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Acute Lymphoblastic Leukemia, in RelapsePhase 1/2HEM-iSMART CNCT05745714

HEM-iSMART-C: Ruxolitinib + Venetoclax + Dexamethasone + Cyclophosphamide and Cytarabine in Pediatric Patients With Relapsed or Refractory Hematological Malignancies

A Phase 1/2 study testing Ruxolitinib, Venetoclax and Dexamethasone in people with Acute Lymphoblastic Leukemia, in Relapse and Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Recurrent, run by Princess Maxima Center for Pediatric Oncology at 33 sites in 14 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record

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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
What is being tested?
Ruxolitinib, Venetoclax and Dexamethasone
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 2 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.
  • 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 molecular profiling at first diagnosis lacking molecular diagnostics at relapse or refractory disease may be allowed to be included after discussion with the sponsor.
  • Patients whose tumor presents alterations in the IL-7R and/or JAK-STAT signaling pathways including but not limited to the following are eligible: CRLF2: Rearrangements and mutations leading to CRLF2 overexpression (P2RY8-CRLF2, IGH-CRLF2, and CRLF2 F232C), CRFL2 overexpression; EPOR: Truncating rearrangements or mutations in exon 8, EPOR fusions; JAK1/2/3: Recurrent or novel missense and in-frame indel mutations in or flanking the pseudokinase and kinase domains, JAK fusion; IL7R: Recurrent or novel missense or in-frame indel mutations in the transmembrane domain; SH2B3: Copy number deletions, or mutations that result in frameshifts or premature termination; JAK2: In frame fusions retaining the tyrosine kinase domain; USP9X truncating mutation or USP9X-DDX3X fusion; STAT5B and DNM2 mutations; PTPN2 deletion described as involved in IL7R/JAK/STAT pathway activation; IL7R mutations
  • Adequate organ function:
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  • 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 JAK inhibitors: JAK1 Phe958 and Pro960 mutations and JAK2 Y931C mutations.
  • Patients whose tumor present known mutationts confering resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations).
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  • 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.
  • Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
  • 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 ruxolitinib 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.
  • History of progressive multifocal leuko-encephalopathy (PML).
  • History of endocrine or kidney related growth retardation 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.

Anne Elsinghorst contact

+316 5000 6270

hem-ismart@prinsesmaximacentrum.nl

33 sites in 14 countries

France6 sites, 6 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

    Not yet recruiting

Other trials in France

Germany5 sites, 5 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

    Recruiting

  • Universitätsklinikum Essen

    Essen, 45147

    Evangelia Antoniu, evangelia.antoniou@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

    Not yet recruiting

Other trials in Germany

Italy5 sites, 5 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

    Not yet recruiting

Other trials in Italy

United Kingdom4 sites, 4 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

    Not yet recruiting

Other trials in United Kingdom

Spain3 sites, 3 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

    Not yet recruiting

Other trials in Spain

Israel2 sites, 2 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

    Not yet recruiting

Other trials in Israel

Austria1 site, 1 recruiting

  • St. Anna Kinderspital

    Vienna, 1090

    Andishe Attarbaschi, andishe.attarbaschi@stanna.at

    Not yet recruiting

Other trials in Austria

Belgium1 site, 1 recruiting

  • Universitair Ziekenhuis Gent

    Ghent, 9000

    Barbara De Moerloose, Barbara.DeMoerloose@uzgent.be

    Not yet recruiting

Other trials in Belgium

Denmark1 site, 1 recruiting

  • Rigshospitalet Copenhagen

    Copenhagen, DK-2100

    Ruta Tuckuviene, ruta.tuckuviene@regionh.dk

    Recruiting

Other trials in Denmark

Finland1 site, 1 recruiting

  • Helsinki University Hospital, New Children's Hospital

    Helsinki, FI00029

    Antti Kyrönlahti, antti.kyronlahti@hus.fi

    Not yet recruiting

Other trials in Finland

Ireland1 site, 1 recruiting

  • Our Lady's Hospital for Sick Children

    Dublin, D12N512

    Andrea Malone, andrea.malone@olchc.ie

    Not yet recruiting

Other trials in Ireland

Netherlands1 site, 1 recruiting

  • Princess Máxima Center for Pediatric Oncology

    Utrecht, Utrecht, 3584CS

    Anne A.L Elsinghorst, hem-ismart@prinsesmaximacentrum.nl

    Not yet recruiting

Other trials in Netherlands

Norway1 site, 1 recruiting

  • Oslo University Hospital

    Oslo, 0373

    Jochen Büchner, jocbuc@ous-hf.no

    Not yet recruiting

Other trials in Norway

Sweden1 site, 1 recruiting

  • Karolinska university hospital

    Stockholm, 171 76

    Anna Nilsson, anna.nilsson.1@ki.se

    Recruiting

Other trials in Sweden

About this study

Official title: International Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory HEMatological Malignancies in Children, Subprotocol C Ruxolitinib + 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 C is a phase I/II trial evaluating the safety and efficacy of ruxolitinib and venetoclax in combination with dexamethasone, cyclophosphamide and cytarabine in children and AYA with R/R ped ALL/LBL whose tumor present with alterations in the IL7R/JAK-STAT 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 C 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 ruxolitinib with venetoclax in combination with dexamethasone, cyclophosphamide and cytarabine in children, adolescents and young with R/R ALL and LBL. Patients with alterations in the IL-7R and/or JAK-STAT signaling pathways will be eligible for sub-protocol C.

Keywords
acute lymphoblastic leukemia, Lymphoblastic lymphoma, Biomarker driven clinical trial, Ruxolitinib, Venetoclax, Chemotherapy, Relapse, Children, Adolescents, Young adults
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.

Study groups in NCT05745714
Study groupRoleWhat they receive
Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabineExperimentalEach cycle has 28 days Cycle 1: All patients will receive 14 days of of ruxolitinib (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: All patients will receive 14 days of of ruxolitinib (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 1) and two blocks of four consecutive days of cytarabine (days 3 to 6 and days 10 to 13). Patients in dose level -1, will receive a lower dose of venetoclax compared to dose level 1. Patients in dose level 2, will receive a higher dose of venetoclax compared to dose level 1. All patients receive age adapted intrathecal chemotherapy.
Receives: Drug: Ruxolitinib; 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.

  1. 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

  2. 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 (8)

  1. Overall survival (OS)

    Defined as time from C1D1 until death of any cause.

    Measured: 7 years

  2. 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

  3. 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

  4. Number of patients proceeding to hematopoietic stem cell transplantation (HSCT) after the experimental therapy

    The rate of those proceeding to subsequent allogenic HSCT

    Measured: 7 years

  5. 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

  6. Rate of dose limiting toxicities (DLTs)

    Number of participants with dose limiting toxicities (DLTs).

    Measured: 7 years

  7. Peak plasma concentration (Cmax)

    Estimation of ruxolitinib Cmax.

    Measured: 6 years

  8. Peak plasma concentration (Cmax)

    Estimation of venetoclax 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.

  1. First posted27 Feb 2023
  2. Study start1 Oct 2025 (estimated)
  3. Primary completion1 Feb 2032 (estimated)
  4. Study completion2 Feb 2032 (estimated)

Resources

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)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05745714
Sponsor's protocol ID
2022-501867-42-00
Acronym
HEM-iSMART C
Status last verified
Sep 2025
First submitted
16 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.

Publications

  • Montanaro A, Monica G, Zamponi R, D'Antuono A, Andreani A, Andrei P, Su AH, Ciringione A, Sammarelli G, Todaro G, Rosati R, La Starza R, Mecucci C, Elia L, Gherli A, Vento F, Simoncini E, Lorusso B, Lagrasta CAM, Giaimo M, Pagliaro L, Marchesini M, Jimenez CR, Quaini F, Stegmaier K, Roti G. Inhibition of the atypical kinase WNK1 as a therapeutic strategy in TAL-related T-cell acute lymphoblastic leukemia. Blood. 2026 Sep 10;148(11):1423-1439. doi: 10.1182/blood.2025029901.

    PubMed 42154791

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