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

NCT05745714 | Recruiting Phase 1 DMC

• 1 other identifier: 2022-501867-42-00
• Study Type: interventional
• Target: 26
• Locations: 14 countries
• Sites: 33

Brief 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. 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.

Conditions

Acute Lymphoblastic Leukemia, in Relapse; 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

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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

  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.

  6 years

Secondary Outcomes (8)

• Overall survival (OS)

  7 years

• Event-free survival (EFS)

  7 years

• Cumulative incidence of relapse (CIR)

  7 years

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

  7 years

• Cumulative overall response rate (ORR)

  7 years

Study Arms (1)

Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabine

EXPERIMENTAL

Each 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.

Drug: Ruxolitinib; Drug: Venetoclax; Drug: Dexamethasone; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: intrathecal chemotherapy

Interventions

Ruxolitinib DRUG

oral

Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabine

Venetoclax DRUG

oral

Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabine

Dexamethasone DRUG

oral/intravenous

Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabine

Cyclophosphamide DRUG

intravenous

Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabine

Cytarabine DRUG

intravenous

Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabine

intrathecal chemotherapy DRUG

IT: Methotrexate +/- prednisone/hydrocortisone/cytarabine according to the degree of central nervous involvement

Ruxolitinib + venetoclax + dexamethasone + cyclophosphamide + cytarabine

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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 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:
• 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.

You may not qualify if:

• 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).
• 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.

Sponsors & Collaborators

• Princess Maxima Center for Pediatric Oncology: lead
• Innovative Therapies For Children with Cancer Consortium: collaborator
• IBFM: collaborator
• Fight Kids Cancer: collaborator

Study Sites (33)

St. Anna Kinderspital

Vienna, 1090, Austria

NOT YET RECRUITING

Universitair Ziekenhuis Gent

Ghent, 9000, Belgium

NOT YET RECRUITING

Rigshospitalet Copenhagen

Copenhagen, DK-2100, Denmark

RECRUITING

Helsinki University Hospital, New Children's Hospital

Helsinki, FI00029, Finland

NOT YET RECRUITING

Hôpital des Enfants GH Pellegrin - CHU de Bordeaux

Bordeaux, 33076, France

NOT YET RECRUITING

CHRU Lille - Hôpital Jeanne de Flandre

Lille, 59037, France

NOT YET RECRUITING

Centre Léon Bérard

Lyon, 69 373, France

NOT YET RECRUITING

Hopital La Timone - Enfants

Marseille, 13005, France

NOT YET RECRUITING

CHU Nantes Hôpital Mère-Enfant

Nantes, 44093, France

NOT YET RECRUITING

Hôpital Robert Debré

Paris, 75019, France

NOT YET RECRUITING

Universitätsklinikum Augsburg

Augsburg, 86156, Germany

NOT YET RECRUITING

Charité Universitätsmedizin Berlin

Berlin, 13353, Germany

RECRUITING

Universitätsklinikum Essen

Essen, 45147, Germany

NOT YET RECRUITING

Universitätsklinikum Frankfurt

Frankfurt, 60590, Germany

NOT YET RECRUITING

Universitätsklinikum Münster

Münster, 48149, Germany

NOT YET RECRUITING

Our Lady's Hospital for Sick Children

Dublin, D12N512, Ireland

NOT YET RECRUITING

Schneider's Children's Medical Center

Petah Tikva, 4920235, Israel

NOT YET RECRUITING

Sheba Medical Center Hospital

Ramat Gan, 52621, Israel

NOT YET RECRUITING

IRCCS Istituto Giannina Gaslini

Genova, 16147, Italy

NOT YET RECRUITING

Fondazione MBBM c/o Centro ML Verga

Monza, 20900, Italy

NOT YET RECRUITING

Padova Azienda Ospedaliera

Padua, 35128, Italy

NOT YET RECRUITING

Ospedale Pediatrico Bambino Gesù, IRCCS

Roma, 0165, Italy

NOT YET RECRUITING

Ospedale Infantile Regina Margherita

Turin, 10126, Italy

NOT YET RECRUITING

Princess Máxima Center for Pediatric Oncology

Utrecht, Utrecht, 3584CS, Netherlands

NOT YET RECRUITING

Oslo University Hospital

Oslo, 0373, Norway

NOT YET RECRUITING

Hospital Sant Joan de Déu de Barcelona

Barcelona, 08950, Spain

NOT YET RECRUITING

Hospital Infantil Universitario Niño Jesús

Madrid, 28009, Spain

NOT YET RECRUITING

La Fe

Valencia, 46026, Spain

NOT YET RECRUITING

Karolinska university hospital

Stockholm, 171 76, Sweden

RECRUITING

Bristol Royal Hospital for Children

Bristol, B52 8BJ, United Kingdom

NOT YET RECRUITING

Great Ormond Street Hospital for Children NHS Trust

London, WC1N 2BH, United Kingdom

NOT YET RECRUITING

Great North Children's Hospital

Newcastle, NE1 4LP, United Kingdom

NOT YET RECRUITING

Royal Marsden NHS Trust

Sutton, SM2 5PT, United Kingdom

NOT YET RECRUITING

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Leukemia; Recurrence; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Interventions

ruxolitinib; venetoclax; Dexamethasone; Cyclophosphamide; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Michel Zwaan, Prof. Dr.

  Princess Máxima Center

  STUDY CHAIR

• Paco Bautista, MD PhD

  Princess Máxima Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anne Elsinghorst

CONTACT

+316 5000 6270; hem-ismart@prinsesmaximacentrum.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 16, 2023
• First Posted: February 27, 2023
• Study Start: October 1, 2025
• Primary Completion (Estimated): February 1, 2032
• Study Completion (Estimated): February 2, 2032
• Last Updated: September 16, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: SRs will also be provided at the end of specific sub-protocols or specific phases of a sub-protocol, and when needed for regulatory purposes. Examples for generating 'primary CSRs' may include: * After Last Patient Last Visit (LPLV) in a study having ORR as endpoint. * After the RP2D is determined in a Phase I part of a given sub-protocol. * After the follow-up of a specific sub-protocol is completed.
• Access Criteria: A summary of the study results will be made public via clinicaltrials.gov as well as to Ethical committees/ Health Authorities and all participating patients by providing them through their treating physicians a patient letter with a summary of the results.

Locations

DK (1); ES (3); BE (1); DE (5); IL (2); AU (1); NL (1); IT (5); NO (1); SE (1); FR (6); GB (4); FI (1); IE (1)