A first-in-human Phase I, non-randomized, open-label, multi-center dose escalation trial of BI 765049 and BI 765049 + ezabenlimab administered by repeated intravenous infusions in patients with malignant solid tumors expressing B7-H6

Bl 754091 selectively binds to and blocks the activation of PD-1 , an immunoglobulin (lg) superfamily transmembrane protein, which is overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells (APCs). This results in the activation of T cells and T-cell-mediated immune responses against tumor cells. | Bl 765049 is a bispecific monoclonal antibody that binds B7 homolog 6 (B7-H6) and CD3 on T-cells.

• How much of the study agent(s) can be given with an acceptable level of side effects
• The effects of the study agent(s) (good and bad)
• How much of the study agent(s) is absorbed into the blood and how fast they are removed
• If research tests can be used in the future to predict who will benefit from the study agent(s)

One to four dosing regimens (Regimens A, B, C, and D) will be evaluated in this study.
• Regimen A – Study agent 1 given once every 3 weeks. This regimen is closed to further enrollment.
• Regimen B – Study agent 1 given once every week for about 6 weeks, then every 3 weeks thereafter
• Regimen C – Study agent 1 given in combination with study agent 2 once every week for about 6 weeks, then every 3 weeks thereafter
• Regimen D – Study agent 1 given once every week for about 6 weeks, then every 3 weeks thereafter.

All regimens will follow a dose escalation structure to begin. This means that the amount of the study agent given will be increased in each group of research participants to find the most appropriate dose for further study. Once the appropriate dose for further study is identified in the dose escalation phase of each regimen, additional participants will receive the study agent at that dose in what is called the dose expansion phase. The dose of the study agent you receive will be determined by when you enroll into the study and what regimen you are assigned to.

The study regimen will be given in cycles. Each cycle is 3 weeks. Once you complete 1 cycle, the amount of study agent you receive may be increased to a higher dose that has been determined to be safe.

Depending on the regimen you are assigned, the dose of the study agent may be calculated using your body weight (weight-based dose) or the dose may be pre-determined (fixed dose). Step-in doses (a dose of the study drug lower than the intended full dose) will be administered weekly to work up to the intended full dose (or target dose), which, once reached, will make up the full dose per study treatment cycle to be given thereafter. All participants will initially receive step-in doses of BI 765049 before receiving the target dose.

The following is additional information on the dosing schedule for each regimen:
• Regimen B: If you are assigned to Regimen B, you will receive study agent 1 once every week for about 6 weeks, then every 3 weeks thereafter via IV over a period of two hours.
• Regimen C: If you are assigned to Regimen C, you will receive study agent 1 via IV over a period of two hours, followed by a one-hour break, and then you will receive study agent 2 via IV over a period of one hour. For Regimen C, you will receive study agent 1 once every week for about 6 weeks, then once every 3 weeks thereafter and receive study agent 2 on Day 1 every 3 weeks.
• Regimen D: If you are assigned to Regimen D, you will receive study agent 1 via subcutaneous (SC) injection (with a needle beneath the skin) once every week for about 6 weeks, then once every 3 weeks thereafter.

Before you receive the study agent(s), you will be given pre-medications (an antihistamine and acetaminophen/paracetamol, and a steroid, as needed) 30-60 minutes before your infusion or SC injection to help with potential side effects.
This study involves hospitalization in Medical City Dallas. All participants will remain in the hospital for up to 24-72 hours after their first infusion or SC injection of study agent(s) on Cycle 1, Day 1 for safety observation. The following is additional information on the hospitalizations and observation periods for each regimen:
• Regimen B: If you are assigned to Regimen B, you will also remain in the hospital for 24 hours after your infusion of study agent on Cycle 1, Days 1, 8 and 15, and Cycle 4 Day 1. You will also have an 8 hour observation period in the clinic on Cycle 2 Day 1.
• Regimen C: If you are assigned to Regimen C, you will also remain in the hospital for 24 hours after your infusion of study agent on Cycle 1, Days 1, 8 and 15, Cycle 2, Day 1, and Cycle 4 Day 1.
• Regimen D: If you are assigned to Regimen D, you will also remain in the hospital for at least 72 hours after your SC injection of study agent on Cycle 1, Days 8 and 15. In addition during Cycle 2 Days 1 and 8 (if an extra step in dose is needed) and during Cycle 4 Day 1 you will also remain in the hospital for at least 24 hours after your SC injection of study agent.

Further hospitalization is optional at the discretion of your study doctor.