of at least 10-4.5 at any time prior to maintenance therapy, after completing consolidation therapy\n- Molecular response defined by a B/A ratio ≤ 0.0003% in bone marrow\n- Time to best molecular response- this will be measured as time to event\n- Adverse event grade 3 to 5, measured at each treatment cycle\n- Discontinuation of study treatment due to an adverse event\n- Adverse events of special interest: cardiovascular and thromboembolic AE, pancreatitis, cytokine release syndrome, tumour lysis syndrome, neurologic AEs ≥ grade 3, measured at each treatment cycle\n- Early death: defined by death during the induction period from inclusion to complete remission or before day 56\n- Death in complete remission-measured as a proportion\n- Detection of a T315I or p-loop mutation\n- Detection of a compound mutation\n- Relapse - measured as a proportion\n- Premature discontinuation of ponatinib or imatinib due to toxicity\n- Relapse free survival - Relapse free survival (RFS) is calculated from the date of documented complete remission to date of relapse or death, whatever is earlier. Patients still in remission will be censored at the time of last follow-up\n- Overall survival- Overall survival (OS) is calculated from the first day of therapy to the date of death. Surviving patients will be censored at the time of last follow-up","definition_or_measurement_approach":"Endpoints include survival outcomes (EFS, RFS, OS) calculated from defined timepoints as specified (e.g., OS from first day of therapy; RFS from date of documented CR), molecular endpoints measured by BCR-ABL1 transcript assays with specified sensitivities (e.g., 10^-4.5), mutation detection by standard molecular genetic techniques, and adverse events graded per toxicity criteria and measured each treatment cycle."}

Sweden

Earliest CTIS Part Ii Submission Date

16-01-2025

Latest Decision Or Authorization Date

08-10-2025

Processing Time Days

265

Number Of Sites

1

Number Of Participants

5

Finland

Earliest CTIS Part Ii Submission Date

16-01-2025

Latest Decision Or Authorization Date

06-10-2025

Processing Time Days

263

Number Of Sites

1

Number Of Participants

5

France

Earliest CTIS Part Ii Submission Date

16-01-2025

Latest Decision Or Authorization Date

03-10-2025

Processing Time Days

260

Number Of Sites

7

Number Of Participants

90

Primary sponsor

Full Name

Cardiff University

Organisation Type

Educational Institution

Country Of Registered Address

United Kingdom

Third parties

• {"country":"","full_name":"Incyte","duties_or_roles":"Monetary support","organisation_type":""}