Purpose: 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 TP53 wild-type tumors.

Methods: 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.

Results: 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 TP53 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 >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg.

Conclusion: ALRN-6924 was well tolerated and demonstrated anti-tumor activity.

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