A Study to Test Different Doses of BI 765049 Alone and in Combination With Ezabenlimab in Asian People With Advanced Cancer (Solid Tumours) Positive for B7-H6

Study Overview
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Brief Summary
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This is a study in adults from Asia with different types of advanced cancer (solid tumours). People can join the study if they have cancer of the stomach, large bowel and rectum, pancreas, liver, head and neck or non-small cell lung cancer. This is a study for people for whom previous treatment was not successful or no treatment exists. People can participate if their tumour has the B7-H6 marker. The purpose of this study is to find the highest dose of BI 765049 that people with advanced cancer can tolerate when taken (alone and) together with ezabenlimab. Another purpose is to check whether BI 765049 taken (alone and) together with ezabenlimab can make tumours shrink. Both medicines may help the immune system fight cancer. Participants can stay in the study up to 3 years, as long as they can tolerate it and can benefit from it. During this time, they visit the study site about every 3 weeks. At the study site they get BI 765049 alone or in combination with ezabenlimab as an infusion into a vein. BI 765049 is given in 3-week cycles, ezabenlimab is given once every 3 weeks. The doctors check the health of the participants and note any health problems that could have been caused by BI 765049 or ezabenlimab. Doctors regularly check the size of the tumour and check whether it has spread to other parts of the body.

Official Title
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Phase I, Non-randomised, Open-label, Multi-centre Dose Escalation and Expansion Trial of BI 765049 and BI 765049 + Ezabenlimab Administered by Repeated Intravenous Infusion in Asian Patients With Malignant Solid Tumours Expressing B7-H6

Conditions
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Gastrointestinal Cancer, Lung Cancer, Pancreatic Cancer, Colorectal Cancer, Head and Neck Cancer, Liver Cancer

Intervention / Treatment
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* Drug: BI 765049
* Drug: Ezabenlimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated, written inform consent form (ICF) (ICF1 for B7-H6 testing for all patients except those with colorectal cancer (CRC); ICF2 for all patients) describing the study in accordance with International Council on Harmonisation Good Clinical Practice (ICH-GCP) and local legislation prior to any trial-specific procedures, sampling, or analyses. ≥18 years of age at the time of signature on the ICFs (ICF1 and ICF2). Histologically or cytologically confirmed diagnosis of an advanced, unresectable, and/or metastatic gastrointestinal cancer, colorectal cancer, pancreatic cancer, liver cancer, head and neck cancer, or lung cancer. Disease progression despite conventional treatment, intolerant to or not a candidate for conventional treatment, or with a tumour for which no conventional treatment exists. Agree to the collection of tumour samples (as slides from archival diagnostic samples or fresh tumour biopsies) for confirmation of B7-H6 expression at Screening Visit 02 for colorectal cancer (CRC) patients or at Screening Visit 01 for all other patients. Confirmed B7-H6 expression on tumour tissue sample (archived or fresh tumour biopsy) based on central pathology review except for patients diagnosed with advanced or metastatic colorectal cancer (CRC). Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. At least one evaluable target lesion as defined per response evaluation criteria in solid tumors (RECIST v1.1), outside of the central nervous system (CNS), separate from any lesion(s) identified for tumour biopsy. Tumour lesions that have been irradiated ≥28 days before the start of treatment, and have subsequently had documented progression, may be chosen as target lesions only in the absence of measurable lesions that have not been irradiated. Further inclusion criteria apply Exclusion Criteria: History of a major surgery within 28 days prior to first dose of BI 765049 (major according to the Investigator's assessment). Presence of other active invasive cancers other than the one treated in this trial within 3 years prior to screening, except for appropriately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix, or other local tumours considered cured by local treatment. Known leptomeningeal disease or spinal cord compression due to disease. Require anticoagulant