A First-in-Pediatric Study of ALRN-6924, a Novel Stapled-Peptide Dual MDM2/MDMX Inhibitor, for Children with Advanced Hematologic and Solid Malignancies.

PURPOSE: ALRN-6924 is a stapled peptide that disrupts MDM2/MDMX-mediated inhibition of p53. We evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ALRN-6924 in children with advanced malignancies.PATIENTS AND METHODS: Patients with TP53 wild-type malignancies were enrolled in a monotherapy arm (solid/central nervous system tumors) or a combination arm with cytarabine (acute leukemia). Monotherapy dosing used the Targeted-Agent Continual Reassessment Method design for dose escalation. Pharmacodynamic assessment included serum macrophage inhibitory cytokine-1 (MIC-1) as a biomarker of p53 activation. Circulating tumor DNA (ctDNA) was analyzed for emergent TP53 mutations.RESULTS: Twenty-two patients enrolled; 20 received treatment (17 monotherapy and 3 combination). The most common diagnosis was Ewing sarcoma (n = 5). One dose-limiting toxicity (DLT) occurred at monotherapy dose level 2 (2.7 mg/kg). Six patients were treated at dose level 3 (3.5 mg/kg) without DLT, and 1 patient was treated at dose level 4 (4.3 mg/kg) without DLT before study closure. No DLT occurred on the combination arm. Common treatment-related adverse events included anemia (90%) and nausea (70%). MIC-1 levels increased 30- to 50-fold by 24 hours after dose at dose levels 2 to 4, confirming on-target p53 activation. Among 19 response-evaluable patients, 1 partial remission occurred in a patient with relapsed acute lymphoblastic leukemia on the combination arm. Drug exposure was lower than in adults at equivalent doses. One patient with Ewing sarcoma had an emergent TP53 mutation detected in their baseline on-therapy ctDNA sample.CONCLUSIONS: ALRN-6924 was well tolerated in children, with on-target activity. Future efforts to evaluate this agent should focus on biomarker-selected populations, combination strategies, and the evaluation of higher dose levels.