First-in-human phase 1 dose escalation study of HX009, a novel recombinant humanized anti-PD-1 and CD47 bispecific antibody, in patients with advanced malignancies.
Authors: Roohullah Aflah , Ganju Vinod , Zhang Faming , Zhang Lei , Yu Ting , Wilkinson Kate , Cooper Adam , de Souza Paul 
Published: June 2021

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Background: HX009 is a novel humanized antibody fusion protein which binds to CD47 and PD-1 concurrently. HX009 significantly inhibited tumor growth in mouse xenograft models. In Cynomolgus monkeys, the highest non-severely toxic dose in repeat dose testing was 15mg/kg. HX009-I-01 (ClinicalTrials.gov：NCT04097769) is a first-in-human study evaluating the safety and efficacy of HX009 in subjects with advanced malignancies. Here we report the preliminary results from this study. Methods: The study is being conducted in Australia at 3 sites. The study design follows a 3+3 dose-escalation scheme, enrolling cohorts of at least 3 subjects (except the first dose level) sequentially until MTD or the maximum dose is reached. HX009 is administered as single agent every 2 weeks via intravenous infusion. The 7 dose levels planned are: 0.1mg/kg (1 subject), 0.3mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 5mg/kg, 7.5mg/kg. All AEs are graded using NCI CTCAE v5.0. Efficacy assessments are per RECIST 1.1. Blood samples are obtained for pharmacokinetics (PK) and for immunogenicity assessments by the development of Antidrug Antibodies. Results: As of the January 22 2021 cutoff date, 21 patients (12M/9F) with a median age of 69.0 years (range 38-86) have received dose levels of 0.1-7.5 mg/kg. Patients with the following tumor types have been enrolled: colorectal cancer (7), squamous cell carcinoma (3), endometrial cancer (2), breast cancer (3), malignant epithelioid mesothelioma (1), gallbladder cancer (1), pancreatic cancer (1), glioblastoma(1), ovarian cancer (1), gastroesophageal junction adenocarcinoma (1). Patients had received a median of 3 (range 1-9) prior anti-cancer regimens. Treatment-related AEs have been reported in 10 (47.6%) patients to date. Most AEs are grade 1 or 2. The most frequent treatment-related AEs include nausea (n = 2, G1), rash (n = 2, G1), vomiting (n = 2, G1), and decreased appetite (n = 2, G1). Only 1 treatment-related SAE of pneumonitis. One treatment-related anemia (G2), and no thrombocytopenia. No DLT was observed in all 7 dose levels. Among 18 patients who have had at least one post-baseline tumor assessments, partial responses (PR) have been achieved in 3 patients with the following tumor types (dose level): gallbladder adenocarcinoma (1mg/kg), triple negative breast cancer (5mg/kg), metastatic squamous cell carcinoma of head and neck (5mg/kg). In addition, there are 6 patients with best overall response of stable disease. As of the data cutoff date, 6 patients are still receiving treatment. Updated clinical and PK results will be presented at the meeting. Conclusions: HX009, on an every 2 weeks dosing schedule, up to 7.5 mg/kg, is well-tolerated, without any DLT to date. Antitumor activity was seen at 1 mg/kg and 5 mg/kg cohorts with objective responses in multiple tumor types; Further investigation in phase Ib/II studies is warranted. Clinical trial information: NCT04097769.