Phase I study of CN201, a novel CD3xCD19 bispecific antibody, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.
Authors: Xie Yang , Cai Qingqing , Liu Haisheng , Guo Ye , Huang Wenrong , Zhang Mingzhi , Xia Yi , Gao Yuhuan , Chen Xilin , Tang Yongjing , Yin Shaoning , Yuan Shunzong , Li Haiying , Song Yuqin 
Published: June 2024

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Background: CN201 is a novel CD19-targeting T-cell-engager IgG4 bispecific antibody, designed to reduce cytokine release syndrome (CRS) while retaining potent T-cell mediated cytotoxicities. A silenced Fc fragment was used to prevent antibody-dependent cellular cytotoxicity while prolonging half-life of the molecule. Here, we report results of the phase I study of CN201 in patients with relapsed or refractory B-cell non-hodgkin lymphoma (R/R B-NHL) (ClinicalTrials.gov identifier: NCT06189391). Methods: The i3+3 dose-escalation design was used in adult patients with CD19+ R/R B-NHL to investigate safety, tolerability, maximum tolerated dose, and preliminary anti-tumor activity. Patients with R/R DLBCL who failed≧2 prior lines of therapy, or R/R indolent NHL(iNHL) who had at least 1 prior systemic therapy were eligible for enrollment. Patients received CAR-T therapy can be enrolled after 90 days washout periord provided that CD19 was still positive on tumor cells. Response were evaluated according to the Lugano 2014 criteria. Single-agent CN201 was administered intravenously once per week. Intial dose escalation was conducted in the patients at fixed ascending doses; later, a step-up dosing regimen was adopted, including a priming dose on cycle 1 Day 1 followed by an intermediate dose on Day 8 and the target dose administered on Day 15 and thereafter. Results: As of December 29, 2023, 58 adult patients received CN201, including 19 patients with fixed doses from 2.5μg to 600μg, 39 patients with step-up doses from 1.2mg to 40mg of the target doses. Maximum tolerated dose has not been reached. The most common treatment-related adverse effects (AEs) (≥20%) of any grade were white blood cell decreased (32%), neutropenia (30%), lymphopenia (29%), anemia (29%), pyrexia (25%) and platelet decreased (23%). The most common AEs (≥10%) of grade 3 or higher were lymphopenia (24%) and neutropenia (14%). CRS occurred in 4 (7%) patients, mainly occurred following the first dose. All of those CRS were low-grade, no ≥Grade 3. No immune effector cell-associated neurotoxicity syndrome was observed. In patients with fixed doses up to 600 μg and target dose up to 2.5mg, stable diseases (SD) were observed. The best overall responses dramatically improved in patients received full doses ≥ 5mg, ranging from 5 mg to 40 mg investigated so far. Among 22 evaluable patients with full doses ≥ 5mg, the objective response rate (ORR) was 77% and the complete remission (CR) rate was 22%. Among 11 patients with indolent B-NHL, the ORR was 91%, CR rate was 45.5%, including one patient had failed previous CAR-T therapy. The responses at higher doses are still under evaluation, and additional data will be reported. Conclusions: CN201 has a well tolerable safety profile and promising anti-tumor activity in patients with R/R B-NHL. Clinical trial information: NCT06189391 .