A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies

Graux, Carlos; Sonet, Anne; Maertens, Johan; Duyster, Justus; Greiner, Jochen; Chalandon, Yves; Martinelli, Giovanni; Hess, Dagmar; Heim, Dominik; Giles, Francis J.; Kelly, Kevin R.; Gianella‐Borradori, Athos; Longerey, B.; Asatiani, Ekaterine; Rejeb, N.; Ottmann, Oliver G.

doi:10.1016/j.leukres.2013.04.025

Cited by 17 publications

(8 citation statements)

References 9 publications

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“…Other drugs including AMG900 [102,103], AS703569 [104][105][106], BI-847325 [112], CYC116, PF-03814735 [126], and SNS-314 are also in phase I clinical trials.…”

Section: Pan Aurora Kinase Inhibitorsmentioning

confidence: 99%

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

et al. 2021

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Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

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“…Other drugs including AMG900 [102,103], AS703569 [104][105][106], BI-847325 [112], CYC116, PF-03814735 [126], and SNS-314 are also in phase I clinical trials.…”

Section: Pan Aurora Kinase Inhibitorsmentioning

confidence: 99%

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

et al. 2021

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“…Complete responses occurred in 3 patients. However, there was hematologic and gastrointestinal toxicity at clinically effective doses 137 . Moreover, in two phase I trials of MSC1992371A in solid tumors the only responses seen were disease stabilization 138, 139 .…”

Section: Clinical Trials Of Aurora Kinase Inhibitorsmentioning

confidence: 99%

The aurora kinases in cell cycle and leukemia

2014

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The Aurora kinases, which include Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) and meiosis (AURKC). Since their discovery nearly twenty years ago, Aurora kinases have been studied extensively in cell and cancer biology 1. Several early studies found that Aurora kinases are amplified and overexpressed at the transcript and protein level in various malignancies, including several types of leukemia. These discoveries and others provided a rationale for the development of small molecule inhibitors of Aurora kinases as leukemia therapies. The first generation of Aurora kinase inhibitors did not fare well in clinical trials, owing to poor efficacy and high toxicity. However, the creation of second generation, highly selective Aurora kinase inhibitors has increased the enthusiasm for targeting these proteins in leukemia. This review will describe the functions of each Aurora kinase, summarize their involvement in leukemia and discuss inhibitor development and efficacy in leukemia clinical trials.

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“…While we have provided a link to access user friendly R code for simulating the operating characteristics of this work, we intend to make functions available for both implementing and simulating the design in an R library. The methods outlined in this paper can also be applied to other two‐dimensional dose‐finding problems, such as those aiming to estimate an MTC under multiple treatment schedules .…”

Section: Discussionmentioning

confidence: 99%

Identifying a maximum tolerated contour in two‐dimensional dose finding

Wages

2016

Statistics in Medicine

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The majority of Phase I methods for multi-agent trials have focused on identifying a single maximum tolerated dose combination (MTDC) among those being investigated. Some published methods in the area have been based on the notion that there is no unique MTDC, and that the set of dose combinations with acceptable toxicity forms an equivalence contour in two dimensions. Therefore, it may be of interest to find multiple MTDC's for further testing for efficacy in a Phase II setting. In this paper, we present a new dose-finding method that extends the continual reassessment method to account for the location of multiple MTDC's. Operating characteristics are demonstrated through simulation studies, and are compared to existing methodology. Some brief discussion of implementation and available software is also provided.

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A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies

Cited by 17 publications

References 9 publications

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

The aurora kinases in cell cycle and leukemia

Identifying a maximum tolerated contour in two‐dimensional dose finding

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