A phase I study of the HDM2 antagonist SAR405838 combined with the MEK inhibitor pimasertib in patients with advanced solid tumours
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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.
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Combination of SAR405838 with MEK1/2 inhibitor pimasertib in locally advanced or metastatic solid tumors did not find significant drug interactions.
“Further exploration of its potential in combination with the MEK1/2 (MAP kinase kinase 1/2) inhibitor pimasertib in the treatment of locally advanced or metastatic solid tumors did not find significant drug interactions [43].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [43]
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References 25 · Cited by 62
- Authors
- de Weger, V. A., de Jonge, M., Langenberg, M. H. G., Schellens, J. H. M., Lolkema, M., Varga, A., Demers, B., Thomas, K., Hsu, K., Tuffal, G., Goodstal, S., Macé, S., & Deutsch, E.
- Affiliations
- University Medical Center Utrecht (NL)
- Utrecht University (NL)
- Sanofi (France) (FR)
- Merck Healthcare KGaA, Darmstadt (Germany) (DE)
- Venue
- British Journal of Cancer
- Published
- 2018-12-26
- Volume
- 120
- Issue
- 3
- Pages
- 286-293
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC6354023
- OpenAlex
- W2905870549
- Cited by
- 62
- References
- 25
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 15 · 2023: 10 · 2022: 6 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 1
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- British Journal of Cancer (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- HAL (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- Sanofi
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- pimasertib, MEK inhibitors, combination therapy, advanced solid tumors, maximum tolerated dose, dose-limiting toxicity, thrombocytopenia, pharmacokinetics, pharmacodynamics, wild-type p53, antitumour activity, biomarkers
- MeSH terms
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Female, Humans, Indoles, Male, Middle Aged, Neoplasms, Niacinamide, Spiro Compounds, Thrombocytopenia, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Maximum Tolerated Dose, MAP Kinase Kinase Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-mdm2
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