Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type <i>TP53</i> Solid Tumors and Acute Leukemia

Stein, Eytan M.; DeAngelo, Daniel J.; Chromik, Jörg; Chatterjee, Manik; Bauer, Sebastian; Lin, Chia Chi; Suárez, Cristina; Vos, Filip Y.F. De; Steeghs, Neeltje; Cassier, Philippe; Tai, David; Kiladjian, Jean‐Jacques; Yamamoto, Noboru; Mous, Rogier; Esteve, Jordi; Minami, Hironobu; Ferretti, Stéphane; Guerreiro, Nelson; Meille, Christophe; Radhakrishnan, Rajkumar; Pereira, Bernard; Mariconti, Luisa; Halilovic, Ensar; Fabre, Claire; Carpio, Cecilia

doi:10.1158/1078-0432.ccr-21-1295

Cited by 50 publications

(34 citation statements)

References 33 publications

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“…Recently published clinical data on siremadlin [ 28 , 33 ] and trametinib [ 29 , 34 ] combined with the findings of this study may support the extrapolation of animal PBPK/PD data into a clinical situation. Nonetheless, due to the limited amount of in vivo drug combination data available from this study, such extrapolation may only predict the initial efficacy in patients.…”

Section: Discussionsupporting

confidence: 77%

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II

Witkowski

Polak

Rogulski

et al. 2022

IJMS

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The development of in vitro/in vivo translational methods for synergistically acting drug combinations is needed to identify the most effective therapeutic strategies. We performed PBPK/PD modelling for siremadlin, trametinib, and their combination at various dose levels and dosing schedules in an A375 xenografted mouse model (melanoma cells). In this study, we built models based on in vitro ADME and in vivo PK/PD data determined from the literature or estimated by the Simcyp Animal simulator (V21). The developed PBPK/PD models allowed us to account for the interactions between siremadlin and trametinib at PK and PD levels. The interaction at the PK level was described by an interplay between absorption and tumour disposition levels, whereas the PD interaction was based on the in vitro results. This approach allowed us to reasonably estimate the most synergistic and efficacious dosing schedules and dose levels for combinations of siremadlin and trametinib in mice. PBPK/PD modelling is a powerful tool that allows researchers to properly estimate the in vivo efficacy of the anticancer drug combination based on the results of in vitro studies. Such an approach based on in vitro and in vivo extrapolation may help researchers determine the most efficacious dosing strategies and will allow for the extrapolation of animal PBPK/PD models into clinical settings.

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Section: Discussionsupporting

confidence: 77%

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II

Witkowski

Polak

Rogulski

et al. 2022

IJMS

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“…The imidazopyrrolidinone siremadlin is an advanced molecule that has been tested in patients with solid tumors and hematological malignancies harboring no p53 mutations. In a phase I clinical study involving patients with AML, siremadlin has demonstrated promising results ( 28 ). Moreover, siremadlin is being investigated alone or in combination with other drugs in five different clinical trials that are still recruiting patients ( 29 – 34 ).…”

Section: Mdm2 Inhibitorsmentioning

confidence: 99%

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Romani

Zauli²,

Zauli³

et al. 2022

Front. Oncol.

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MDM2 is the principal inhibitor of p53, and MDM2 inhibitors can disrupt the physical interaction between MDM2 and p53. The half-life of p53 is very short in normal cells and tissues, and an uncontrolled increase in p53 levels has potential harmful effects. It has been shown that p53 is frequently mutated in most cancers; however, p53 mutations are rare in retinoblastoma. Therefore, therapeutic strategies aimed at increasing the expression levels of wild-type p53 are attractive. In this minireview, we discuss the potential use of nutlin-3, the prototype small molecule inhibitor that disrupts the MDM2-p53 interaction, for the treatment of retinoblastoma. Although p53 has pleiotropic biological effects, the functions of p53 depend on its sub-cellular localization. In the nucleus, p53 induces the transcription of a vast array of genes, while in mitochondria, p53 regulates mitochondrial metabolism. This review also discusses the relative contribution of p53-mediated gene transcription and mitochondrial perturbation for retinoblastoma treatment.

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“…HDM201 was recently investigated in a phase I, multicenter, open-label trial ( 170 ). In total, 115 patients with treatment-refractory locally advanced or metastatic solid tumors and 93 patients with relapsed or refractory hematologic malignancies were included.…”

Section: Clinical Trial Results For Mdm2 Pathway Inhibitors In Liposa...mentioning

confidence: 99%

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

et al. 2022

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Dedifferentiated liposarcoma (DDLPS) is an aggressive adipogenic cancer with poor prognosis. DDLPS tumors are only modestly sensitive to chemotherapy and radiation, and there is a need for more effective therapies. Genetically, DDLPS is characterized by a low tumor mutational burden and frequent chromosomal structural abnormalities including amplification of the 12q13-15 chromosomal region and the MDM2 gene, which are defining features of DDLPS. The MDM2 protein is an E3 ubiquitin ligase that targets the tumor suppressor, p53, for proteasomal degradation. MDM2 amplification or overexpression in human malignancies is associated with cell-cycle progression and worse prognosis. The MDM2–p53 interaction has thus garnered interest as a therapeutic target for DDLPS and other malignancies. MDM2 binds p53 via a hydrophobic protein interaction that is easily accessible with synthetic analogues. Multiple agents have been developed, including Nutlins such as RG7112 and small molecular inhibitors including SAR405838 and HDM201. Preclinical in vitro and animal models have shown promising results with MDM2 inhibition, resulting in robust p53 reactivation and cancer cell death. However, multiple early-phase clinical trials have failed to show a benefit with MDM2 pathway inhibition for DDLPS. Mechanisms of resistance are being elucidated, and novel inhibitors and combination therapies are currently under investigation. This review provides an overview of these strategies for targeting MDM2 in DDLPS.

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Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia

Abstract: Utrecht as recipient); expert testimony form Bristol-Myers Squibb (with FdV as recipient); travel, accommodations from Roche/Genentech (with FdV as recipient).NS reports consultation or acting in an advisory role for AIMM Therapeutics,

Cited by 50 publications

References 33 publications

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II

MDM2 inhibitors-mediated disruption of mitochondrial metabolism: A novel therapeutic strategy for retinoblastoma

Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma

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