A Study to Find the Best Dose of BI 1387446 Alone or in Combination With Ezabenlimab (BI 754091) in Patients With Different Types of Advanced or Metastatic Cancer (Solid Tumors)

The MTD in each arm is defined as the highest dose that is expected to cause less than 25% risk of the true DLT rate being above or equal to 33% during the MTD evaluation period. Estimation of the MTD will be based upon the estimation of the posterior probability of the incidence of DLT in toxicity categories during the MTD evaluation period for all evaluable participants. The MTD evaluation period is defined as the time from the first administration of any trial medication to the start of the second treatment cycle. Specifically, this is the time from the first dose to either the second administration of ezabenlimab or the fourth administration of BI 1387446, whichever occurs first. If the second dose of ezabenlimab or the fourth dose of BI 1387446 is not given, the evaluation period ends 90 days after the last administration.

Time frame: From first administration of BI 1387446 until to end of treatment cycle 1 (up to 3 weeks).

Population: The MTD set includes all treated participants evaluable per the clinical trial protocol. This covers those completing required BI 1387446 (and ezabenlimab in Arm B) doses in Cycle 1 and undergoing the Echo/MUGA scan at Cycle 2 Visit 1. Patients stopping due to dose-limiting toxicities are still evaluable. Crossover participants from Arm A to B are included only if evaluable in Arm A. Replaced participants during MTD evaluation are excluded.

The MTD evaluation period is defined as the time from the first administration of any trial medication to the start of the second treatment cycle. Specifically, this is the time from the first dose to either the second administration of ezabenlimab or the fourth administration of BI 1387446, whichever occurs first. If the second dose of ezabenlimab or the fourth dose of BI 1387446 is not given, the evaluation period ends 90 days after the last administration.

Time frame: From first administration of BI 1387446 until to end of treatment cycle 1 (up to 3 weeks).

Population: The MTD set includes all treated participants evaluable per the clinical trial protocol. This covers those completing required BI 1387446 (and ezabenlimab in Arm B) doses in Cycle 1 and undergoing the Echo/MUGA scan at Cycle 2 Visit 1. Patients stopping due to dose-limiting toxicities are still evaluable. Crossover participants from Arm A to B are included only if evaluable in Arm A. Replaced participants during MTD evaluation are excluded.

This endpoint evaluated the best percentage change (i.e., greatest reduction) in the size of injected lesions from baseline (the first measurement at the start of treatment) over time. The best percentage change from baseline in the size of injected lesions was analyzed using descriptive statistics. All lesion measurements recorded from the start of trial treatment until the earliest of the following were considered: disease progression (assessed under CTP v1 and v2 using RECIST 1.1), initiation of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent. Cross-over patients appear in both Arm A (initial treatment) and Arm B (post-crossover treatment). Their best overall response is counted, regardless of timing. Negative values indicate a reduction in injected lesion diameters; positive values indicate an increase.

Time frame: From start of treatment up to the earliest of progression, death or end of trial (approximately 1 year).

Population: Treated Set (TS): This set included all participants who received at least one dose of study medication and had both a baseline and at least one post-baseline tumor assessment. Data for this endpoint was collected and evaluated only for participants enrolled under CTP versions 1 and 2 using RECIST 1.1. In these versions, injection of target lesions was not permitted; therefore, injected lesions were collected and assessed separately from target lesions.

This endpoint evaluated the best percentage change (i.e., greatest reduction) in the size of injected target lesions from baseline (the first measurement at the start of treatment) over time. The best percentage change from baseline in the size of injected target lesions was analyzed using descriptive statistics. All lesion measurements recorded from the start of trial treatment until the earliest of the following were considered: disease progression (assessed under CTP version 3 and later using itRECIST), initiation of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent. Negative values indicate reduced lesion diameters; positive values indicate increases. Cross-over patients are included in Arm A (initial treatment) and Arm B (first post-crossover treatment), with their best response counted regardless of timing.

Time frame: From start of treatment up to the earliest of progression, death or end of trial (approximately 1 year).

Population: Treated Set (TS): This set included all participants who received at least one dose of any study medication. Only participants with both a baseline and at least one post-baseline tumor assessment were included in the analysis. Due to a protocol amendment, disease progression for participants consented under CTP version 1 and 2 was assessed using RECIST1.1 and therefore excluded from this endpoint. As a result, the number of participants analyzed is lower than the total number in the treated set.

