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 safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ALRN-6924 in children with advanced malignancies. EXPERIMENTAL DESIGN: Patients with TP53-wild-type malignancies were enrolled to a monotherapy arm (solid/CNS tumors) or combination arm with cytarabine (acute leukemia). Monotherapy dosing used the TARGET-CRM design for dose escalation. Pharmacodynamic assessment included serum MIC-1 as a biomarker of p53 activation. Circulating tumor DNA was analyzed for emergent TP53 mutations. RESULTS: Twenty-two patients enrolled; 20 received treatment (17 monotherapy, 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 one patient was treated at dose level 4 (4.3 mg/kg) without DLT before study closure. No DLTs occurred on the combination arm. Common treatment-related adverse events included anemia (90%) and nausea (70%). MIC-1 levels increased 30-50-fold by 24 hours post-dose at dose levels 2-4, confirming on-target p53 activation. Among 19 response-evaluable patients, one partial remission occurred in a patient with relapsed ALL 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 evaluation of higher dose levels.