Phase 1 study of 2 high dose intensity schedules of the pan-Notch inhibitor crenigacestat (LY3039478) in combination wit
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PHASE I STUDIES
Phase 1 study of 2 high dose intensity schedules of the pan-Notch inhibitor crenigacestat (LY3039478) in combination with prednisone in patients with advanced or metastatic cancer Analía Azaro 1 & Capucine Baldini 2 & Jordi Rodon 3,4 & Jean-Charles Soria 2,5 & Eunice Yuen 6 & Andrew Lithio 6 & Gerard Oakley 6 & Karim A. Benhadji 6 & Christophe Massard 2 Received: 24 February 2020 / Accepted: 4 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Background Crenigacestat is a potent Notch inhibitor that decreases Notch signaling and its downstream biological effects. Here, we report the results from Part F of study 16F-MC-JJCA designed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of crenigacestat with prednisone in advanced or metastatic cancer. The combination was planned to mitigate gastrointestinal toxicities. Methods Eligible patients (Study Part F) received crenigacestat loading dose (75 mg, escalating to 150 mg) administered thrice weekly (TIW) (F1) or twice weekly (BIW) (F2) for 2 weeks during Cycle 1, followed by 50 mg TIW from week 3 onwards. Prednisone was co-administered for 2 weeks in Cycle 1. Results Twenty-eight patients were enrolled; 11 in F1 (median age, 63 years), 17 in F2 (median age, 50 years). Dose-limiting toxicities were Grade 3 increased serum amylase and Grade 2 fatigue in F1, and Grade 4 hypophosphatemia and Grade 3 rash maculo-papular in F2. The maximum tolerated dose was 75 mg in F1 and 100 mg in F2. Best overall response was stable disease (F1, 6 [54.5%] patients; F2, 11 [64.7%] patients). Pharmacokinetic was dose proportional. Prednisone did not modify PK of crenigacestat, and both F1 and F2 achieved pharmacodynamics effects on evaluable tumor tissue samples. Conclusions This study demonstrated the potential use of prednisone to reduce gastrointestinal (GI) toxicities of a Notch inhibitor without affecting its PK. The safety profile observed was consistent with Notch pathway inhibitors, and the maximum tolerated dose was 75 mg TIW and 100 mg BIW in F1 and F2, respectively. ClinicalTrials.gov: NCT01695005. Keywords Notch pathway . Crenigacestat . LY3039478 . Solid tumors
Introduction
* Christophe Massard [email protected] 1
Molecular Therapeutics Research Unit, Medical Oncology Department, Vall d´Hebron University Hospital and Vall d´Hebron Institute of Oncology, Barcelona, Spain
2
Drug Development Department, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant 94800, Villejuif Cedex, France
3
Vall d´Hebron Institute of Oncology, Barcelona, Spain
4
MD Anderson Cancer Center, TX Houston, USA
5
Université Paris-Sud, Orsay, France
6
Eli Lilly and Company, Indianapolis, IN, USA
Notch signaling is involved in both normal and pathologic physiology [1–3]. Deregulation of Notch signaling by mutation or overexpression of Notch ligands and/or receptors is implicated in a number of malignancies including cancers of the breast, ovary, lung, pancreas, colon, head and neck, cervix, and kidney
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