TY - JOUR
T1 - Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma
AU - Even, C.
AU - Lassen, U.
AU - Merchan, J.
AU - Le Tourneau, C.
AU - Soria, J. C.
AU - Ferte, C.
AU - Ricci, F.
AU - Diener, J. T.
AU - Yuen, E.
AU - Smith, C.
AU - Oakley, G. J.
AU - Benhadji, K. A.
AU - Massard, Christophe
N1 - Funding Information:
C. Even has a consulting/advisory role in AstraZeneca; Bristol-Myers Squibb; Innate Pharma; Merck Serono. J.R. Merchan has a consulting/advisory role in Exelixis, received research funding from Rexahn, Eli Lilly, Novartis, Tocagen, Agensys, Tracon. C. Le Tourneau received honoraria from Bristol-Myers Squibb; Novartis; has a consulting/advisory role in Debiopharm Group; GamaMabs Pharma; has advisory roles for MSD, BMS, Merck Serono, Astra Zeneca, Novartis, and Roche. J-C. Soria is an advisory board member at Eli Lilly. J-C. Soria has received Consultancy fees from AstraZeneca, Astex, Clovis, GSK, GAmaMabs, Lilly, MSD, Mission Therapeutics, Merus Pfizer, PharmaMar, Pierre Fabre, Roche/Genetech, Sanofi, Servier, Symphogen, and Takeda. Dr. Soria is fulltime employee of MedImmune since Sept 2017 and is a shareholder of AstraZeneca and Gritstone. C. Ferte received travel, accommodations, expenses from Amgen; Genentech; GlaxoSmithKline; MedImmune. C. Massard is an advisory board member, speaker, investigator at Amgen, Astellas, Astra Zeneca, Bayer, Celgene, Genentech, Ipsen, Janssen, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, Orion. K.A. Benhadji and Gerard Oakley are employees and stockholders of Eli Lilly and Company. JT Diener, C Smith, E.S.M. Yuen are Employees of Eli Lilly and Company. All the other authors have no relationships to disclose.
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/4/1
Y1 - 2020/4/1
N2 - Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911–17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.
AB - Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911–17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.
KW - Adenoid cystic carcinoma
KW - Crenigacestat
KW - LY3039478
KW - Notch pathway
KW - Phase 1
UR - http://www.scopus.com/inward/record.url?scp=85072038678&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072038678&partnerID=8YFLogxK
U2 - 10.1007/s10637-019-00739-x
DO - 10.1007/s10637-019-00739-x
M3 - Article
C2 - 30953269
AN - SCOPUS:85072038678
VL - 38
SP - 402
EP - 409
JO - Investigational New Drugs
JF - Investigational New Drugs
SN - 0167-6997
IS - 2
ER -