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

<jats:p>&lt;div&gt;Abstract Purpose:&lt;p&gt;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.&lt;/p&gt; Patients and Methods:&lt;p&gt;Patients with &lt;i&gt;TP53&lt;/i&gt; 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 &lt;i&gt;TP53&lt;/i&gt; mutations.&lt;/p&gt; Results:&lt;p&gt;Twenty-two patients enrolled; 20 received treatment (17 monotherapy and 3 combination). The most common diagnosis was Ewing sarcoma (&lt;i&gt;n&lt;/i&gt; = 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 &lt;i&gt;TP53&lt;/i&gt; mutation detected in their baseline on-therapy ctDNA sample.&lt;/p&gt; Conclusions:&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;</jats:p>