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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

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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.

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Data availability

Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms will be provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.

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Acknowledgements

The authors are grateful to the participating patients and acknowledge all the global investigators who were involved in this study. Medical writing support was provided by Prudence Stanford and Ira Ayene, and editorial support was provided by Antonia Baldo of Syneos Health, which was funded by Eli Lilly and Company. This study was sponsored by Eli Lilly and Company.

Funding

This study was funded by Eli Lilly and Company.

Author information

Authors and Affiliations

  1. Molecular Therapeutics Research Unit, Medical Oncology Department, Vall d´Hebron University Hospital and Vall d´Hebron Institute of Oncology, Barcelona, Spain

    Analía Azaro

  2. Drug Development Department, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant 94800, Villejuif Cedex, France

    Capucine Baldini, Jean-Charles Soria & Christophe Massard

  3. Vall d´Hebron Institute of Oncology, Barcelona, Spain

    Jordi Rodon

  4. MD Anderson Cancer Center, TX, Houston, USA

    Jordi Rodon

  5. Université Paris-Sud, Orsay, France

    Jean-Charles Soria

  6. Eli Lilly and Company, Indianapolis, IN, USA

    Eunice Yuen, Andrew Lithio, Gerard Oakley & Karim A. Benhadji

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Contributions

Conceptualization; KAB; supervision: KAB; study design: EY, KAB, CM; study conduct: AA, CB, JR, J-CS, CM; data collection: AA, CB, JR, J-CS, CM; data analysis: AL, KAB; biomarker analysis: GO; pharmacokinetic analysis: EY; interpretation of results: all authors; writing: the initial draft of the manuscript was written with support from a medical writer.

Corresponding author

Correspondence to Christophe Massard.

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Conflict of interest

Analia Azaro declares consulting fees from Orian Pharmaceuticals and Amcure GmbH. Capucine Baldini has nothing to declare. Jordi Rodon declares personal fees from Eli Lilly and Company, Orion Pharmaceuticals, Peptomyc, Roche Pharmceuticals, Ellipses Pharma, Certara, iOnctura SA; personal fees and other from Bayer, Kelun Pharmaceuticals/Klus Pharma, Novartis, Pfizer, Spectrum Pharmaceuticals Inc; travel reimbursement from Cancer Core Europe Karolinska Institute, Chinese University of Hong Kong, Department of Defense, Elsevier, ESMO, European Journal of Cancer, Huntsman Cancer Institute, Janssen, King Abdullah International Medical Research Center, Lousiania State University, Merck Sharp & Dohme, SOLTI, VHIO/ Ministero de Empleo Y Seguridad Social, WIN Consortium; and research funding from, BioAtla, CytomX, GlaxoSmithKline, Genmab, Ipsen, Kelun-Biotech, Symphogen, TakedaMillenium Pharmaceuticals Inc., Tocagen Inc. outside the submitted work. Jean-Charles Soria declares personal fees during the conduct of this study from AstraZeneca and Eli Lilly and Company; and personal fees from AstraZeneca, Astex, Clovis, GammaMabs Pharma, GlaxoSmithKline, Merus, MSD, Mission Therapeutics, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Symphogen, and Takeda, outside the submitted work; and is a shareholder of AstraZeneca and Gritstone Oncology. Eunice Yuen and Andrew Lithio are employees of Elli Lilly and Company. Gerard Oakley is a stockholder and employee of Eli Lilly and Company. Karim A. Benhadji is a patent holder, an employee of Taiho Oncology Inc., and a stockholder and former employee of Eli Lilly and Company. Christophe Massard declares consultant/advisory fees from Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Eli Lilly and Company, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, and Orion; has been a principal/sub-investigator of clinical trials for Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration Helsinki and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Azaro, A., Baldini, C., Rodon, J. et al. 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. Invest New Drugs 39, 193–201 (2021). https://doi.org/10.1007/s10637-020-00944-z

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