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

Amer M. Zeidan; Daniel J. DeAngelo; Jeanne Palmer; Christopher S. Seet; Martin S. Tallman; Xin Wei; Heather Raymon; Priya Sriraman; Stephan Kopytek; Jan Philipp Bewersdorf; Michael R. Burgess; Kristen Hege; Wendy Stock

doi:10.1007/s00277-021-04734-2

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

Amer M. Zeidan^*, Daniel J. DeAngelo, Jeanne Palmer, Christopher S. Seet, Martin S. Tallman, Xin Wei, Heather Raymon, Priya Sriraman, Stephan Kopytek, Jan Philipp Bewersdorf, Michael R. Burgess, Kristen Hege, Wendy Stock

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

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.

Original language	English (US)
Pages (from-to)	557-569
Number of pages	13
Journal	Annals of Hematology
Volume	101
Issue number	3
DOIs	https://doi.org/10.1007/s00277-021-04734-2
State	Published - Mar 2022

Funding

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. 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.

Keywords

Hematological cancer
IgG4PE
Macrophages
SIRPα
Safety

ASJC Scopus subject areas

Hematology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00277-021-04734-2

Cite this

Zeidan, A. M., DeAngelo, D. J., Palmer, J., Seet, C. S., Tallman, M. S., Wei, X., Raymon, H., Sriraman, P., Kopytek, S., Bewersdorf, J. P., Burgess, M. R., Hege, K., & Stock, W. (2022). Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes. Annals of Hematology, 101(3), 557-569. https://doi.org/10.1007/s00277-021-04734-2

@article{209ef1d0259d4affa37b742908938fc9,

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

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.",

keywords = "Hematological cancer, IgG4PE, Macrophages, SIRPα, Safety",

author = "Zeidan, {Amer M.} and DeAngelo, {Daniel J.} and Jeanne Palmer and Seet, {Christopher S.} and Tallman, {Martin S.} and Xin Wei and Heather Raymon and Priya Sriraman and Stephan Kopytek and Bewersdorf, {Jan Philipp} and Burgess, {Michael R.} and Kristen Hege and Wendy Stock",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2022",

month = mar,

doi = "10.1007/s00277-021-04734-2",

language = "English (US)",

volume = "101",

pages = "557--569",

journal = "Annals of Hematology",

issn = "0939-5555",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "3",

}

Zeidan, AM, DeAngelo, DJ, Palmer, J, Seet, CS, Tallman, MS, Wei, X, Raymon, H, Sriraman, P, Kopytek, S, Bewersdorf, JP, Burgess, MR, Hege, K & Stock, W 2022, 'Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes', Annals of Hematology, vol. 101, no. 3, pp. 557-569. https://doi.org/10.1007/s00277-021-04734-2

TY - JOUR

T1 - Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes

AU - Zeidan, Amer M.

AU - DeAngelo, Daniel J.

AU - Palmer, Jeanne

AU - Seet, Christopher S.

AU - Tallman, Martin S.

AU - Wei, Xin

AU - Raymon, Heather

AU - Sriraman, Priya

AU - Kopytek, Stephan

AU - Bewersdorf, Jan Philipp

AU - Burgess, Michael R.

AU - Hege, Kristen

AU - Stock, Wendy

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2022/3

Y1 - 2022/3

N2 - 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.

AB - 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.

KW - Hematological cancer

KW - IgG4PE

KW - Macrophages

KW - SIRPα

KW - Safety

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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

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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