Initial findings from a first-in-human, multicenter, open-label study of ATOR-1017, a 4-1BB antibody, in patients with advanced solid malignancies.
Authors: Ullenhag Gustav J. , Carneiro Ana , Enell Smith Karin , Schultz Lena , Ambarkhane Sumeet Vijay , Landstrom Tova , Yachnin Jeffrey 
Published: June 2022

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Background: ATOR-1017 is a human agonist Fcγ-receptor cross-linking dependent IgG4 antibody targeting the co-stimulatory receptor 4-1BB (CD137). ATOR-1017 activates T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell killing. Methods: In this first-in-human, dose escalation, multicenter, phase 1 study (NCT04144842), adult patients with solid tumors refractory to standard therapy were enrolled in single patient cohorts for doses up to 40 mg, and thereafter in cohorts of 3-6 patients, to receive ATOR-1017 in a 21-day cycle. Intra-patient dose escalation of ATOR-1017 is allowed depending on the occurrence of Dose-Limiting Toxicities (DLTs) during cycle 1. ATOR-1017 is administered intravenously as monotherapy every three weeks until unacceptable toxicity, progressive disease, or withdrawal of consent. The primary objectives of the study are to determine the maximum tolerated dose, assess adverse events (AEs), evaluate DLTs, and to determine the recommended phase 2 dose. Secondary objectives include pharmacokinetics (PK), immunogenicity, and clinical efficacy, assessed with CT scans using Immune Response Evaluation Criteria in Solid Tumors (iRECIST). Exploratory objectives include assessment of pharmacodynamic (PD) biomarkers. Results: 22 patients (18 females), median age 55 years (34-76) with solid tumors, previously treated with median of 4 (0-6) lines of chemotherapy and/or 2 (0-3) lines of immunotherapy, were included and received at least one cycle ATOR-1017. Nine dose levels have been evaluated; 0.38 mg, 1.5 mg, 5 mg, 15 mg; 40 mg, 100 mg, 200 mg, 360 mg, and 600 mg and dose escalation is ongoing. Treatment-related (TRAEs) were reported in 12 out of 22 patients (54.5%); most common (≥10%) were fatigue (13.6%) and neutropenia (13.6%). Five patients experienced a grade 3-4 TRAE; neutropenia (n = 2), febrile neutropenia (n = 1), chest pain (n = 1), increased liver enzymes (n = 1) and leukopenia/thrombocytopenia (n = 1). No patients discontinued due to TRAEs, no DLTs were observed, and the maximum tolerated dose has not been reached. The median time for patients in the study was 12 weeks (range 4-67). As per data cut-off, January 18, 2022, four patients remained on treatment and 18 patients had discontinued treatment. The reasons for discontinuation include confirmed disease progression (n = 10), clinical deterioration (n = 4), withdrawal of consent (n = 1), death due to disease progression (n = 3). Preliminary PK data showed dose-proportional kinetics. Dose-dependent increase in PD biomarkers demonstrated target-mediated biological activity and proof-of-mechanism. The best response was stable disease observed in a total of 10 patients (45%). Conclusions: ATOR-1017 is safe and well-tolerated at doses up to 600 mg and has shown biologic activity. No DLTs have been reported so far and dose escalation continues. Clinical trial information: NCT04144842.