DASATINIB for Acute lymphoblastic leukemia (relapsed or refractory) | Precursor B-cell lymphoblastic lymphoma/leukaemia (relapsed or refractory) | Precursor T-cell lymphoblastic lymphoma/leukaemia (relapsed or refractory)

Inclusion criteria

• {"criterion_text":"-Children between 1 year (≥ 12 months) and 18 years of age at the time of first diagnosis and less than 21 years at the time of inclusion"}
• {"criterion_text":"-Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 50%"}
• {"criterion_text":"-Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study specific screening procedures are conducted, according to local, regional or national guidelines."}
• {"criterion_text":"-For all oral medications patients must be able to comfortably swallow capsules (except for those for which an oral solution is available or dissolving of tablets is allowed based on investigator brochure (IB); nasogastric or gastrostomy feeding tube administration is allowed only if indicated)."}
• {"criterion_text":"-Patients must have had advanced molecular profiling and flow-cytometric analysis of their recurrent or refractory disease at a time-point before the first inclusion into this trial (see section 9.1 for detailed description of the molecular diagnostics required). Drug response profiling and methylation is highly recommended but not mandatory. Patients with advanced molecular profiling at diagnosis may be allowed to be included after discussion with the sponsor."}
• {"criterion_text":"-Patients whose tumor present the following alterations: NUP214-ABL1 fusion or other ABL1 fusion, activating the kinase domain, or ABL1 amplification, or PDGFRβ-fusion with various fusion partners including but not limited to: AGGF1, DOCK2, SATB1, ETV6 and/or Patients showing a very deep ex-vivo dasatinib IC50 below 10 nM (only data generated in the Zurich Leukemia Research Laboratory Assay will be considered)"}
• {"criterion_text":"-Adequate organ function: RENAL AND HEPATIC FUNCTION (Assessed within 48 hours prior to C1D1) : Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age or calculated creatinine clearance as per the Schwartz formula or radioisotope glomerular filtration rate ≥ 60 mL/min/1.73 m2. Direct bilirubin ≤ 2 x ULN (≤ 3.0 × ULN for patients with Gilbert's syndrome). Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 5 x ULN. Note: Patients with hepatic disfunction related to the underling disease can be eligible even if they do not fulfill the aforementioned values for hepatic transaminases. In these cases, patients need to be discussed with the sponsor to confirm the eligibility. CARDIAC FUNCTION: Shortening fraction (SF) >29% (>35% for children < 3 years) and/or left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography or MUGA. Absence of QTcF prolongation (QTc prolongation is defined as >450 msec on baseline ECG, using the Friedericia correction), or other clinically significant ventricular or atrial arrhythmia"}

Exclusion criteria

• {"criterion_text":"-Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1."}
• {"criterion_text":"-Sexually active participants not willing to use highly effective contraceptive method (pearl index <1) as defined in CTFG HMA 2020 (Appendix II) during trial participation and until 6 months after end of antileukemic therapy."}
• {"criterion_text":"-Breast feeding."}
• {"criterion_text":"-Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome) in case of oral IMPs."}
• {"criterion_text":"-Patients whose tumor present known mutationts confering resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations)."}
• {"criterion_text":"-Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drugs, or drugs chemically related to study treatment or excipients that contraindicate their participation, including conventional chemotherapeutics (i.e. cytarabine and cyclophosphamide when applicable, intrathecal agents) and corticoids."}
• {"criterion_text":"-Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection. a.\tAdditional specifications for SARS-CoV-2 (COVID-19): i.\tPatients with a recent positive test for SARS-CoV-2 (COVID-19) and no follow-up negative PCR test are not eligible. ii.\tPatients with recent contact to persons with COVID-19 and persons with signs and symptoms of COVID-19 infection must be tested before enrolling. In case of contact with a COVID-19 positive person, at least 5 days should be observed between last contact and COVID testing. A negative PCR test is required to be eligible. iii.\tA negative COVID-19 test result is defined as at least 1 negative PCR test at least 24 hours after resolution of clinical symptoms. Resolution of clinical symptoms is defined as resolution of fever without use of antipyretics and improvement in respiratory symptoms (e.g., cough, shortness of breath). iv.\tFrequency or timing of COVID-19 testing and interval between testing for the above viral clearance criteria may be adjusted to the applicable country and institutional guidelines."}
• {"criterion_text":"-Severe concomitant disease that does not allow treatment according to the protocol at the investigator’s discretion"}
• {"criterion_text":"-Subjects unwilling or unable to comply with the study procedures."}
• {"criterion_text":"-Previous treatment with dasatinib and venetoclax in combination (Patients who have previously received any of these two drugs separately can be eligible for this sub-protocol)."}
• {"criterion_text":"-Current use of a prohibited medication or herbal preparation or requires any of these medications during the study. See Section 7, Appendix III and IV for details. In general, CYP3A4 inhibitors/Pgp inhibitors, moderate or strong inducers of CYP3A4 or drugs inducing QTc changes (prolongation of the QT interval or inducing Torsade de Points) are not permitted. Among others and not exclusively that relates to antiviral, antifungal, antibiotic, antimalarial, antipsychotic and antidepressive drugs."}
• {"criterion_text":"-Patients who have consumed grapefruit, grapefruit products, Seville oranges (Including marmalade containing Seville oranges) or starfruit within 72 hours prior to the first dose of study drug."}
• {"criterion_text":"-Unresolved toxicity greater than NCI CTCAE v 5.0 ≥ grade 2 from previous anti-cancer therapy, including major surgery, except those that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profile of the study treatment (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy)."}
• {"criterion_text":"-Active acute graft versus host disease (GvHD) of any grade or chronic GvHD of grade 2 or higher. Patients receiving any agent to treat or prevent GvHD post bone marrow transplant are not eligible for this trial."}
• {"criterion_text":"-Received immunosuppression post allogenic HSCT within one month of study entry."}
• {"criterion_text":"-Evidence of clinically active tuberculosis (clinical diagnosis per local practice)."}
• {"criterion_text":"-Wash-out periods of prior medication: a.\tCHEMOTHERAPY: At least 7 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea, 6-mercaptopurine, oral methotrexate and steroids which are permitted up until 48 hours prior to initiating protocol therapy. Patients may have received intrathecal therapy (IT) at any time prior to study entry. b.\tRADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first dose of drug. Palliative radiation in past 21 days is allowed. c.\tHEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT): a.\tAutologous HSCT within 2 months prior to the first study drug dose. b.\tAllogeneic HSCT within 3 months prior to the first study drug dose. d.\tIMMUNOTHERAPY: At least 42 days must have elapsed after the completion of any type of immunotherapy other than monoclonal antibodies (e.g. CAR-T therapy) e.\tMONOCLONAL ANTIBODIES AND INVESTIGATIONAL DRUGS: At least 21 days or 5 times the half-life (whichever is shorter) from prior treatment with monoclonal antibodies or any investigational drug under investigation must have elapsed before the first study drug. f.\t SURGERY: Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery."}

Primary endpoints

• {"endpoint_text":"-Phase I: determine the maximum tolerated dose (MTD)/RP2D","definition_or_measurement_approach":"Phase I primary objective: assess safety and tolerability of investigational agents and define the MTD/RP2D(s). Dose-limiting toxicities (DLTs) and safety/tolerability assessments are used to determine MTD/RP2D (rate of DLTs is a listed secondary endpoint)."}
• {"endpoint_text":"-Phase II: best overall response rate (ORR)","definition_or_measurement_approach":"Best overall response rate (ORR) defined as best overall response recorded from the start of treatment until patient gets off-study or the clinical cut-off date; cumulative ORR elsewhere defined as CR, CRp, CRi and MRD-negativity rates after more than 1 cycle."}

