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

Weger, Vincent de; Varga, A; Jonge, Maja de; Langenberg, Marlies H.G.; Mergui-Roelvink, Marja; Massard, C.; Vlist, A. van Der; Devriese, Lot A.; Goodstal, Samantha; Zheng, Wei; Tuffal, Gilles; Semiond, Dorothée; Macé, Sandrine; Watters, James; Demers, Brigitte; Schellens, Jhm; Deutsch, E

doi:10.1016/s0959-8049(16)30169-1

Cited by 3 publications

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“…In a second Phase I study, a combination of MI-773 with MEK inhibitor pimasertib was assessed in eligible patients with solid tumors with wild-type p53 and RAS/RAF mutations. However, the dose required to achieve the beneficial effects of the combination treatment was associated with a significant later toxicity (De Weger et al, 2015). The results of the study using MDM2 inhibitor MK-8242 as a monotherapy in patients with advanced/refractory solid tumors harboring wild-type p53 have been recently reported (Wagner et al, 2017).…”

Section: Restoration Of Wild-type P53 Functionmentioning

confidence: 99%

Inhibition of p53 inhibitors: progress, challenges and perspectives

Sanz

Singh

Peuget

et al. 2019

Journal of Molecular Cell Biology

111

110

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p53 is the major tumor suppressor and the most frequently inactivated gene in cancer. p53 could be disabled either by mutations or by upstream negative regulators, including, but not limited to MDM2 and MDMX. p53 activity is required for the prevention as well as for the eradication of cancers. Restoration of p53 activity in mouse models leads to the suppression of established tumors of different origin. These findings provide a strong support to the anti-cancer strategy aimed for p53 reactivation. In this review, we summarize recent progress in the development of small molecules, which restore the tumor suppressor function of wild-type p53 and discuss their clinical advance. We discuss different aspects of p53-mediated response, which contribute to suppression of tumors, including non-canonical p53 activities, such as regulation of immune response. While targeting p53 inhibitors is a very promising approach, there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.

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Section: Restoration Of Wild-type P53 Functionmentioning

confidence: 99%

Inhibition of p53 inhibitors: progress, challenges and perspectives

Sanz

Singh

Peuget

et al. 2019

Journal of Molecular Cell Biology

111

110

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“…In preclinical RAS pathway-activated, TP53 wild-type xenograft melanoma models (UACC62), a therapeutic benefit was observed for the SAR405838 and pimasertib combination over the activity of either single-agent; durable tumour regression was observed with the combination. 13…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present)

Rusiecki

Witkowski

Jaszczewska-Adamczak

2020

PRA

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Background: Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer therapy. Objective: This updated patent review is an attempt to compile the research and achievements of the various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most relevant patents which have recently appeared in the literature. Methods: Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective compounds which are or were examined in clinical trials. Results: Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types of cancer or non-cancer diseases. A great number of patents and research work around new MDM2- p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years prove that this targeted therapy is in the scope of interest for many business and academic research groups. Conclusion: Novel MDM2 inhibitors thanks to higher potency and better ADME properties have shown effectiveness in preclinical and clinical development however the final improvement of therapeutic potential for MDM2 inhibitors might depend on the useful combination therapy and exploring new cancer and non-cancer indications.

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

Cited by 3 publications

References 0 publications

Inhibition of p53 inhibitors: progress, challenges and perspectives

Inhibition of p53 inhibitors: progress, challenges and perspectives

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

MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present)

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