First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors

• Published in: Journal of experimental & clinical cancer research Vol. 42; no. 1; p. 76
• Main Authors: Cole, Christopher B, Morelli, Maria Pia, Fantini, Massimo, Miettinen, Markku, Fetsch, Patricia, Peer, Cody, Figg, William D, Yin, Tyler, Houston, Nicole, McCoy, Ann, Lipkowitz, Stanley, Zimmer, Alexandra, Lee, Jung-Min, Pavelova, Miroslava, Villanueva, Erin N, Trewhitt, Kathryn, Solarz, B Brooke, Fergusson, Maria, Mavroukakis, Sharon A, Zaki, Anjum, Tsang, Kwong Y, Arlen, Philip M, Annunziata, Christina M
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29-03-2023; BioMed Central; BMC
• Subjects: Adult; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - therapeutic use; Antibody-dependent cellular cytotoxicity; Antigens; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Cancer; Cancer immunotherapy; Cancer therapies; Clinical trials; Colorectal cancer; Colorectal Neoplasms - drug therapy; Cytotoxicity; Disease Progression; Drug therapy; FDA approval; Febrile Neutropenia - chemically induced; Female; Humans; Immune system; Immunoglobulin G; Immunotherapy; Killer cells; Metastasis; Monoclonal antibodies; Monoclonal antibody; NEO-201; Neutropenia; Neutrophils; O-glycan; Ovarian cancer; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Patients; Pharmacokinetics; Polysaccharides; Product development; Proteins; Regulatory T cells; T cells; Thrombocytopenia; Tumors; O-glycan; Clinical trial; Monoclonal antibody; Cancer immunotherapy; NEO-201; Regulatory T cells; Antibody-dependent cellular cytotoxicity
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-023-02649-6

NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments.
This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response.
Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1-15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD.
NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors.
NCT03476681 . Registered 03/26/2018.