Acute Lymphoblastic LeukemiaPhase 1/2HEM-iSMART BNCT05751044
HEM-iSMART-B: Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies
A Phase 1/2 study testing Dasatinib, Venetoclax and Dexamethasone in people with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Recurrent, run by Princess Maxima Center for Pediatric Oncology at 33 sites in 14 countries.
Trial summary
HEM-iSMART is a master protocol which investigates multiple investigational medicinal products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R) ALL and LBL. Read more about this study
- Who is it for?
- Ages 1 year to 21 years
- Conditions the study is for
- Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Recurrent, Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Recurrent
- What is being tested?
- Dasatinib, Venetoclax and Dexamethasone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 33 sitesin 14 countries
- Study dates
- 1 Oct 2025to 1 Feb 2032
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
- Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 50% (Appendix I).
- 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.
- 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).
- 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.
- 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 centralized laboratory, where a robust DRP platform has been established with a reference cohort in place, will be considered)
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- 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.
Who cannot join
- Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1.
- 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.
- Breast feeding.
- 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.
- Patients whose tumor present known mutationts confering resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations).
- 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.
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- Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
- Additional specifications for SARS-CoV-2 (COVID-19): i. Patients with a recent positive test for SARS-CoV-2 (COVID-19) and no follow-up negative PCR test are not eligible.
- Patients 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.
- A 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).
- Frequency 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.
- Severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion.
- Subjects unwilling or unable to comply with the study procedures.
- 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).
- 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.
- 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.
- 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) (Common Terminology Criteria for Adverse Events (CTCAE) (cancer.gov).
- 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.
- Received immunosuppression post allogenic HSCT within one moth of study entry.
- History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis.
- Evidence of clinically active tuberculosis (clinical diagnosis per local practice).
- Wash-out periods of prior medication:
- CHEMOTHERAPY: 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.
- RADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first dose of drug. Palliative radiation in past 21 days is allowed.
- HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT):
- Autologous HSCT within 2 months prior to the first study drug dose.
- Allogeneic HSCT within 3 months prior to the first study drug dose.
- IMMUNOTHERAPY: At least 42 days must have elapsed after the completion of any type of immunotherapy other than monoclonal antibodies (e.g. CAR-T therapy)
- MONOCLONAL 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.
- 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.
Trial locations and contacts
33 sites in 14 countries. Contact the study team or a site near you to ask about taking part.
33 sites in 14 countries
France6 sites, 6 recruiting
- Not yet recruiting
Hôpital des Enfants GH Pellegrin - CHU de Bordeaux
Bordeaux, 33076
Stephane Ducassou, stephane.ducassou@chu-bordeaux.fr
- Not yet recruiting
CHRU Lille - Hôpital Jeanne de Flandre
Lille, 59037
Bigitte Nelken, brigitte.nelken@chu-lille.fr
- Not yet recruiting
Centre Léon Bérard
Lyon, 69 373
Nathalie Garnier, nathalie.garnier@ihope.fr
- Not yet recruiting
Hopital La Timone - Enfants
Marseille, 13005
Paul Saultier, paul.saultier@ap-hm.fr
- Not yet recruiting
CHU Nantes Hôpital Mère-Enfant
Nantes, 44093
Fanny Rialland, fanny.rialland@chu-nantes.fr
- Not yet recruiting
Hôpital Robert Debré
Paris, 75019
Marion Strullu, marion.strullu@aphp.fr
Germany5 sites, 5 recruiting
- Not yet recruiting
Universitätsklinikum Augsburg
Augsburg, 86156
Michael Frühwald, Michael.Fruehwald@uk-augsburg.de
- Not yet recruiting
Charité Universitätsmedizin Berlin
Berlin, 13353
