A Study to Test How Well Different Doses of BI 764532 in Combination With Ezabenlimab Are Tolerated by People With Small Cell Lung Cancer and Other Neuroendocrine Tumours That Are Positive for DLL3

Study Overview
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Brief Summary
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This study is open to adults with small cell lung cancer and other neuroendocrine tumours that are positive for the tumour marker Delta-like 3 (DLL3). The study is in people with advanced cancer for whom previous treatment was not successful or no standard treatment exists. The purpose of this study is to find out the highest dose of BI 764532 that people can tolerate when taken together with another medicine called ezabenlimab. BI 764532 and ezabenlimab are antibodies that may help the immune system fight cancer. Participants get BI 764532 and ezabenlimab as infusions into a vein. If there is benefit for the participants and if they can tolerate it, the treatment is given for a maximum of 3 years. During this time, participants visit the study site about every week. The visits also depend on the response to the treatment. At the study visits, the doctors check the health of the participants, take necessary laboratory tests, and note any health problems that could have been caused by the study treatment.

Official Title
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A Phase I, Non-randomized, Open-label, Multi-center Dose Escalation Trial of BI 764532 Combined With Ezabenlimab in Patients With Small Cell Lung Carcinoma and Other Neuroendocrine Neoplasms Expressing DLL3

Conditions
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Small Cell Lung Carcinoma (SCLC), Neuroendocrine Neoplasms

Intervention / Treatment
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* Drug: BI 764532
* Drug: Ezabenlimab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age ≥18 years Signed and dated, written informed consent form (main ICF) in accordance with ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or analyses. Diagnosed with locally advanced, metastatic or relapsed cancer not amenable to curative treatment of the following histologies: Small cell lung carcinoma (SCLC) Large cells neuroendocrine lung carcinoma(LCNEC) Neuroendocrine carcinoma (NEC) or small cell carcinoma of any other origin Tumours must be positive for Delta-like 3 (DLL3) expression (on archived tissue) according to central pathology review in order to start BI 764532 . Patients with tumors with mixed histologies for any above type are eligible only if neuroendocrine carcinoma/small tumor cells component is predominant and represent at least 50% of the overall tumor tissue. Patient who failed conventional treatment or for whom no therapy of proven efficacy exists or who is not eligible for established treatment options. Patient must have exhausted available treatment options known to prolong survival for their disease. Previous therapies should include at least one line of platinum-based chemotherapy. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. At least one evaluable lesion outside of Central Nervous System (CNS) as defined per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Subjects with brain metastases are eligible provided they meet the following criteria: radiotherapy or surgery for brain metastases was completed at least 2 weeks or 4 weeks respectively, prior to the first administration of BI 764532 patient is off steroids for at least 7 days (physiologic doses of steroids are permitted), and the patient is off anti-epileptic drugs for at least 7 days or on stable doses of anti-epileptic drugs for malignant CNS disease. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly.These methods must be used during the study and for at least 3 months after the last dose of BI 764532. A list of contraception methods meeting these criteria is provided in the patient information. Further inclusion criteria apply. Exclusion criteria Previous treatment with T-cell-engager (TcE) or cell therapies targeting DLL3. Other DLL3 targeting agents (like RovaT) are allowed only if DLL3 positivity is documented after completion of treatment with DLL3 targeting agent in post-treatment biopsy. Previous or concomitant malignancies other than the one treated in this trial within the last 2 years except: effectively treated non-melanoma skin cancers effectively treated carcinoma in situ of the cervix effectively treated ductal carcinoma in situ other effectively treated malignancy that is considered cured by local treatment Major injuries and/or surgery or bone fracture within 28 days of first dose BI 764532, or planned surgical procedures Known leptomeningeal disease or spinal cord compression due to metastatic disease Anticoagulant treatment that cannot be safely interrupted based on opinion of the investigator if medically needed Active infection that requires medical therapy or other clinically significant intervention Severe acute respiratory syndrome coronavirus 2 (SARS COV2) infection within 2 weeks prior to study entry (confirmed via Polymerase chain reaction (PCR) test or other applicable test as per local requirements) or suspected SARS-CoV-2 infection as per physician assessment, or close contact (within 1 week) with an individual with confirmed SARS-CoV-2 infection Any of the following known laboratory evidence of hepatitis virus infection: Positive results of hepatitis B surface (HBs) antigen Presence of hepatitis B core (HBc) antibody together with hepatitis B virus (HBV)-Deoxyribonucleic Acid (DNA) Presence of hepatitis C Ribonucleic acid (RNA) 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 764532 + ezabenlimab treatment group<br>Successive cohorts of patients will receive increasing doses of BI 764532 in combination with ezabenlimab until the maximum tolerated dose (MTD) is reached, or upon decision of Dose Escalation Committee (DEC). | Drug: BI 764532<br>* BI 764532<br>Drug: Ezabenlimab<br>* Ezabenlimab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) evaluation period |  | up to 17 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of DLTs during the on-treatment period |  | up to 17 months | 
| Objective response, defined as best overall response of complete response (CR) or partial response (PR) | Objective response, defined as best overall response of complete response (CR) or partial response (PR), where best overall response is determined by the investigator's assessment according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in patients with measurable disease from date of first treatment administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up or withdrawal of consent | up to 17 months | 
| Cmax (maximum measured concentration of BI 764532) |  | up to 17 months | 
| Cmax (maximum measured concentration of ezabenlimab) |  | up to 17 months | 
| AUCτ (area under the concentration-time curve of BI 764532 over a uniform dosing interval τ) |  | up to 17 months | 
| AUCτ (area under the concentration-time curve of ezabenlimab) over a uniform dosing interval τ) |  | up to 17 months |