treatment which cannot be safely interrupted, if medically needed for a study procedure (e.g., biopsy) based on the opinion of the Investigator. Any of the following laboratory evidence of hepatitis virus infection. Test results obtained in routine diagnostics are acceptable for screening if done within 14 days before the ICF2 date: positive results of hepatitis B surface (HBs) antigen, presence of hepatitis B core (HBc) antibody together with hepatitis B virus (HBV)-DNA and presence of hepatitis C-RNA Infection requiring systemic antimicrobial, antiviral, antiparasitic, or antifungal therapy at the start of treatment in the trial unless otherwise stipulated. Patients with history of human immunodeficiency virus (HIV) infection who meet one or more of the following criteria: cluster of differentiation 4 (CD4)+ count <350 cells/μL, viral load >400 copies/μL, not receiving antiretroviral therapy, receiving established antiretroviral therapy for less than four weeks prior to the start of study treatment, and history of AIDS-defining opportunistic infections within 12 months prior to start of study treatment. Patients with a history of HIV who do not meet any of the criteria above are eligible to participate, but the patient must be under the care of a HIV/Infectious Diseases specialist, or a HIV/Infectious Diseases specialist must be consulted prior to inclusion. Previous treatment history: previous treatment in this trial or another trial with a B7-H6 targeting agent, treatment with a systemic anti-cancer therapy or investigational drug within 21 days or 5 half-lives (whichever is shorter) of the first administration of BI 765049, and treatment with extensive field radiotherapy including whole brain irradiation within14 days prior to first administration of BI 765049. Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The trial is divided in four parts. Part I and Part III will have a sequential assignment while Part II and Part IV will have a parallel assignment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: BI 765049<br>BI 765049 monotherapy - dose escalation | Drug: BI 765049<br>* BI 765049<br>|
| Experimental: Part II: BI 765049<br>BI 765049 monotherapy - dose expansion | Drug: BI 765049<br>* BI 765049<br>|
| Experimental: Part III: BI 765049 + ezabenlimab<br>BI 765049 + ezabenlimab combination therapy - dose escalation | Drug: BI 765049<br>* BI 765049<br>Drug: Ezabenlimab<br>* Ezabenlimab<br>* Other names: BI 754091;|
| Experimental: Part IV: BI 765049 + ezabenlimab<br>BI 765049 + ezabenlimab combination therapy - dose expansion | Drug: BI 765049<br>* BI 765049<br>Drug: Ezabenlimab<br>* Ezabenlimab<br>* Other names: BI 754091;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Occurrence of dose-limiting toxicity (DLTs) during the maximum tolerated dose (MTD) evaluation period for BI 765049 monotherapy |  | One treatment cycle, defined as 3 weeks after first administration of BI 765049 or 1 week after the administration of first full dose of BI 765049, whichever is longer | 
| Part II: Objective response based on the response evaluation criteria in solid tumors (RECIST v1.1) | Objective response will be determined by the Investigator in patients with measurable disease and will be defined as the best overall response of complete response (CR) or partial response (PR), from the first administration of trial medication until the earliest of progressive disease (PD), death, last evaluable tumour assessment before the start of subsequent anti-cancer therapy, lost to follow-up, or withdrawal of consent. | Up to month 36 | 
| Part III: Occurrence of dose-limiting toxicity (DLTs) during the maximum tolerated dose (MTD) evaluation period for BI 765049 in combination with ezabenlimab |  | From first BI 765049 administration to 1 week after the first ezabenlimab dose | 
| Part IV: Objective response based on the response evaluation criteria in solid tumors (RECIST v1.1) |  | Up to month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I: Maximum measured concentration of BI 765049 (Cmax) after first administration |  | Up to 1 day | 
| Part I: Maximum measured concentration of BI 765049 (Cmax) after multiple administrations |  | Up to month 37 | 
| Part III: Maximum measured concentration of BI 765049 (Cmax) after the first administration |  | Up to 1 day | 
| Part III: Maximum measured concentration of BI 765049 (Cmax) after multiple administrations |  | Up to month 37 | 
| Part I: Area under the concentration-time curve of BI 765049 over a uniform dosing interval τ (AUCτ) after the first administration |  | Up to 1 day | 
