Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes.
Adult
Aged
Aged, 80 and over
Animals
Female
Humans
Male
Mice
Middle Aged
Antineoplastic Agents, Immunological
/ adverse effects
CD47 Antigen
/ antagonists & inhibitors
Leukemia, Myeloid, Acute
/ drug therapy
Macaca fascicularis
Maximum Tolerated Dose
Mice, SCID
Myelodysplastic Syndromes
/ drug therapy
Neoplasm Recurrence, Local
/ drug therapy
Hematological cancer
IgG4PE
Macrophages
SIRPα
Safety
Journal
Annals of hematology
ISSN: 1432-0584
Titre abrégé: Ann Hematol
Pays: Germany
ID NLM: 9107334
Informations de publication
Date de publication:
Mar 2022
Mar 2022
Historique:
received:
16
09
2021
accepted:
29
11
2021
pubmed:
5
1
2022
medline:
11
2
2022
entrez:
4
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34981142
doi: 10.1007/s00277-021-04734-2
pii: 10.1007/s00277-021-04734-2
pmc: PMC9414073
mid: NIHMS1829803
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
CD47 Antigen
0
CC-90002
0
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
557-569Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016359
Pays : United States
Organisme : NIH HHS
ID : P30 CA016359
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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