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Ruxolitinib and venetoclax added to chemotherapy for children and young adults with relapsed or refractory ALL/LBL

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

Phase1; Phase2 Interventional Princess Maxima Center for Pediatric Oncology · NCT05745714

This trial tests whether adding ruxolitinib and venetoclax to dexamethasone, cyclophosphamide and cytarabine helps children and young adults with relapsed or refractory acute lymphoblastic leukemia or lymphoblastic lymphoma who have IL7R/JAK-STAT pathway changes.

Quick facts

PhasePhase1; Phase2
Study typeInterventional
Enrollment26 (estimated)
Ages1 Year to 21 Years
SexAll
SponsorPrincess Maxima Center for Pediatric Oncology Academic / other
Drugs / interventionsruxolitinib, CAR-T, chemotherapy, IMMUNOTHERAPY, radiation, methotrexate, cyclophosphamide
Locations33 sites (Vienna and 32 other locations)
Trial IDNCT05745714 on ClinicalTrials.gov

What this trial studies

HEM-iSMART is a master protocol using a biomarker-driven approach to match targeted therapies to children, adolescents and young adults with relapsed or refractory ALL and LBL. Sub-protocol C is a multicenter, international, open-label phase I/II trial that combines the JAK inhibitor ruxolitinib and the BCL-2 inhibitor venetoclax with dexamethasone, cyclophosphamide and cytarabine. The trial will collect safety, tolerability, pharmacokinetics and efficacy data specifically in patients whose tumors show alterations in the IL7R/JAK-STAT signaling pathway. Enrollment requires prior molecular profiling to confirm the pathway alterations and patients will be followed for response and treatment-related adverse events.

Who should consider this trial

Good fit: Children, adolescents and young adults (diagnosed ≥12 months to <21 years at inclusion) with relapsed or refractory ALL or LBL whose tumor shows IL7R and/or JAK-STAT pathway alterations and who meet performance status and consent requirements are eligible.

Not a fit: Patients without IL7R/JAK-STAT pathway alterations, those who are medically unfit for intensive chemotherapy combinations, or those outside the eligible age range are unlikely to benefit from this sub-protocol.

Why it matters

Potential benefit: If successful, this targeted combination could increase remission rates and offer a new therapeutic option for children and young adults with IL7R/JAK-STAT–altered relapsed or refractory ALL/LBL.

How similar studies have performed: Targeted agents like ruxolitinib and venetoclax have shown activity in adult and preclinical leukemia models, but combining these two agents with chemotherapy in pediatric IL7R/JAK-STAT–altered ALL/LBL remains largely untested in children.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

1. 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
2. Performance status: Karnofsky performance status (for patients \>12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 50% (Appendix I).
3. 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.
4. 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.
5. 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
6. 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:
7. Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1.
8. 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.
9. Breast feeding.
10. 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.
11. Patients whose tumor present known mutationts confering resistance to JAK inhibitors: JAK1 Phe958 and Pro960 mutations and JAK2 Y931C mutations.
12. Patients whose tumor present known mutationts confering resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations).
13. 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.
14. Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
15. Severe concomitant disease that does not allow treatment according to the protocol at the investigator's discretion.
16. Subjects unwilling or unable to comply with the study procedures.
17. 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).
18. 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.
19. 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.
20. 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).
21. 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.
22. Received immunosuppression post allogenic HSCT within one moth of study entry.
23. History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis.
24. History of progressive multifocal leuko-encephalopathy (PML).
25. History of endocrine or kidney related growth retardation prior to the underlying diagnosis.
26. Evidence of clinically active tuberculosis (clinical diagnosis per local practice).
27. Wash-out periods of prior medication:

    1. 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.
    2. RADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first dose of drug. Palliative radiation in past 21 days is allowed.
    3. 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.
    4. 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)
    5. 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.
    6. 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.

Where this trial is running

Vienna and 32 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Acute Lymphoblastic Leukemia, in RelapseLymphoblastic Lymphoma RecurrentLymphoblastic Lymphoma Refractoryacute lymphoblastic leukemiaLymphoblastic lymphomaBiomarker driven clinical trialRuxolitinibVenetoclax
Last reviewed 2026-06-10 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.