A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours

Jonge, Maja de; Weger, Vincent A. de; Dickson, Mark A.; Langenberg, Marlies H.G.; Cesne, Axel Le; Wagner, Andrew J.; Hsu, Karl; Zheng, Wei; Macé, Sandrine; Tuffal, Gilles; Thomas, Koruth; Schellens, Jan H.M.

doi:10.1016/j.ejca.2017.02.005

Cited by 111 publications

(79 citation statements)

References 15 publications

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“…Full results from the recently completed Phase I trial of RO6839921 in adults with advanced solid tumours and AML are pending (NCT02098967). However, interim data from the advanced solid tumour arm of the trial show that RO6839921 was generally well tolerated and main dose limiting toxicities observed were thrombocytopenia and neutropenia, in line with adult trial data for oral idasanutlin, as well as other MDM2 inhibitors . Gastrointestinal toxicity was reported but not dose limiting as previously reported with oral Idasanutlin .…”

Section: Discussionsupporting

confidence: 81%

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

Chen

Pastorino

Berry

et al. 2019

Intl Journal of Cancer

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High‐risk neuroblastoma, a predominantly TP53 wild‐type (wt) tumour, is incurable in >50% patients supporting the use of MDM2 antagonists as novel therapeutics. Idasanutlin (RG7388) shows in vitro synergy with chemotherapies used to treat neuroblastoma. This is the first study to evaluate the in vivo efficacy of the intravenous idasanutlin prodrug, RO6839921 (RG7775), both alone and in combination with temozolomide in TP53 wt orthotopic neuroblastoma models. Detection of active idasanutlin using liquid chromatography‐mass spectrometry and p53 pathway activation by ELISA assays and Western analysis showed peak plasma levels 1 h post‐treatment with maximal p53 pathway activation 3–6 h post‐treatment. RO6839921 and temozolomide, alone or in combination in mice implanted with TP53 wt SHSY5Y‐Luc and NB1691‐Luc cells showed that combined RO6839921 and temozolomide led to greater tumour growth inhibition and increase in survival compared to vehicle control. Overall, RO6839921 had a favourable pharmacokinetic profile consistent with intermittent dosing and was well tolerated alone and in combination. These preclinical studies support the further development of idasanutlin in combination with temozolomide in neuroblastoma in early phase clinical trials.

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Section: Discussionsupporting

confidence: 81%

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

Chen

Pastorino

Berry

et al. 2019

Intl Journal of Cancer

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“…The demonstration of the onset of pharmacological resistance to an MDM2 inhibitor at the clinical level has been recently reported by Jung and colleagues [146]. Data were collected from the phase I trial (NCT01636479) with patients affected by de-differentiated/MDM2 amplified liposarcoma under SAR405838 treatment [105]. TP53 mutations appeared during treatment as shown by cell-free DNA analysis and the frequency of mutations increased during the time with a correlation with tumor mass [146].…”

Section: Discussionmentioning

confidence: 99%

“…Results from a second clinical trial assessing SAR405838 safety, tolerability, pharmacokinetics, and biological activity in patients with advanced cancer, including solid tumors and lymphoma, for which no further effective standard treatment is available, have been recently published. The pharmacological treatment resulted to be acceptable in terms of safety, and a dose-dependent MIC-1 modulation following P53 pathway activation was observed suggesting that, although a limited activity was observed with the single-agent schedule, SAR405838 might have a potential in combination regimens [105]. …”

Section: Introductionmentioning

confidence: 99%

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

et al. 2017

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The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.

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“…Clinical activity of MDM2 inhibitors among unselected diverse cancers has been limited 17–19 ; however, occasional responses have been observed in individuals selected for wild-type TP53 . 20,21 The low response rate with single-agent MDM2 inhibitors may be due to the lack of patient selection for MDM2 amplification or to co-altered genes (Data Supplement).…”

Section: Discussionmentioning

confidence: 99%

“…Although preliminary results demonstrated no responses to MDM2 inhibitors among unselected patients, 17–19 responses occurred in wildtype TP53 liposarcoma (MK-8242; response rate [RR], 11.1% [three of 27 patients]) or melanoma (AMG232; RR, 28.6% [six of 21 patients]). 20,21 …”

Section: Introductionmentioning

confidence: 99%

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Kato

Ross

Gay

et al. 2018

JCO Precision Oncology

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Purpose MDM2 amplification can promote tumorigenesis directly or indirectly through p53 inhibition. MDM2 has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and MDM2 amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti–PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain MDM2 amplification status across a large number of diverse cancers. Methods We interrogated the molecular profiles of 102,878 patients with diverse malignancies for MDM2 amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). Results MDM2 amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with MDM2 amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied MDM2 amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), PI3K signaling (25.4% [926 of 3,650]), TP53 (24.9% [910 of 3,650]), and MAPK signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and PD-L1 amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration–approved or investigational agent. MDM2 amplifications were less frequently associated with high tumor mutation burden compared with the MDM2 wild-type population (2.9% v 6.5%; P < .001). An illustrative patient who harbored MDM2 amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. Conclusion MDM2 amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have MDM2 amplification as well as pharmacologically tractable co-alterations.

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A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours

Cited by 111 publications

References 15 publications

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

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