| Part I: Area under the concentration-time curve of BI 765049 over a uniform dosing interval τ (AUCτ) after multiple administrations |  | Up to month 37 | 
| Part III: Area under the concentration-time curve of BI 765049 over a uniform dosing interval τ (AUCτ) after the first administration |  | Up to 1 day | 
| Part III: Area under the concentration-time curve of BI 765049 over a uniform dosing interval τ (AUCτ) after multiple administrations |  | Up to month 37 | 
| Part I: Objective response based on the response evaluation criteria in solid tumors (RECIST v1.1) | Objective response will be determined by the Investigator in patients with measurable disease who have been treated with either BI 765049 monotherapy or BI 765049 in combination with ezabenlimab and will be defined as the best overall response of complete response (CR) or partial response (PR), according to response evaluation criteria in solid tumors (RECIST v1.1). from the first administration of trial medication until the earliest of progressive disease (PD), death, or last evaluable tumour assessment before the start of subsequent anti-cancer therapy, lost to follow-up, or withdrawal of consent. | Up to month 36 | 
| Part III: Objective response based on the response evaluation criteria in solid tumors (RECIST v1.1) |  | Up to month 36 | 
| Part II: Progression free survival (PFS) | Progression free survival (PFS) will be defined as the time from first treatment administration until tumour progression according to response evaluation criteria in solid tumors (RECIST v1.1) as determined by the Investigator or death from any cause, whichever occurs earlier. | Up to month 36 | 
| Part IV: Progression free survival (PFS) |  | Up to month 36 | 
| Part II: Duration of response | Duration of response will be defined as the time from a patient's first documented complete response (CR) or partial response (PR), according to response evaluation criteria in solid tumors (RECIST v1.1), until the earliest of disease progression, or death. | Up to month 36 | 
| Part IV: Duration of response |  | Up to month 36 | 
| Part II: Disease control | Disease control will be defined as best overall response of complete response (CR), partial response (PR) or stable disease (SD) where best overall response is as determined by the Investigator according to response evaluation criteria in solid tumors (RECIST v1.1) from the first administration of trial medication until the earliest of progression disease (PD), death, or last evaluable tumour assessment before start of subsequent anti-cancer therapy, lost to follow-up, or withdrawal of consent. | Up to month 36 | 
| Part IV: Disease control |  | Up to month 36 | 
| Part II: Objective response based on the immune response evaluation criteria in solid tumors (iRECIST) | Objective response based on immune response evaluation criteria in solid tumors (iRECIST) criteria will be determined by the Investigator in patients with measurable disease and will be defined as the best overall response of complete response (CR) or partial response (PR), from the first administration of trial medication until the earliest of immune confirmed progressive disease (PD), death, or last evaluable tumour assessment before start of subsequent anti-cancer therapy, lost to follow-up, or withdrawal of consent. | Up to month 36 | 
| Part IV: Objective response based on the immune response evaluation criteria in solid tumors (iRECIST) |  | Up to month 36 | 
| Part II: Maximum measured concentration of BI 765049 (Cmax) after first administration |  | Up to 1 day | 
| Part II: Maximum measured concentration of BI 765049 (Cmax) after multiple administrations |  | Up to month 37 | 
| Part IV: Maximum measured concentration of BI 765049 (Cmax) after first administration |  | Up to 1 day | 
| Part IV: Maximum measured concentration of BI 765049 (Cmax) after multiple administrations |  | Up to month 37 | 
| Part II: Area under the concentration-time curve of BI 765049 over a uniform dosing interval τ (AUCτ) after first administration |  | Up to 1 day | 
| Part II: Area under the concentration-time curve of BI 765049 over a uniform dosing interval τ (AUCτ) after multiple administrations |  | Up to month 37 | 
| Part IV: Area under the concentration-time curve of BI 765049 over a uniform dosing interval τ (AUCτ) after first administration |  | Up to 1 day | 
| Part IV: Area under the concentration-time curve of BI 765049 over a uniform dosing interval τ (AUCτ) after multiple administrations |  | Up to month 37 |