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A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma

  • PHASE I STUDIES
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Summary

Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A “3 + 3” dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by Millendo Therapeutics, Inc., Ann Arbor, Michigan, United States of America.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA

    David C. Smith, Rashmi Chugh & Bryan J. Schneider

  2. Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany

    Matthias Kroiss & Martin Fassnacht

  3. Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany

    Matthias Kroiss & Martin Fassnacht

  4. Stanford University, Palo Alto, CA, USA

    Electron Kebebew

  5. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Mouhammed Amir Habra

  6. Millendo Therapeutics US, Inc., Ann Arbor, MI, USA

    Pegah Jafarinasabian, M. Marian Ijzerman, Vivian H. Lin & Pharis Mohideen

  7. Department of Investigational Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Aung Naing

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Contributions

PJN and VHL authored substantial sections of the manuscript and incorporated reviewer comments. DCS, MF, EK, MAH, MK, MMI, PM, and AN reviewed and edited the manuscript, and provided many helpful comments.

Corresponding author

Correspondence to Aung Naing.

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Conflict of interest

David C. Smith received research funding for this project from Millendo Therapeutics, formerly Atterocor. David C. Smith received research funding from Bayer, Bristol-Myers Squibb (Medarex), Eli Lilly, Genentech, Astellas, MedImmune, Seattle Genetics, Millenium, Incyte, Novartis, F. Hoffman-La Roche, ESSA, and OncoMed. Matthias Kroiss received research support from Ipsen. Electron Kebebew declares no conflict of interest. Mouhammed Amir Habra received research funding from Exelixis. Mouhammed Amir Habra is a consultant and on the advisory board of Corcept Therapeutics and HRA Pharma. Rashmi Chugh declares no conflict of interest. Bryan J. Schneider received institutional research funding from Incyte, Genentech and Bristol-Meyers Squibb. Martin Fassnacht declares no conflict of interest. Pegah Jafarinasabian is a former employee of Millendo Therapeutics. M. Marian Ijzerman is a current employee of Millendo Therapeutics. Vivian H. Lin is a current employee of Millendo Therapeutics. Pharis Mohideen is a former employee of Millendo Therapeutics and currently owns shares in Millendo Therapeutics. Aung Naing received research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Meyers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, PsiOxus, and Immune Deficiency Foundation (spouse). Aung Naing is on the advisory board for CytomX Therapeutics and Novartis and received reimbursement for travel and accommodation from ARMO BioSciences, a wholly owned subsidiary of Eli Lilly and Company.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration 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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Smith, D.C., Kroiss, M., Kebebew, E. et al. A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma. Invest New Drugs 38, 1421–1429 (2020). https://doi.org/10.1007/s10637-020-00899-1

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