Safety, tolerability, and pharmacokinetics of the OX40 agonist ABBV-368 in patients with advanced solid tumors (2018)

Background: ABBV-368 is a novel humanized IgG1 agonist monoclonal antibody specific for human OX40, a TNF receptor superfamily member expressed on activated and memory T-cell subsets, as well as T regulatory cells. The proposed ABBV-368 therapeutic mechanism of action includes activation of T effector cells and inhibition of the suppressive capacity of T regulatory cells. This ongoing first-in-human, phase 1, two-part study (NCT03071757) is investigating the safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity of ABBV-368 in patients (pts) with advanced solid tumors. Methods: Eligible pts include adults (≥18 years) with advanced or metastatic solid tumors. ABBV-368 was administered intravenously in a 3 + 3 dose-escalation design at doses ranging from 0.01 to 3.0 mg/kg every 2 weeks (4 cohorts). PK was assessed in cycle 1 and cycle 3. OX40 receptor saturation, Ki67 proliferation marker expression in peripheral blood immune cell subsets, and additional PD biomarkers were evaluated. Results: As of Feb 12, 2018, 38 pts with advanced or metastatic tumors were enrolled in dose-escalation cohorts. Median age was 65 years (range, 38–78). No dose-limiting toxicities were reported during dose escalation. Overall, 15 (39.5%) pts reported grade (Gr) ≥3 treatment-emergent adverse events (TEAEs). Three (7.9%) pts reported Gr ≥ 3 TEAEs related to ABBV-368. Two investigator-reported immune-related AEs were documented, including hypothyroidism; neither were serious. ABBV-368 PK was approximately dose-proportional from 0.1- to 3-mg/kg doses during cycle 1, with dose-dependent target saturation. Initial antitumor activity has been observed. Updated safety, PK, PD, and efficacy data will be reported. Conclusions: ABBV-368 was well tolerated; a maximum tolerated dose was not reached. Antitumor activity was observed at doses predicted to be biologically active. Further evaluation of ABBV-368 is ongoing in pts with advanced solid tumors. Clinical trial identification: NCT03071757. Editorial acknowledgement: Medical writing support was provided by Mary L. Smith, PhD, CMPP, from TRM Oncology, Atlanta, GA, and funded by AbbVie. Legal entity responsible for the study: AbbVie Inc. Funding: AbbVie Inc. Disclosure: A. Spira: Consultant and Institutional research support: AbbVie. A. Patnaik: Research grants to institution: Merck & Co., Inc. LG; Advisory board member: Merck & Co., Inc., AstraZeneca, AbbVie, Pfizer, Genentech/Roche; Research grant: Bristol-Myers Squibb. A.W. Tolcher: Consultant: AbbVie. M.E. Blaney, A. Parikh, A. Reddy, W. Henner, M. McDevitt, D. Afar: Employee and may own stock: AbbVie. J. Powderly: Employee and leadership role: Carolina BioOncology Institute PLLC; Stock/ownership: Iovance, Juno, Bluebird Bio, Kite Pharma, ZioPharm; Speaker bureau: Genentech, Bristol-Myers Squibb, Merck; Research funding: AstraZeneca, Genentech, Clovis, Corvus, Incyte, AbbVie, Bristol-Myers Squibb, MacroGenics; Patent or intellectual property: Founder of BioCytics, developing T-cell immunotherapies. All other authors have declared no conflicts of interest.