A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours
| Autor: | 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, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology |
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| Přispěvatelé: | Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Medical Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Cancer Research Indoles Gastroenterology Neoplastic/drug effects 0302 clinical medicine Neoplasms/classification Neoplasms Antineoplastic Combined Chemotherapy Protocols Thrombocytopenia/chemically induced MEK inhibitor Proto-Oncogene Proteins c-mdm2 Indoles/administration & dosage Antineoplastic Combined Chemotherapy Protocols/administration & dosage Middle Aged MAP Kinase Kinase Kinases Gene Expression Regulation Neoplastic Oncology Outcomes research 030220 oncology & carcinogenesis Toxicity Vomiting Female Tumor Suppressor Protein p53/genetics Drug medicine.symptom Niacinamide Proto-Oncogene Proteins B-raf Adult medicine.medical_specialty Combination therapy Maximum Tolerated Dose Nausea Article Dose-Response Relationship Proto-Oncogene Proteins p21(ras) Proto-Oncogene Proteins p21(ras)/genetics 03 medical and health sciences Targeted therapies Niacinamide/administration & dosage Pharmacokinetics Internal medicine Proto-Oncogene Proteins B-raf/genetics medicine Humans Spiro Compounds Adverse effect Protein Kinase Inhibitors Aged Spiro Compounds/administration & dosage Dose-Response Relationship Drug business.industry Protein Kinase Inhibitors/administration & dosage Antagonist Thrombocytopenia MAP Kinase Kinase Kinases/antagonists & inhibitors Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors Gene Expression Regulation Gene Expression Regulation Neoplastic/drug effects Tumor Suppressor Protein p53 business |
| Zdroj: | British Journal of Cancer British Journal of Cancer, 120(3), 286-293. Nature Publishing Group British Journal of Cancer, 120(3), 286. Nature Publishing Group |
| ISSN: | 0198-5191 0007-0920 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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