Arend von Stackelberg, arend.stackelberg@charite.de
- Not yet recruiting
Universitätsklinikum Essen
Essen, 45147
Dirk Reinhardt, dirk.reinhardt@uk-essen.de
- Not yet recruiting
Universitätsklinikum Frankfurt
Frankfurt, 60590
Jan-Hemming Klusmann, Jan-Henning.Klusmann@ukffm.de
- Not yet recruiting
Universitätsklinikum Münster
Münster, 48149
Birgit Burkhardt, birgit.burkhardt@ukmuenster.de
Italy5 sites, 5 recruiting
- Not yet recruiting
IRCCS Istituto Giannina Gaslini
Genova, 16147
Concetta Micalizzi, concettamicalizzi@gaslini.org
- Not yet recruiting
Fondazione MBBM c/o Centro ML Verga
Monza, 20900
Carmelo Rizzari, carmelo.rizzari@gmail.com
- Not yet recruiting
Padova Azienda Ospedaliera
Padova, 35128
Marta Pillon, marta.pillon@unipd.it
- Not yet recruiting
Ospedale Pediatrico Bambino Gesù, IRCCS
Roma, 0165
Franco Locatelli, franco.locatelli@opbg.net
- Not yet recruiting
Ospedale Infantile Regina Margherita
Turin, 10126
Franca Fagioli, franca.fagioli@unito.it
United Kingdom4 sites, 4 recruiting
- Not yet recruiting
Bristol Royal Hospital for Children
Bristol, B52 8BJ
Kristina Marshall, kristina.marshall@uhbw.nhs.uk
- Not yet recruiting
Great Ormond Street Hospital for Children NHS Trust
London, WC1N 2BH
David O'Connor, david.oconnor@gosh.nhs.uk
- Not yet recruiting
Great North Children's Hospital
Newcastle, NE1 4LP
Frederik van Delft, Frederik.Van-Delft@newcastle.ac.uk
- Not yet recruiting
Royal Marsden NHS Trust
Sutton, SM2 5PT
Donna Lancaster, donna.lancaster@rmh.nhs.uk
Spain3 sites, 3 recruiting
- Not yet recruiting
Hospital Sant Joan de Déu de Barcelona
Barcelona, 08950
Jose Luis Dapena Diaz, joseluis.dapena@sjd.es
- Not yet recruiting
Hospital Infantil Universitario Niño Jesús
Madrid, 28009
Alba Rubio San Simón, alba.rubio@salud.madrid.org
- Not yet recruiting
La Fe
Valencia, 46026
Carol Fuentes, fuentes_car@gva.es
Israel2 sites, 2 recruiting
- Not yet recruiting
Schneider's Children's Medical Center
Petah Tikva, 4920235
Gil Gilad, gilgi@clalit.org.il
- Not yet recruiting
Sheba Medical Center Hospital
Ramat Gan, 52621
Bella Bielorai, bella.bielorai@sheba.health.gov.il
Austria1 site, 1 recruiting
- Not yet recruiting
St. Anna Kinderspital
Vienna, 1090
Andishe Attarbaschi, andishe.attarbaschi@stanna.at
Belgium1 site, 1 recruiting
- Not yet recruiting
Universitair Ziekenhuis Gent
Ghent, 9000
Barbara De Moerloose, Barbara.DeMoerloose@uzgent.be
Denmark1 site, 1 recruiting
- Recruiting
Rigshospitalet Copenhagen
Copenhagen, DK-2100
Ruta Tuckuviene, ruta.tuckuviene@regionh.dk
Finland1 site, 1 recruiting
- Not yet recruiting
Helsinki University Hospital, New Children's Hospital
Helsinki, FI00029
Antti Kyrönlahti, antti.kyronlahti@hus.fi
Ireland1 site, 1 recruiting
- Not yet recruiting
Our Lady's Hospital for Sick Children
Dublin, D12N512
Andrea Malone, andrea.malone@olchc.ie
Netherlands1 site, 1 recruiting
- Not yet recruiting
Princess Máxima Center for Pediatric Oncology
Utrecht, Utrecht, 3584CS
Anne A.L Elsinghorst, hem-ismart@prinsesmaximacentrum.nl
Norway1 site, 1 recruiting
- Not yet recruiting
Oslo University Hospital
Oslo, 0373
Jochen Büchner, jocbuc@ous-hf.no
Sweden1 site, 1 recruiting
- Recruiting
Karolinska university hospital
Stockholm, 171 76
Anna Nilsson, anna.nilsson.1@ki.se
About this study
Official title: International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Sub-protocol B Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies
HEM-iSMART is a master protocol which investigates multiple investigational medicinal products in children, adolescents and young adults (AYA) with relapsed/refractory (R/R) ALL and LBL. Sub-protocol B is a phase I/II trial evaluating the safety and efficacy of dasatinib + venetocolax in combination with dexamethasone + Cyclophosphamide and cytarabine in children and AYA with R/R ped ALL/LBL whose tumor present with alterations in the MAPK/SRC pathway.
Read the detailed description
HEM-iSMART is a master protocol with sub-protocols. The overarching objective is that introducing targeted therapy using a biomarker driven approach for treatment stratification may improve the outcome of children with R/R acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) It is characterized by a shared framework that allows for the investigation of multiple IMPs and generate pivotal safety and efficacy evidence within the sub-protocols to establish and define the benefits and risks of new treatments for children with R/R leukemia.
Sub-protocol B within HEM-iSMART, is a phase I/II, multicenter, international, open-label clinical trial designed to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of dasatinib + venetoclax in combination with dexamethasone, cyclophosphamide and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with actionable alterations in the MAPK/SRC pathway will be eligible for sub-protocol B including but not limited to 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).
