Targeting the Rare: A New Therapy for Pediatric Acute Myeloid Leukemia With CBFA2T3-GLIS2 Fusions

STUDY TITLE: Luveltamab Tazevibulin (STRO-002) in Infants and Children <12 Years of Age with Relapsed/Refractory CBFA2T3::GLIS2 AML

CLINICALTRIALS.GOV IDENTIFIER: NCT06679582

PARTICIPATING CENTERS: Children’s Hospital of Alabama (Birmingham, AL); Children’s National Hospital (Washington, DC); Children’s Hospital of Philadelphia (Philadelphia, PA); and Virginia Commonwealth University Massey Comprehensive Cancer Center (Richmond, VA)

SPONSOR: Sutro Biopharma, Inc.

ACCRUAL GOAL: 24

STUDY DESIGN: This trial is designed to evaluate the safety and efficacy of luveltamab tazevibulin in treating a rare and aggressive subtype of acute myeloid leukemia (AML) bearing the CBFA2T3-GLIS2 gene fusion, which uniquely affects infants and young children. This specific genetic lesion is exceptionally rare, with approximately 17 new cases annually in the U.S. and 10 in Europe. Luveltamab tazevibulin, an antibody-drug conjugate, precisely delivers the tubulin-targeting 3-aminophenyl hemiasterlin compound SC209 to malignant cells by targeting FOLR1, a molecule that has been found expressed at high levels on the surface cells carrying the CBFA2T3-GLIS2 fusion.

The study is structured as an international, multicenter, two-part, open-label phase I/II trial. Phase I involves a 1:1 randomization of participants into two dosing cohorts, with the goal of identifying the optimal dose of luveltamab. In part II, the study will further evaluate the safety and clinical efficacy of the selected dose in a larger cohort. Participants who achieve complete remission after two treatment cycles may continue receiving luveltamab as monotherapy (given every two weeks). Those who do not respond may receive luveltamab (given every four weeks) in combination with standard-of-care AML therapy.

The trial’s primary objective is to assess the efficacy of luveltamab by evaluating the complete remission (CR) rate within 12 weeks. Secondary objectives include evaluating additional efficacy outcomes for two years, such as the duration of CR, response rate (including CR with partial hematologic recovery), and event-free, relapse-free, and overall survival. The study will also assess the incidence and severity of adverse events. In addition, the drug’s pharmacokinetics will be characterized by measuring blood concentrations of luveltamab, while its immunogenic potential will be assessed by monitoring the incidence of anti-drug antibodies.

RATIONALE: The CBFA2T3-GLIS2 genetic abnormality, first discovered in 2012,¹  has transformed our understanding of pediatric acute megakaryoblastic leukemia (AMKL). Characterized by malignant blasts expressing platelet-specific surface proteins, AMKL is a rare subtype of AML, occurring in only 1% of adult AML²  cases but up to 4% to 15% of pediatric AML^3,4  cases. In children with Down syndrome (DS), AMKL is the most common AML subtype, driven by somatic GATA1 mutations and associated with excellent outcomes.³  However, in non-DS patients, AMKL is a vastly different disease, marked by distinct genetic fusions and carrying a grim prognosis. Among these, the CBFA2T3-GLIS2 fusion is the most frequently identified genetic abnormality,¹  but it has been observed in non-AMKL cases as well.⁵ 

The CBFA2T3-GLIS2 fusion orchestrates a unique molecular gene-expression program,^1,6,7  presenting a diagnostic beacon and a potential Achilles’ heel for therapy. CD56 (neural cell adhesion molecule 1) stands out as a key diagnostic marker,⁸  and when combined with other elements of the RAM immunophenotype,⁹  it enables precise detection via flow cytometry. Furthermore, FOLR1 is emerging as a therapeutic target.¹⁰  With a mature pipeline of FOLR1-targeting drugs already in development for ovarian cancer, these therapies offer a unique opportunity to accelerate treatment innovation for this rare and devastating pediatric leukemia.

COMMENT: This study marks a significant step forward in addressing one of the most aggressive and rare forms of pediatric leukemia through the innovative application of precision medicine and repurposed therapeutic strategies. Two major advances highlight its importance, the first being the ability to translate detailed molecular insights of CBFA2T3-GLIS2-positive AMKL into targeted, actionable therapies. Second is the exploration of treatments that may reduce or even eliminate dependence on traditional cytotoxic chemotherapy, especially for AML subtypes that are less responsive to conventional approaches. By incorporating monotherapy and combination therapy into its design, the study could potentially lower treatment-related toxicity while improving outcomes and quality of life for young patients.

Using existing therapeutic platforms to tackle this rare pediatric malignancy underscores the ingenuity of adapting proven therapeutics to address unmet needs in rare disease research. Such an approach accelerates the timeline for developing effective treatments and demonstrates a practical pathway for overcoming the unique challenges posed by rare conditions. This trial sets a new benchmark, showcasing how precision medicine can transform cutting-edge discoveries into meaningful clinical solutions. It serves as a beacon of hope, offering a scalable, lifesaving treatment model for underserved and vulnerable populations.