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

C Massard; A Azaro; J-C Soria; U Lassen; C Le Tourneau; D Sarker; C Smith; U Ohnmacht; G Oakley; B K R Patel; E S M Yuen; K A Benhadji; J Rodon

doi:10.1093/annonc/mdy244

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

C Massard, A Azaro, J-C Soria, U Lassen, C Le Tourneau, D Sarker, C Smith, U Ohnmacht, G Oakley, B K R Patel, E S M Yuen, K A Benhadji, J Rodon

Department of Clinical Medicine

44 Citations (Scopus)

Abstract

Background Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. Î 3-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an '1/480% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID NCT01695005.

Original language	English
Journal	Annals of oncology : official journal of the European Society for Medical Oncology
Volume	29
Issue number	9
Pages (from-to)	1911-1917
Number of pages	7
ISSN	0923-7534
DOIs	https://doi.org/10.1093/annonc/mdy244
Publication status	Published - 1 Sept 2018

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http://www.annalsofoncology.org/article/S0923753419341651/pdfLicence: CC BY-NC-ND

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Massard, C., Azaro, A., Soria, J-C., Lassen, U., Le Tourneau, C., Sarker, D., Smith, C., Ohnmacht, U., Oakley, G., Patel, B. K. R., Yuen, E. S. M., Benhadji, K. A., & Rodon, J. (2018). First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Annals of oncology : official journal of the European Society for Medical Oncology, 29(9), 1911-1917. https://doi.org/10.1093/annonc/mdy244

Massard, C, Azaro, A, Soria, J-C, Lassen, U, Le Tourneau, C, Sarker, D, Smith, C, Ohnmacht, U, Oakley, G, Patel, BKR, Yuen, ESM, Benhadji, KA & Rodon, J 2018, 'First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer', Annals of oncology : official journal of the European Society for Medical Oncology, vol. 29, no. 9, pp. 1911-1917. https://doi.org/10.1093/annonc/mdy244

@article{9490ac1f55a5411a9313361ce06eeda4,

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

abstract = "Background Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. {\^I} 3-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an '1/480% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID NCT01695005.",

author = "C Massard and A Azaro and J-C Soria and U Lassen and {Le Tourneau}, C and D Sarker and C Smith and U Ohnmacht and G Oakley and Patel, {B K R} and Yuen, {E S M} and Benhadji, {K A} and J Rodon",

year = "2018",

month = sep,

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doi = "10.1093/annonc/mdy244",

language = "English",

volume = "29",

pages = "1911--1917",

journal = "Annals of Oncology",

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T1 - First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer

AU - Massard, C

AU - Azaro, A

AU - Soria, J-C

AU - Lassen, U

AU - Le Tourneau, C

AU - Sarker, D

AU - Smith, C

AU - Ohnmacht, U

AU - Oakley, G

AU - Patel, B K R

AU - Yuen, E S M

AU - Benhadji, K A

AU - Rodon, J

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Background Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. Î 3-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an '1/480% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID NCT01695005.

AB - Background Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. Î 3-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an '1/480% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID NCT01695005.

U2 - 10.1093/annonc/mdy244

DO - 10.1093/annonc/mdy244

M3 - Journal article

C2 - 30060061

SN - 0923-7534

VL - 29

SP - 1911

EP - 1917

JO - Annals of Oncology

JF - Annals of Oncology

IS - 9

ER -

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

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