A first-in-human, multicenter, open-label, phase 1 study of ATOR-1017, a 4-1BB antibody, in patients with advanced solid malignancies.

Abstract

2646 Background: ATOR-1017 is a human agonistic IgG4 antibody targeting the co-stimulatory receptor 4-1BB (CD137). It is developed to activate T cells and natural killer cells in the tumor environment, leading to immune-mediated tumor cell killing. This is a first-in-human, multicenter, phase 1 study (NCT04144842). Methods: In this study, ATOR-1017 is administered intravenously every 21 days as a single agent to patients with solid malignancies. ATOR-1017 is administered until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to determine the maximum tolerated dose, assessed by adverse events (AEs) and dose limiting toxicities (DLTs), and the recommended phase 2 dose. Secondary objectives include pharmacokinetics, immunogenicity and clinical efficacy, assessed with CT scans using response criteria for use in studies testing immunotherapeutics (iRECIST). The study uses a single cohort design for doses up to 40 mg, and thereafter a modified 3+3 design. Results: The first patient was dosed in December 2019; by 22 Jan 2021, twelve patients have been exposed to ATOR-1017. The following dose levels have been evaluated; 0.38 mg; 1.5 mg; 5 mg; 15 mg; 40 mg and 100 mg. Dose escalation is ongoing, and the 200 mg dose level is under evaluation. The maximum tolerated dose has not been reached. The following cancer types are included; ovarian cancer (n = 1), choroidal melanoma (n = 3), anal cancer (n = 1), cholangiocarcinoma (n = 1), gastrointestinal stromal tumor (n = 1), breast cancer (n = 1), pancreatic cancer (n = 1), adenoid cystic cancer (n = 1), malignant melanoma (n = 1), colorectal cancer (n = 1). Drug-related AEs were reported in 5 out of 12 patients; one patient experienced a grade 3, all others were grade 1 or 2. There have been two episodes each of chest pain (grades 2 and 3) and headache (grades 1 and 2). Single cases of pyrexia, upper abdominal pain, mouth ulceration, nausea, leukopenia, neutropenia, cytokine release syndrome (CRS), arthralgia, neck pain, and rash were also reported. No DLTs have been observed in the study to date. The median age of the patients were 48.5 years (range 34-76). Patients received a median of 2 prior lines of therapy (range 1-4). The median time on study were 15 weeks (range 0.14-51). Six patients are on study, and six patients have discontinued treatment. Reasons for discontinuation include; investigator decision (n = 1), confirmed disease progression (n = 1), withdrawal of consent (n = 1), death due to disease progression (n = 1) and other reason (n = 2). Preliminary PK data show dose-proportional kinetics up to 100 mg. Best response has been stable disease. Conclusions: ATOR-1017 is safe and well-tolerated up to 100 mg. Dose escalation continues and the current dose level is 200 mg. Clinical trial information: NCT04144842.

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

“…336 Dose escalation for ATOR-1017 is still ongoing with the best response of SD observed. 337 In summary, agonists targeting costimulatory receptors appear powerful candidates for future immunotherapy and a wave of new agonistic molecules has been developed many of which have entered clinical trials. However, agonist development is more difficult than the development of antagonists because more parameters have to be taken into account.…”

The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy

“…The available published data on clinical results is limited because most trials are ongoing. 38 , 39 , 41 , 45 , 47 , 50 , 52 , 54 , 57 , 104 As described above, hepatitis induction was the main challenge for first-generation 4–1BB agonist urelumab, a CRD1-binding IgG4 antibody. AGEN2373 is a IgG1 antibody binding to CRD4 in a non-4-1BBL competing manner.…”

“…Common adverse events (AEs) are mostly grade 1 and 2. 38 , 39 , 41 , 45 , 47 , 50 , 52 , 54 , 57 , 104 Some side effects, like pneumonitis, pruritus, rash or injection-related AEs, ALT/AST increase, hypothyroidism, diarrhea and colitis, are common during cancer immunotherapies and could be defined as common immune-related AEs (irAEs). 107 If these irAEs correlate with a better or a worse outcome is still not fully understood, but a first meta-study indicates that irAEs occurring during cancer immunotherapy correlate with better outcome shown as overall survival (OS) and progression-free survival (PFS).…”

“… 119 , 124 All this may play a role in the 4–1BB-mediated MoA as well as irAEs, and has to be carefully considered. One obvious irAE is neutropenia, which occurs with a rate of 4.9–17.6% 39 , 45 , 47 , 54 , 57 and may directly be linked with a 4–1BB MoA, as 4–1BB-activation on neutrophils has been reported to abrogate granulocyte-macrophage colony-stimulating factor-mediated neutrophil survival. 117 …”