Secondary endpoints

• {"endpoint_text":"-Overall survival (OS) is defined as time from C1D1 until death of any cause. Patients stil alive at the time of clinical cut-off date will be censored at their last known date alive.","definition_or_measurement_approach":"OS measured as time (days/months) from Cycle 1 Day 1 until death from any cause; censoring at last known alive date for survivors at clinical cut-off."}
• {"endpoint_text":"-Event-free survival (EFS) is defined as time from C1D1 to the first event (subsequent relapse after CR (including molecular reappearance), death of any cause, failure to achieve remission (CR, CRp or CRi), or secondary malignancy). Patients who are event-free will be censored at date of last adequate disease assessment. Treatment failure (defined by morphology and/or flow-cytometry as not achieving remission after 1 cycle) is calculated as an event at day 1.","definition_or_measurement_approach":"EFS measured from C1D1 to first event as defined; patients event-free censored at last adequate disease assessment; treatment failure counted as event at Day 1."}
• {"endpoint_text":"-Cumulative incidence of relapse (CIR): Estimate of the risk, that a patient will develop a relapse over a specified period of time. Deaths without relapse will be considered competing events.","definition_or_measurement_approach":"CIR estimated over specified time; competing risk methodology with death without relapse treated as competing event."}
• {"endpoint_text":"-Number of patients proceeding to HSCT after the experimental therapy: The rate of those proceeding to subsequent allogenic hematopoietic stem cell transplantation as consolidation therapy is calculated as the number of patients who receive an HSCT divided by the total number of patients enrolled.","definition_or_measurement_approach":"Rate calculated as number receiving allogeneic HSCT divided by total enrolled."}
• {"endpoint_text":"-Cumulative overall response rate (ORR), defined as the CR, CRp, CRi and MRD neg-ativity rates after more than 1 cycle of treatment. The best overall response is the best response recorded from the start of the treatment until patient gets off-study or the cut-off date, whichever comes first (taking as reference for progressive disease the small-est measurements recorded since the treatment started).","definition_or_measurement_approach":"Cumulative ORR comprises CR, CRp, CRi and MRD-negativity after >1 cycle; best overall response is the best response from treatment start until off-study or cut-off."}
• {"endpoint_text":"-Rate of dose limiting toxicities (DLTs); number of participants with dose limiting toxicities.","definition_or_measurement_approach":"Count and rate of participants experiencing protocol-defined DLTs during the DLT assessment period."}
• {"endpoint_text":"-PK parameters, including but not limited to plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, clearance, half-life time.","definition_or_measurement_approach":"Standard PK analyses of plasma concentration-time data to derive AUClast, AUCtau, Cmin, Cmax, Tmax, clearance and half-life."}
• {"endpoint_text":"-QoL will be assessed at baseline and after cycle 1 and at the end of treatment using the PedsQL™ Cancer Module.","definition_or_measurement_approach":"Quality of life measured using PedsQL™ Cancer Module at specified time points (baseline, after cycle 1, end of treatment)."}

France

Earliest CTIS Part Ii Submission Date

12-06-2025

Latest Decision Or Authorization Date

20-10-2025

Processing Time Days

130

Number Of Sites

6

Number Of Participants

3

Netherlands

Earliest CTIS Part Ii Submission Date

16-07-2024

Latest Decision Or Authorization Date

13-06-2025

Processing Time Days

332

Number Of Sites

1

Number Of Participants

3

Denmark

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

13-06-2025

Processing Time Days

242

Number Of Sites

1

Number Of Participants

1

Spain

Earliest CTIS Part Ii Submission Date

18-09-2024

Latest Decision Or Authorization Date

13-06-2025

Processing Time Days

268

Number Of Sites

4

Number Of Participants

2

Germany

Earliest CTIS Part Ii Submission Date

18-09-2024

Latest Decision Or Authorization Date

20-06-2025

Processing Time Days

275

Number Of Sites

5

Number Of Participants

3

Sweden

Earliest CTIS Part Ii Submission Date

30-09-2024

Latest Decision Or Authorization Date

24-06-2025

Processing Time Days

267

Number Of Sites

1

Number Of Participants

1

Norway

Earliest CTIS Part Ii Submission Date

24-09-2024

Latest Decision Or Authorization Date

24-06-2025

Processing Time Days

273

Number Of Sites

1

Number Of Participants

1

Finland

Earliest CTIS Part Ii Submission Date

18-09-2024

Latest Decision Or Authorization Date

25-06-2025

Processing Time Days

280

Number Of Sites

1

Number Of Participants

1

Austria

Earliest CTIS Part Ii Submission Date

16-10-2024

Latest Decision Or Authorization Date

27-06-2025

Processing Time Days

254

Number Of Sites

1

Number Of Participants

1

Italy

Earliest CTIS Part Ii Submission Date

19-09-2024

Latest Decision Or Authorization Date

02-07-2025

Processing Time Days

286

Number Of Sites

5

Number Of Participants

3

Belgium

Earliest CTIS Part Ii Submission Date

06-10-2025

Latest Decision Or Authorization Date

05-12-2025

Processing Time Days

60

Number Of Sites

1

Number Of Participants

1

Primary sponsor

Full Name

Princess Maxima Center For Pediatric Oncology

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands

Contract research organisations

Name

Julius Clinical International B.V.

Third parties

• {"country":"Netherlands","full_name":"Julius Clinical International B.V.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Denmark","full_name":"Frederiksberg Hospital","duties_or_roles":"","organisation_type":"Hospital/Clinic/Other health care facility"}