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Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes

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Abstract

CC-90002 is an anti-CD47 antibody that inhibits CD47-SIRPα interaction and enables macrophage-mediated killing of tumor cells in hematological cancer cell lines. In this first clinical, phase 1, dose-escalation and -expansion study (CC-90002-AML-001; NCT02641002), we evaluated CC-90002 in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). CC-90002 was administered in escalating doses of 0.1–4.0 mg/kg, using a modified 3 + 3 design. Primary endpoints included dose-limiting toxicities (DLTs), non-tolerated dose (NTD), maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary endpoints included preliminary efficacy, pharmacokinetics, and presence/frequency of anti-drug antibodies (ADAs). Between March 2016 and July 2018, 28 patients were enrolled (24 with AML and 4 with MDS) at 6 sites across the USA. As of July 18, 2018, all patients had discontinued, mainly due to death or progressive disease. The most common treatment-emergent adverse events were diarrhea (46.4%), thrombocytopenia (39.3%), febrile neutropenia (35.7%), and aspartate aminotransferase increase (35.7%). Four patients experienced DLTs (1 patient had grade 4 disseminated intravascular coagulation and grade 5 cerebral hemorrhage, 1 had grade 3 purpura, 1 had grade 4 congestive cardiac failure and grade 5 acute respiratory failure, and another had grade 5 sepsis). The NTD and MTD were not reached. No objective responses occurred. CC-90002 serum exposure was dose-dependent. ADAs were present across all doses, and the proportion of ADA-positive patients in cycle 1 increased over time. Despite no unexpected safety findings, the CC-90002-AML-001 study was discontinued in dose escalation for lack of monotherapy activity and evidence of ADAs. However, as other anti-CD47 agents in clinical trials are showing promising early results for AML and MDS, understanding preclinical and clinical differences between individual agents in this class will be of high importance.

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Data availability

Bristol Myers Squibb company policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. Data requests may be submitted to Celgene, a Bristol Myers Squibb Company, at https://vivli.org/ourmember/Celgene/ and must include a description of the research proposal.

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Acknowledgements

We thank the patients, families, and caregivers who have made the study possible and the clinical study teams.

Funding

The study was supported by Celgene, a Bristol Myers Squibb Company. This work was supported in part by the National Cancer Institute of the National Institutes of Health (grant P30 CA016359). Bristol-Myers Squibb,National Institutes of Health,P30 CA016359. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Internal Medicine, Yale University and Yale Cancer Center, New Haven, CT, USA

    Amer M. Zeidan & Jan Philipp Bewersdorf

  2. Yale School of Medicine, Smilow Cancer Hospital Care Center at Yale New Haven, 35 Park Street, Ste NP-7, New Haven, CT, 06511, USA

    Amer M. Zeidan

  3. Division of Leukemia, Dana-Farber Cancer Institute, Boston, MA, USA

    Daniel J. DeAngelo

  4. Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ, USA

    Jeanne Palmer

  5. Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Christopher S. Seet

  6. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Martin S. Tallman

  7. Bristol Myers Squibb, Princeton, NJ, USA

    Xin Wei, Heather Raymon, Priya Sriraman, Stephan Kopytek, Michael R. Burgess & Kristen Hege

  8. University of Chicago Medicine, Chicago, IL, USA

    Wendy Stock

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  1. Amer M. Zeidan
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Contributions

Matthew Myers contributed to pharmacokinetic data analyses. All authors contributed to and approved the manuscript; writing and editorial assistance were provided by Hannah H. Chang, PhD, of Bio Connections LLC, and Christine Khoo, Spark Medica Inc, funded by Bristol Myers Squibb.

Corresponding author

Correspondence to Amer M. Zeidan.

Ethics declarations

Ethics approval and consent to participate

The protocol was reviewed and approved by each site’s Institutional Review Board prior to initiation of the study. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in adherence to Good Clinical Practice as described in the International Council for Harmonisation E6 guidance. All patients provided written informed consent.

Conflict of interest

A.M.Z. received research funding from Celgene (a Bristol Myers Squibb Company), AbbVie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics; served as a consultant for and received honoraria from AbbVie, Otsuka, Pfizer, Celgene (a Bristol Myers Squibb Company), Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, BeyondSpring, Trovagene, Takeda, Ionis, Tyme, Amgen, Janssen, Gilead, Kura, Aprea, and Epizyme; and received travel support for meetings from Pfizer, Novartis, and Trovagene. D.J.D. received research funding from AbbVie, Glycomimetics, Novartis, and Blueprint Pharmaceuticals and served as a consultant for and received honoraria from Amgen, Autolus, Blueprint, Incyte, Jazz, Novartis, Pfizer, Servier, and Takeda. M.S.T. received research funding from AbbVie, Cellerant, Orsenix, ADC Therapeutics, and Biosight; served as a consultant for AbbVie, BiolineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, and Jazz Pharma; and holds royalties with UpToDate. M.B. holds patents and royalties with Celgene (a Bristol Myers Squibb Company) and University of California and is an employee and equity owner with Bristol Myers Squibb. K.H. is an employee and equity owner with Bristol Myers Squibb and served as a member of advisory board for Arcus Biosciences, Mersana Therapeutics, and Society for Immunotherapy of Cancer. W.S. received research funding from AbbVie, Amgen, Jazz, Pfizer, and Xencor; received honoraria from AbbVie, Amgen, and Pfizer; and served as a consultant for AbbVie, Amgen, Astella, GlaxoSmithKline, Kite, Jazz, Morphosys, and Pfizer. H. Raymon was an employee of and is an equity owner with Bristol Myers Squibb. X.W., P.S., and S.K. are employees of and equity owners with Bristol Myers Squibb. J.P., J.P.B. and C.S.S. declare no potential conflicts of interest.

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Zeidan, A.M., DeAngelo, D.J., Palmer, J. et al. Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes. Ann Hematol 101, 557–569 (2022). https://doi.org/10.1007/s00277-021-04734-2

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