Background/Purpose Activation of the stimulator of interferon genes (STING) pathway in intratumoral immune cells leads to increased type I interferon production, promoting recruitment and priming of T-cells against tumor antigens and triggering anti-tumor activity. In patients with cancer, STING agonists have shown clinical activity, with effects increased when combined with an anti-programmed cell death [PD]-1 antibody. BI 1387446 potently and highly selectively activates the STING pathway; ezabenlimab (BI 754091) is a humanized IgG4 anti-PD-1 monoclonal antibody. Tumor regression and enhanced activity of anti-PD-1 therapy was observed after BI 1387446 administration in syngeneic tumor models.

Methods NCT04147234 is a first-in-human, Phase I, open-label, multicenter trial of BI 1387446 recruiting a planned 122 patients from six sites across Europe and the USA. Patients will have advanced, unresectable and/or metastatic solid tumors. The main objectives are to characterize safety and determine the maximum tolerated dose (MTD) of BI 1387446 alone and in combination with ezabenlimab. BI 1387446 will be administered intratumorally at escalating doses as monotherapy in Arm A (~34 patients), and + ezabenlimab (240 mg every 3 weeks, IV) in Arm B (~44 patients); BI 1387446 will be administered in superficial lesions in both Arms. In a potential Arm C (~44 patients), BI 1387446 will be administered in deep/visceral lesions + ezabenlimab, IV. Arm B will open at the starting dose level once the starting dose level in Arm A is considered safe by the safety monitoring committee; Arm C may open at the starting dose level once this dose level is considered safe in Arm B. Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control.

Patients (≥18 years of age) must have exhausted standard treatment options, have ≥1 tumor lesion suitable for injection, ≥1 additional tumor lesion amenable to biopsy, and ECOG performance status ≤1. Treatment will continue until progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum of 34 cycles (for cycles 19–34, only patients with partial response will receive BI 1387446), whichever occurs first.

Primary endpoints are the MTD based on number of dose-limiting toxicities (DLTs) and number of patients with DLTs. Secondary endpoints are objective response rate (based on RECIST 1.1 criteria) and best change from baseline in size of target and injected (and uninjected) lesions. Plasma, blood, and tumor tissue will be collected at baseline and on-therapy for pharmacodynamic analyses.

The trial is actively recruiting, and eight patients have been treated as of December 2020.

Citation Format: Kevin Harrington, Eileen Parkes, Jared Weiss, Mathew Ingham, Andrés Cervantes, Emiliano Calvo, Ute Klinkhardt, Patricia Sikken, Michael Schmohl, Elena Garralda. Phase I, first-in-human trial evaluating BI 1387446 (STING agonist) alone and in combination with ezabenlimab (BI 754091; anti-PD-1) in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT217.