A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours. Academic Article uri icon

Overview

abstract

  • PURPOSE: In tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours (NCT01636479). METHODS: In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible. In the MTD expansion cohort, only patients with de-differentiated liposarcoma were included. Primary end-points were MTD and efficacy in the MTD expansion cohort. Secondary end-points included safety, pharmacokinetics and pharmacodynamics biomarkers. RESULTS: Seventy-four patients were treated with SAR405838 (50-800 mg once daily [QD], 800-1800 mg weekly and 1800 mg twice weekly). Two patients treated with SAR405838 400 mg QD had thrombocytopaenia as a dose-limiting toxicity (DLT). The MTD for the QD schedule of SAR405838 was 300 mg QD. No DLTs were observed with the weekly schedule; one patient had a DLT of nausea with the 1800 mg twice-weekly dose. Treatment with SAR405838 was associated with increased plasma MIC-1, reflecting p53 pathway activation. In the de-differentiated liposarcoma MTD cohort, 89% of the patients had HDM2 amplification at baseline and no TP53 mutations were observed; best response was stable disease in 56% and progression-free rate at 3 months was 32%. CONCLUSION: SAR405838 had an acceptable safety profile with limited activity in patients with advanced solid tumours. The MTD of SAR405838 was 300 mg QD; MTD was not reached with the weekly schedule.

publication date

  • March 17, 2017

Research

keywords

  • Antineoplastic Agents
  • Indoles
  • Neoplasms
  • Proto-Oncogene Proteins c-mdm2
  • Spiro Compounds

Identity

Scopus Document Identifier

  • 85015622007

Digital Object Identifier (DOI)

  • 10.1016/j.ejca.2017.02.005

PubMed ID

  • 28324749

Additional Document Info

volume

  • 76