Phase I clinical trial of NEO-201, an anti-tumor-associated CEACAM-5/6 monoclonal antibody in solid tumors.
Authors: Cole Christopher Browning , Morelli Maria Pia , Fantini Massimo , Fergusson Maria , Mavroukakis Sharon A. , Zaki Anjum , Tsang Kwong Y. , Arlen Philip Martin , Annunziata Christina M. 
Published: June 2022

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Background: NEO201 is a humanized IgG1 monoclonal antibody generated against tumor-associated antigens from colorectal cancer which binds specifically to tumor-associated CEACAM-5 and CEACAM-6 variants without binding CECAM 5/6 on normal epithelial tissues. NEO-201 reactivity is positive in the majority of adenocarcinomas including colon (85%), pancreas (86%), lung (79%), and breast (53%). Preclinical data showed that NEO-201 exerts anti-tumor activity through antibody dependent cellular cytotoxicity and complement dependent cytotoxicity. Here we present outcomes from a phase I trial of NEO-201 in advanced solid tumors (NCT03476681). Methods: This was a classic 3+3 dose escalation trial, with cohort expansion at the RP2D. NEO-201 was administered intravenously every two weeks in a 28-day cycle. The primary objective was to assess the MTD/RP2D of NEO-201 in patients with advanced solid tumors. The secondary objective was to assess the preliminary antitumor activity and exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and possible relationships with response. Of 17 patients enrolled, 11 had colorectal, 4 had pancreatic and 2 had breast cancer. 4 patients received NEO-201 at dose level (DL) 1 (1 mg/kg), 6 patients at DL 1.5 (1.5 mg/kg) and 7 patients at dose DL 2 (2 mg/kg). Results: At the time of data cutoff, all patients had discontinued therapy. 11 of 14 evaluable patients discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia and prolonged neutropenia, each in 1/6 patients at DL2, and grade 3 febrile neutropenia in 1/6 patients at DL 1.5). Most common grade 3/4 toxicities were neutropenia (94%), white blood cell decrease (59%), lymphocyte decrease (29%), and febrile neutropenia (24%). Protocol was modified to allow administration of G-CSF and based on safety and PK data the RP2D was established as 1.5mg/Kg. Median number of doses received was 4.7. 13 subjects were able to undergo disease assessment after two cycles. The best response observed was stable disease (SD) in 5/9 evaluable patients with colorectal cancer. Minor CA-19-9 reductions were observed in two pancreatic cancer patients at DL 1.5. Correlative endpoints revealed that all patients enrolled in the trial expressed NEO-201 target antigen on their tumor tissue. 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 T regulatory cells and depleted these cells especially in patients with SD. Conclusions: NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg. Depletion of T regulatory cells suggests that the combination of NEO-201 with immune checkpoint inhibitor should be tested in future clinical trials. Clinical trial information: NCT03476681.