A Phase Ib Clinical Trial Investigating the Safety, Tolerability, and Pharmacokinetics of HX009，a Novel Bsab Dual Targeting PD-1 x CD47，in Patients with EBV+ Non-Hodgkin Lymphoma (NHL)

Background and Significance： HX009 is a first-in-class and rationally designed bispecific antibody (BsAb), targeting PD-1 and CD47 simultaneously, but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD-1 interaction, exerting anti-tumor effects with potentially lower toxicity. Preclinical data has demonstrated strong anti-lymphoma activity in various preclinical lymphoma models in vivo. The safety and pharmacokinetic properties of HX009 were evaluated in Phase I and Phase II study in patients with advanced solid tumors (NCT05731752, NCT04886271). HX009 was well tolerated up to 15mg/kg dose level. These preclinical and clinical experience support further clinical investigation in lymphoma indications. Study Design and Methods: This is a multi-center, open label, single-arm phase I/II study to evaluate the preliminary efficacy of HX009 single agent in patients with Relapsed/Refractory (R/R) lymphoma which includes a dose escalation phase (Phase Ia) and a dose expansion phase (Phase Ib) (NCT05189093). The Phase Ia has been completed without DLT up to 15 mg/kg dose level. Most common AEs (≥20%) were grade 1 and/or grade 2 anemia (42.9%), decreased white blood cell count (42.9%), decreased lymphocyte counts and platelet counts (28.6%), and elevated alkaline phosphatase (28.6%). The Phase Ib is ongoing in 4 parallel cohorts (DLBCL, PTCL, FL or MZL, and EBV+NHL) at dose level of 10 mg/kg, and HX009 was administered as a single agent every 2 weeks (Q2W) in 14-day cycles via intravenous infusion. Here we are reporting the preliminary result from EBV+ NHL cohort. Key eligibility criteria include patients must be r/r or intolerant to prior lymphoma therapies. Prior positive EBER-ISH test result is required. Patients who have received prior PD (L)-1 treatment are allowed while patients who have prior exposure to CD47 agents are excluded. All AEs are graded using NCI CTCAE version 5.0. Efficacy assessments are per Lugano 2014 criteria. Blood samples are obtained for pharmacokinetics (PK) and for immunogenicity assessments by the development of Antidrug Antibodies. Results: A total of 14 patients (6M/8F) with r/r EBV+ NHL have been treated in this cohort as of data cutoff date May 7, 2024. The most common treatment related AEs (≥20%) were fever (35.7%), decreased lymphocyte counts and platelet counts (28.6%), anemia, decreased neutrophil count, and white blood cell count (21.4%). The most common treatment-related AEs of grade 3 or higher (≥10%) were decreased neutrophil count (14.3%), decreased white blood cell count and lymphocyte counts (14.3%) and anemia (14.3%). Treatment-related SAE were anemia (14.3%) and infectious pneumonia (7.1%). There was no treatment-related death event. Among 13 patients who have had at least one post-baseline tumor assessments, partial responses (PR) have been achieved in 3 patients with the following lymphoma subtypes: PD-1 resistant DLBCL, PTCL, and a DLBCL transformed into PTCL. In addition, there are 4 patients with best overall response of stable disease (SD). As of the data cutoff date, 3 patients are still receiving treatment. Conclusions: In summary, HX009 single agent at 10mg/kg Q2W dose level is well tolerated with manageable safety profile, and anti-tumor activity has been demonstrated in treating patients with R/R EBV+ NHL. Further clinical investigation of HX009, either in single agent or in combination settings, is warranted.