- Conditions
- Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Recurrent, Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Recurrent, Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Refractory, Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Refractory
- Being tested
- Dasatinib, Venetoclax, Dexamethasone, Cyclophosphamide, Cytarabine
- Keywords
- Acute lymphoblastic leukemia, Relape, Biomarker driven clinical trial, Dasatinib, Refractory, Chemotherapy, Children, Adolescents, Young adults, Lymphoblastic lymphoma
- Medical subject headings
- Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Recurrence, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DasatinibDrug
Oral
VenetoclaxDrug
oral
DexamethasoneDrug
oral/intervenous
CyclophosphamideDrug
intravenous
CytarabineDrug
intravenous
intrathecal chemotherapyDrug
IT: Methotrexate +/- prednisone/hydrocortisone/cytarabine according to the degree of central nervous involvement
| Study group | Role | What they receive |
|---|---|---|
| Dasatinib + Venetoclax + Dexamethasone + Cyclophosphamide + cytarabine | Experimental | Sub-study B
Each cycle lasts 28 days.
Cycle 1: All patients in cycle 1 will receive 28 days of of dasatinib (days 1-14), 28 days of venetoclax (days 1-28), one block of five days of dexamethasone (days 1-5), one dose of cyclophosphamide (day 3) and two blocks of four consecutive days of cytarabine (days 5 to 8 and days 12 to 15). A 1-day venetoclax ramp-up is proposed in this study.
Cycle 2 and subsequent cycles: Dasatinib and ventoclax one a day (day 1-28); one block of five days of dexamethasone (days 1-5), one dose of cyclophosphamide (day 1) and two blocks of four consecutive days of cytarabine (days 3 to 6 and days 10 to 13).
Patients in dose level -1, receive a lower dose of venetoclax. Patients in dose level 2 receive a higher dose of venetoclax.
All patients receive age adapted intrathecal chemotherapy. Receives: Drug: Dasatinib; Drug: Venetoclax; Drug: Dexamethasone; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: intrathecal chemotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase I: Maximum tolerated dose (MTD) / Recommended phase 2 dose (RP2D).
Defined as the highest dose level tested at which 0/6 or 1/6 patients experiences dose limiting toxicities (DLT) during course 1 with at least 2 patients experiencing DLT at the next higher dose.
Measured: 3 years
Phase II: Best Overall Response Rate (ORR).
For patients with leukemia: CR and MRD response after 1 cycle of treatment. This includes determination of CR, CRp, CRi and minimal residual disease (MRD) negativity rate in patients suffering from overt morphological relapse of T-ALL at time of enrolment (morphological disease (M2/M3)), and the MRD negativity rate in those that entered with high-MRD levels but in morphological CR. These results will together be presented as a composite endpoint Overall Response rate (ORR). MRD negativity will be defined as ≤1x10-4 as generated by multi-parameter flow cytometry.
For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria. In case of bone-marrow involvement MRD will be taken into account.
For patients with lymphoma: Response in LBL patients is defined as CR, PR, minor response (MR) as defined in International pediatric NHL response criteria.
Measured: 6 years
Secondary outcomes (7)
Overall survival (OS)
Defined as time from C1D1 until death of any cause.
Measured: 7 years
Event-free survival (EFS)
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).
Measured: 7 years
Cumulative incidence of relapse (CIR)
Estimate of the risk, that a patient will develop a relapse over a specified period of time.
Measured: 7 years
Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy.
The rate of those proceeding to subsequent allogenic HSC
Measured: 7 years
Cumulative overall response rate (ORR)
Defined as the CR, CRp, CRi and MRD negativity rates after more than 1 cycle of treatment.
Measured: 7 years
Rate of dose limiting toxicities (DLTs)
Number of participants with dose limiting toxicities (DLTs)
Measured: 7 years
Peak Plasma Concentration (Cmax)
Estimation of venetoclax and dasatinib Cmax
Measured: 6 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2023
- Study start1 Oct 2025 (estimated)
- Primary completion1 Feb 2032 (estimated)
- Study completion1 Feb 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Lymphoblastic LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Princess Maxima Center for Pediatric Oncology
- Sponsor type
- University, hospital or other
- Collaborators
- Innovative Therapies For Children with Cancer Consortium, IBFM, Fight Kids Cancer
- Responsible party
- Sponsor
- Investigators
- Michel Zwaan, Prof. Dr., Study chair, Princess Máxima CenterAndrej Lissat, MD PhD, Principal investigator, Charite University, Berlin, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05751044
- Sponsor's protocol ID
- 2022-501866-22-00
- Acronym
- HEM-iSMART B
- Status last verified
- Sep 2025
- First submitted
- 20 Feb 2023
- Last updated
- 16 Sep 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All individual participant data will be used to generate a publication.