Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing wild-type TP53

Mansoor N. Saleh, Manish R. Patel, Todd M. Bauer, Sanjay Goel, Gerald S. Falchook, Geoffrey I. Shapiro, Ki Y. Chung, Jeffrey R. Infante, Robert M. Conry, Guilherme Rabinowits, David S. Hong, Judy S. Wang, Ulrich Steidl, Gurudatta Naik, Vincent Guerlavais, Vojislav Vukovic, D. Allen Annis, Manuel Aivado, Funda Meric-Bernstam

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Purpose: We describe the first-in-human dose-escalation trial for ALRN-6924, a stabilized, cell-permeating peptide that disrupts p53 inhibition by mouse double minute 2 (MDM2) and MDMX to induce cell-cycle arrest or apoptosis in TP53-wild-type (WT) tumors. Patients and Methods: Two schedules were evaluated for safety, pharmacokinetics, pharmacodynamics, and antitumor 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) and 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 (DLT) were grade 3 (G3) hypotension, G3 alkaline phosphatase elevation, G3 anemia, and G4 neutropenia in one patient each. At the MTD 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; 3 discontinued treatment. In 41 efficacy-evaluable patients with TP53-WT disease across both schedules the disease control rate was 59%. Two patients had confirmed complete responses, 2 had confirmed partial responses, and 20 had stable disease. Six patients were treated for >1 year. The recommended phase 2 dose was schedule A, 3.1 mg/kg. Conclusions: ALRN-6924 was well tolerated and demonstrated antitumor activity.

Original languageEnglish (US)
Pages (from-to)5236-5247
Number of pages12
JournalClinical Cancer Research
Volume27
Issue number19
DOIs
StatePublished - Oct 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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