A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours

Abstract

BackgroundThis phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics and pharmacodynamics of combination therapy with the HDM2 inhibitor SAR405838 and the MEK1/2 inhibitor pimasertib administered orally once daily (QD) or twice daily (BID) in locally advanced or metastatic solid tumours (NCT01985191).MethodsPatients with locally advanced or metastatic solid tumours with documented wild-type TP53 and RAS or RAF mutations were enroled. A 3 + 3 dose-escalation design was employed. The primary objective was to assess maximum tolerated dose (MTD).ResultsTwenty-six patients were treated with SAR405838 200 or 300 mg QD plus pimasertib 60 mg QD or 45 mg BID. The MTD was SAR405838 200 mg QD plus pimasertib 45 mg BID. The most common dose-limiting toxicity was thrombocytopenia. The most frequently occurring treatment-related adverse events were diarrhoea (81%), increased blood creatine phosphokinase (77%), nausea (62%) and vomiting (62%). No significant drug–drug interactions were observed. The biomarkers MIC-1 and pERK were, respectively, upregulated and downregulated in response to study treatment. In 24 efficacy-evaluable patients, one patient (4%) had a partial response and 63% had stable disease.ConclusionsThe safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed.

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

“…The most frequently occurring adverse events observed were diarrhoea (81%), blood creatine phosphokinase (77%), nausea (62%) and vomiting (62%). This study indicated that the safety profile of SAR405838 combined with pimasertib was consistent with the safety profiles of both the drugs (de Weger et al, 2019).…”

Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists

“…The components of this pathway play a very important role in the genesis of cancer, which has been reported many times before [183,184,185]. p53 and the MAPK components are the most frequently mutated tumor suppressor and oncogene pathways in human cancers [81]. For this reason, there is a great potential in simultaneous targeting of these two pathways to provide useful therapeutic approaches.…”

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives

“…Development of small molecules disrupting the MDM2–P53 interactions has been highly pursued from academia to industry in recent years 5 , 9 , 10 , 11 , 12 , 13 , 14 . Some of these inhibitors including DS-3032 (also known as Milademetan, DS-3032b) 15 , 16 , NVP-CGM097 17 , 18 , 19 , SAR405838 20 , 21 , 22 , RG7112 23 , 24 , MK-8242 25 , 26 , RG7388 27 and AMG 232 28 , 29 , 30 ( Fig. 2 ) are under clinical evaluation for anticancer treatment.…”