Phase 1 Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-Type TP53

<p> <h2> Abstract </h2></p><p> <strong> Purpose: </strong> We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by MDM2 and MDMX to induce cell cycle arrest or apoptosis in <em> TP53 </em> wild-type tumors.</p><p> <strong> Methods: </strong> Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and anti-tumor effects in patients with solid tumors or lymphomas: In arm A, patients received ALRN-6924 by intravenous infusion once-weekly for 3 weeks every 28 days; arm B, was twice-weekly for 2 weeks every 21 days.</p><p> <strong> Results: </strong> Seventy-one patients were enrolled: 41 in arm A (0.16-4.4 mg/kg), 30 in arm B (0.32-2.7 mg/kg). ALRN-6924 showed dose-dependent pharmacokinetics and increased serum levels of MIC-1, a biomarker of p53 activation. The most frequent treatment-related adverse events were gastrointestinal side effects, fatigue, anemia, and headache. In arm A, at 4.4 mg/kg, dose-limiting toxicities (DLTs) were Grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the maximum tolerated dose in arm A of 3.1 mg/kg, G3 fatigue was observed in one patient. No DLTs were observed in arm B. No G3/G4 thrombocytopenia was observed in any patient. Seven patients had infusion-related reactions; three discontinued treatment. In 41 efficacy-evaluable patients with <em> TP53 </em> wild-type disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, two had confirmed partial responses, 20 had stable disease. Six patients were treated for &gt;1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg.</p><p> <strong> Conclusion: </strong> ALRN-6924 was well tolerated and demonstrated anti-tumor activity.</p>