Background and Significance The prognosis of pediatric patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) is poor. R/R T-ALL generally is difficult to cure and requires novel treatment approaches and allogeneic hematopoietic stem cell transplantation (HSCT) for any possible long-term survival. Relapsed B-ALL occurring in children after allogeneic HSCT or CD19- // CD22-targeting immunotherapies is similarly extremely challenging to cure highlighting a persistent need of novel therapeutic options. These pediatric molecularly and functionally characterized (R/R) populations are small, and international collaboration is needed to successfully develop new agents to improve their prognosis. This calls for international master protocol platform trials that offer a unified operational framework, harmonized treatment stratification, response criteria and adaptive design to align in relative real-time with new scientific developments. The international HEM-iSMART platform study aims to investigate innovative biologically relevant targeted therapies in molecularly defined cohorts of children with R/R ALL or LBL via its master protocol design and associated therapeutic subtrials.

Study Design and Methods HEM-iSMART is a multi-arm, actionable target-driven phase I/II clinical trial. The master protocol includes details about the overarching study goals, hypotheses, study design, risk stratification, statistics and the operational procedures (ie. safety and data management) and data harmonization. Each therapeutic subtrial is designed as an independent protocol with specific scientific background, eligibility criteria, description of the intervention, concomitant medications and management of adverse events. The subtrials are submitted separately in CTIS in Europe, all linked to the master protocol. All subtrials include a phase I safety and dose exploration (rolling 6 design) and a phase II efficacy (Simon´s two-stage design) part. All subtrials include age-adapted pediatric formulations of study drugs for investigation in all ages, including liquid suspensions when available. Quality of life is evaluated by using age-adjusted standardized questionnaires.

HEM-iSMART is sponsored by the Princess Máxima Center in the Netherlands and involves collaboration between ITCC, iBFM, IntReALL, and EICNHL. The trial is deployed via the ITCC network with delegated national coordinating centers and sites. The trial will be conducted at a total of 36 sites (n=5 currently open) across 14 European countries and Israel. Evaluation of potential and enrolled patients, safety, toxicity and response data from on-study subjects are reviewed each week at the coordinating team meetings to ensure sponsor oversight.

Current subtrials include:

  • Subtrial B: dasatinib, venetoclax (VEN) and dexamethasone (DEX) with cyclophosphamide (CP) and cytarabine (CA) for ABL1 fusion-driven disease (approved, will be activated in Q3 2025)

  • Subtrial C: ruxolitinib, VEN and DEX with CP and CA for IL7R-mutant and JAK/STAT pathway-driven disease(approved, will be activated in Q3 2025)

  • Subtrial D: trametinib and DEX with CP and CA for Ras/MAPK pathway-driven disease (recruiting)

  • Subtrial E: capivasertib, VEN and DEX for molecularly unselected patients (generic) and PI3K/AKT/mTOR-driven disease (in process of regulatory submission)

To date, 2 subjects with R/R B-ALL and 1 with R/R T-ALL were enrolled in subtrial D.

Conclusion HEM-iSMART is an international, academic, collaborative, precision-medicine, multi-arm platform trial for pediatric patients with R/R ALL and LBL. Its approach aims to accelerate iterative investigation of most promising kinase, BCL-2 and other small molecule inhibitors in combination with well-tolerated lower-dose chemotherapy to address the high unmet medical need of this patient population. Efficient evaluation of targeted therapies in combined phase 1/2 subtrials will facilitate 'go or no-go’ decision making and help to prioritize most promising drug combinations for evaluation via frontline precision medicine trials in children with specific biologic subtypes of ALL or LBL. EUCT numbers: 2022-501866-22-00 (B), 2022-501867-42-01 (C), 2022-501869-41-00 (D) and 2025-523132-39-00(E). Funded and supported by the Fight Kids Cancer program, internal funding from the sponsor and by drug provision and funding from AbbVie Inc., Astra Zeneca PLC and Novartis AG.

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2025
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