First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer

Massard, Christophe; Azaro, Analía; Soria, Jean‐Charles; Lassen, Ulrik; Tourneau, Christophe Le; Sarker, Debashis; Smith, Claire; Ohnmacht, U.; Oakley, Gerard J.; Patel, Bharvin K.R.; Yuen, Eunice; Benhadji, Karim A.; Rodón, Jordi

doi:10.1093/annonc/mdy244

Cited by 111 publications

(47 citation statements)

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“…This report describes the first clinical study of crenigacestat in Japanese patients with solid tumors. Results of this phase 1, single-center, nonrandomized, single-arm, open-label, doseescalation study indicate that crenigacestat is tolerated at both the 25 mg and 50 mg doses in Japanese patients, with 50 mg TIW confirmed as the recommended phase 2 dose in this population [9].…”

Section: Discussionmentioning

confidence: 88%

“…Crenigacestat is a potent small molecule inhibitor of Notch cleavage that prevents the release of the Notch intracellular domain by inhibiting proteolytic activity of γ-secretase complex, and thereby decreasing Notch signaling and its downstream biologic effects. A phase 1, nonrandomized, open-label, multicenter trial that evaluated the safety and antitumor activity of crenigacestat in non-Japanese patients with advanced or metastatic cancers recommended a phase 2 dose of crenigacestat monotherapy at 50 mg administered 3 times per week (TIW) during a 28-day cycle [9]. In the confirmatory, expansion trial of crenigacestat in patients with adenoid cystic carcinoma, it was demonstrated that crenigacestat has a manageable safety profile and a clinical pharmacodynamic effect on Notch-targeted genes.…”

Section: Introductionmentioning

confidence: 99%

“…In the confirmatory, expansion trial of crenigacestat in patients with adenoid cystic carcinoma, it was demonstrated that crenigacestat has a manageable safety profile and a clinical pharmacodynamic effect on Notch-targeted genes. At the recommended phase 2 dose, the most frequent toxicities included diarrhea, nausea, and vomiting [9]. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma [9].…”

Section: Introductionmentioning

confidence: 99%

“…At the recommended phase 2 dose, the most frequent toxicities included diarrhea, nausea, and vomiting [9]. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma [9]. Crenigacestat was further explored in patients with adenoid cystic carcinoma and sarcoma [10,11].…”

Section: Introductionmentioning

confidence: 99%

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A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors

et al. 2020

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Summary Background This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW. Trial registration: NCT02836600 (ClinicalTrials.gov) registered on July 19, 2016.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors

et al. 2020

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“…Clinical studies targeting Notch have been initiated since a few years ago and have been mainly based in the use of GSIs, although, more recently, monoclonal antibodies against Notch receptors and ligands have been developed (Table 2). LY3039478 is a potent GSI that has demonstrated antitumor activity in xenograft models, including lung cancer [157], and in patients with distinct neoplasias [158,159], and clinical trials are currently undergoing or have just been completed in patients with advanced solid tumors and with gene/protein alterations related to the Notch pathway (NCT02836600, NCT02784795). Another GSI, RO4929097, has significant activity in blocking Notch processing and activity, and is efficacious in markedly inducing tumor growth inhibition in NSCLC xenografts [160].…”

Section: Therapy Perspectivesmentioning

confidence: 99%

Notch Transduction in Non-Small Cell Lung Cancer

Sharif

Shaji

Chammaa

et al. 2020

IJMS

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The evolutionarily-conserved Notch signaling pathway plays critical roles in cell communication, function and homeostasis equilibrium. The pathway serves as a cell-to-cell juxtaposed molecular transducer and is crucial in a number of cell processes including cell fate specification, asymmetric cell division and lateral inhibition. Notch also plays critical roles in organismal development, homeostasis, and regeneration, including somitogenesis, left-right asymmetry, neurogenesis, tissue repair, self-renewal and stemness, and its dysregulation has causative roles in a number of congenital and acquired pathologies, including cancer. In the lung, Notch activity is necessary for cell fate specification and expansion, and its aberrant activity is markedly linked to various defects in club cell formation, alveologenesis, and non-small cell lung cancer (NSCLC) development. In this review, we focus on the role this intercellular signaling device plays during lung development and on its functional relevance in proximo-distal cell fate specification, branching morphogenesis, and alveolar cell determination and maturation, then revise its involvement in NSCLC formation, progression and treatment refractoriness, particularly in the context of various mutational statuses associated with NSCLC, and, lastly, conclude by providing a succinct outlook of the therapeutic perspectives of Notch targeting in NSCLC therapy, including an overview on prospective synthetic lethality approaches.

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Molecular Genetics of Salivary Gland Cancer

Clair¹,

Ha²

2019

Encyclopedia of Life Sciences

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Malignant salivary gland tumours are rare cancers of the head and neck with varied histopathology and clinical behaviour. The most common forms of salivary gland malignancies include mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (AdCC), acinic cell carcinoma (ACC) and a number of more uncommon entities. Novel sequencing techniques and chromosomal analyses have led to an increased understanding of the genetics of these tumours. A characteristic molecular profile of many of these tumours is emerging and involves balanced chromosomal translocations that result in the expression of unique fusion proteins, as well as genomic variants in a limited subset of genes. Early clinical trials targeting these genetic aberrations have demonstrated promising results. Further elucidation of the molecular mechanisms of this heterogeneous group of tumours will be essential to design effective targeted therapies for salivary gland malignancies. Key Concepts Malignant salivary gland tumours are rare tumours with varied clinical behaviour and histopathology. Advances in genetic sequencings have enabled improved insight into the genetics of salivary gland tumours. The majority of salivary gland malignancies result from well‐defined chromosomal translocations. The chromosomal translocations found in salivary gland malignancies result in the expression of fusion genes that are important in the aetiology of these tumours. Salivary gland tumours result from the deregulation of a limited number of pathways and genes – which may enable the development of targeted therapeutics for these rare tumours.

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First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer

Abstract: NCT01695005.

Cited by 111 publications

References 20 publications

A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors

A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors

Notch Transduction in Non-Small Cell Lung Cancer

Molecular Genetics of Salivary Gland Cancer

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