Related Experiment Video
Updated: Mar 5, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours
Maja de Jonge1, Vincent A de Weger2, Mark A Dickson3
1Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
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.
Insights
This study found that SAR405838, an HDM2 inhibitor, has an acceptable safety profile. The maximum tolerated dose (MTD) was 300 mg once daily, with limited activity observed in advanced solid tumors.
Area of Science:
- Oncology
- Pharmacology
Background:
- Tumor suppressor p53 function is often inhibited by HDM2 in tumors with wild-type TP53.
- HDM2 inhibitors represent a therapeutic strategy to restore p53 activity.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of SAR405838, an HDM2 inhibitor.
- To evaluate SAR405838 in patients with advanced solid tumors, including a specific cohort with de-differentiated liposarcoma.
Main Methods:
- Phase I, dose-escalating study of SAR405838 in patients with advanced solid tumors.
- Eligibility criteria included TP53 wild-type or low mutation prevalence tumors; de-differentiated liposarcoma for the MTD expansion cohort.
- Primary endpoints were MTD and efficacy; secondary endpoints included safety and biomarkers.
Main Results:
- The MTD of SAR405838 was 300 mg once daily (QD).
- Treatment showed an acceptable safety profile with dose-limiting toxicities of thrombocytopenia at 400 mg QD.
- In de-differentiated liposarcoma patients (HDM2 amplified, TP53 wild-type), 56% had stable disease and 32% had a 3-month progression-free rate.
Conclusions:
- SAR405838 demonstrated an acceptable safety profile in patients with advanced solid tumors.
- The MTD for SAR405838 was determined to be 300 mg QD.
- Limited anti-tumor activity was observed, suggesting further investigation in specific tumor types like liposarcoma is warranted.