This endpoint evaluated the best percentage change (i.e., greatest reduction) in the size of non-injected target lesions from baseline (the first measurement at the start of treatment) over time. The best percentage change from baseline in the size of non-injected target lesions was analyzed using descriptive statistics. All lesion measurements recorded from the start of trial treatment until the earliest of the following were considered: disease progression (assessed under CTP version 3 and later using itRECIST), initiation of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent.

Time frame: From start of treatment until the earliest of progression, death or end of trial (approximately 1 year).

Population: Treated Set (TS): This set included all participants who received at least one dose of study medication and had both a baseline and at least one post-baseline tumor assessment. Data for this endpoint was collected and evaluated only for participants enrolled under CTP version 3 and later using itRECIST, as these protocol versions allowed injection of target lesions.

This endpoint evaluated the best percentage change (i.e., greatest reduction) in the size of target lesions from baseline (the first measurement at the start of treatment) over time. The best percentage change from baseline in the size of target lesions was analyzed using descriptive statistics. All lesion measurements recorded from the start of trial treatment until the earliest of the following were considered: disease progression (assessed under CTP v1 and v2 using RECIST 1.1), initiation of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent. Cross-over patients appear in both Arm A (initial treatment) and Arm B (post-crossover treatment). Their best overall response is counted, regardless of timing. Negative values indicate a reduction in lesion diameters; positive values indicate an increase.

Time frame: From start of treatment until the earliest of progression, death or end of trial (approximately 1 year).

Population: Treated Set (TS): This set included all participants who received at least one dose of any study medication. Only participants with both a baseline and at least one post-baseline tumor assessment were included in the analysis. Due to a protocol amendment, disease progression for participants consented under CTP version ≥ 3 was assessed using itRECIST and therefore excluded from this endpoint. As a result, the number of participants analyzed is lower than the total number in the treated set.

Objective Response based on Response Criteria for Intratumoural Immunotherapy in Solid Tumours (itRECIST): (CTP version 3 and later) Objective response (OR) by itRECIST will be presented in terms of objective response rate (ORR), which is defined as the rate of patients whose best overall response is confirmed itCR or itPR as determined by the Investigator's assessment according to itRECIST from date of first treatment administration until the earliest of confirmed disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up or withdrawal of consent. Cross-over patients are shown in both Arm A (reflecting their initial treatment) and Arm B (reflecting their first treatment post-crossover). Their best overall response is counted, regardless of whether it occurred before or after the crossover.

Time frame: From start of treatment up to the earliest of progression, death or end of trial (approximately 1 year).

Population: Treated Set (TS): This set included all participants who received at least one dose of any study medication.~Due to a protocol amendment, only participants who consented under CTP version ≥ 3 were analyzed for this endpoint. Participants enrolled under CTP versions 1 and 2 were assessed using RECIST 1.1 and therefore excluded. As a result, the number of participants analyzed for this endpoint is lower than the total in the treated set.

Objective response, as defined by the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1), in accordance with Clinical Trial Protocol (CTP) Version 1 and 2, will be presented in terms of the objective response rate (ORR). The ORR is the proportion of patients whose best overall response is a confirmed complete response (CR) or partial response (PR). This determination is based on the investigator's assessment according to RECIST 1.1 criteria, from the date of the first treatment administration until the earliest occurrence of any of the following events: disease progression, death, the last evaluable tumor assessment before the initiation of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent. Cross-over patients are shown in both Arm A (reflecting their initial treatment) and Arm B (reflecting their first treatment post-crossover). Their best overall response is counted, regardless of whether it occurred before or after the crossover.

Time frame: From start of treatment up to the earliest of progression, death or end of trial (up to 1 year).

Population: Treated Set (TS): This set included all participants who received at least one dose of any study medication.~Due to a protocol amendment, only participants who consented under CTP versions 1 and 2 were analyzed for this endpoint. Participants enrolled under CTP version ≥ 3 were assessed using itRECIST and therefore excluded. As a result, the number of participants analyzed for this endpoint is lower than the total in the treated set.