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

• Published in: British journal of cancer 2019-02, Vol.120 (3), p.286-293
• Main Authors: de Weger, Vincent A., de Jonge, Maja, Langenberg, Marlies H. G., Schellens, Jan H. M., Lolkema, Martijn, Varga, Andrea, Demers, Brigitte, Thomas, Koruth, Hsu, Karl, Tuffal, Gilles, Goodstal, Samantha, Macé, Sandrine, Deutsch, Eric
• Format: Article
• Language: English
• Subjects: 692/308/409; 692/4028/67/1059/602; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Creatine; Creatine kinase; Diarrhea; Dose-Response Relationship, Drug; Drug dosages; Drug Resistance; Epidemiology; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Indoles - administration & dosage; Indoles - adverse effects; Indoles - pharmacokinetics; Life Sciences; Male; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; Maximum Tolerated Dose; MEK inhibitors; Metastases; Metastasis; Middle Aged; Minimum inhibitory concentration; Molecular Medicine; Nausea; Neoplasms - classification; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Niacinamide - administration & dosage; Niacinamide - adverse effects; Niacinamide - analogs & derivatives; Niacinamide - pharmacokinetics; Oncology; p53 Protein; Patients; Pharmacodynamics; Pharmacokinetics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Safety; Solid tumors; Spiro Compounds - administration & dosage; Spiro Compounds - adverse effects; Spiro Compounds - pharmacokinetics; Thrombocytopenia; Thrombocytopenia - chemically induced; Thrombocytopenia - pathology; Toxicity; Tumor Suppressor Protein p53 - genetics; Tumors; Vomiting
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-018-0355-8

Background This 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). Methods Patients 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). Results Twenty-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. Conclusions The safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed.