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A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors

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Summary

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0–82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.

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Acknowledgments

Medical writing support was provided by Debra Hidayetoglu, on behalf of Covance, Inc.

Funding

This trial was funded by Eli Lilly and Company.

Author information

Authors and Affiliations

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

    Analia Azaro

  2. Department of Pharmacology, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

    Analia Azaro

  3. Drug Development Department (DITEP), Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France

    Christophe Massard

  4. Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical College, 1275 York Avenue, New York, NY, USA

    William D. Tap

  5. Department of Medical Oncology, Centre Léon Bérard, Lyon, France

    Philippe A. Cassier

  6. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Jaime Merchan

  7. Institut Bergonié, Bordeaux Cedex, France

    Antoine Italiano

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

    Bailey Anderson, Eunice Yuen, Danni Yu & Gerard Oakley III

  9. Eli Lilly and Company, New York, NY, USA

    Karim A. Benhadji

  10. Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas Medical Center/MD Anderson Cancer Center, Houston, TX, 77030, USA

    Shubham Pant

Authors
  1. Analia Azaro
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Contributions

All authors meet the International Committee of Medical Journal Editors criteria for authorship for this manuscript, take responsibility for the integrity of the work, and have given final approval of the version of the manuscript to be published.

A Azaro: Data analysis and interpretation and manuscript editing and review. C Massard: Data analysis and interpretation and manuscript review. WD Tap: Data acquisition, data analysis and interpretation, and manuscript editing and review. PA Cassier: Data analysis and interpretation and manuscript review. J Merchan: Data acquisition, data analysis and interpretation, and manuscript review. A Italiano: Data acquisition, data analysis and interpretation, and manuscript editing and review. B Anderson: Quality control of data and algorithms, data analysis and interpretation, and manuscript editing and review. E Yuen: Study design, data analysis and interpretation, and manuscript review. D Yu: Quality control of data and algorithms, data analysis and interpretation, statistical analysis, and manuscript review. G Oakley III: Data acquisition, data analysis and interpretation, and manuscript editing and review. KA Benhadji: Study concepts, study design, data analysis and interpretation, and manuscript editing and review. S Pant: Data analysis and interpretation and manuscript review.

Corresponding author

Correspondence to Shubham Pant.

Ethics declarations

Ethics approval

All procedures performed in studies involving human participants were performed in accordance with the Declaration of Helsinki and International Council for Harmonization Good Clinical Practice guidelines with registration of ClinicalTrials.gov NCT02784795.

Consent to participate

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

Consent for publication

Not applicable.

Conflicts of interest/Competing interests

A Azaro, Advisory and Consulting: Amcure GmbH and Orion Corporation. C Massard, Advisory and Consulting: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, and Orion; Principal/Sub-Investigator of Clinical Trials: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boehringer 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, outside of submitted work. WD Tap, Advisory Boards: Eli Lilly and Company, EMD Serono, Eisai, Janssen, Immune design, Daiichi Sankyo, Blueprint, Loxo, Glaxo Smith Kline, Agios Pharmaceuticals, NanoCarrier, Deciphera, and C4 Therapeutics; Consulting: Daiichi Sankyo, FDA ODAXC Meeting Pexidartinib; Scientific Advisory Board: Certis Oncology Solutions (and stock ownership); Co-founder of Atropos Therapeutics (and stock ownership); Patent (pending) on the identification and development of biomarkers for CDK4 inhibitors in cancer. PA Cassier, received honoraria from Amgen, AstraZeneca, Blueprint Medicines, Novartis, Roche/Genentech, and Merck Serono; Investigator/Sub-Investigator of Clinical Trials: Abbvie, AstraZeneca, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Glaxo Smith Kline, Innate Pharma, Janssen, Merck Serono, Merck Sharp Dohme, Novartis, Plexxikon, Genentech/Roche, Taiho Pharmaceuticals, and Transgene, outside of submitted work; Travel Accommodations and Expenses: Amgen, Bristol-Myers Squibb, Merck Sharp and Dohme, Netris Pharma, Novartis, and Roche. J Merchan, Advisory and Consulting: Exelixis; Investigator/Sub-Investigator of Clinical Trials: Eli Lilly and Company, Pfizer, Novartis, Genentech, Merck, Peloton Therapeutics, Corvus Pharmaceuticals, Tizona Therapeutics, Vyriad, Sillagen, Replimune, Seattle Genetics, Eisai, Calithera Biosciences, and Rexahn Pharmaceuticals, outside of the submitted work. A Italiano, Advisory: Bayer, Daiichi Sankyo, Merck, Roche, and Springworks; Grants: Bayer, Chugai, Pharmamar, MSD, Roche, and Merck. K Benhardji, Patents: LY3039478 related patents; S Pant, Advisory and Consulting: Tyme, Inc., 4D-Pharma, Xencor, Ipsen; Principal/Sub-Investigator for Clinical Trials: Arcus, Arqule, Bristol-Myers Squibb, Eli Lilly and Company, Five Prime Therapeutics, Glaxo Smith Kline, Holy Stone Healthcare Co., Tyme, Inc., Ipsen, Mirati Therapeutics, Inc., Novartis, Onco Response, Red Hill Biopharma, Ltd., Rgenix, Sanofi-Aventis, Xencor, Astellas, and Janssen, outside of submitted work. B Anderson, E Yuen, D Yu, G Oakley III, and KA Benhadji are current or past employees of Eli Lilly and Company and may hold company stocks. B Anderson is an employee of PRA Health Sciences and K Benhadji is an employee of Taiho Oncology, and may hold company stocks.

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Azaro, A., Massard, C., Tap, W.D. et al. A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors. Invest New Drugs 39, 1089–1098 (2021). https://doi.org/10.1007/s10637-021-01094-6

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