This Study Tests the New Medicine BI 754111 Alone or in Combination With Another New Substance BI 754091 in Patients With Advanced Cancer. The Study Tests Different Doses to Find the Best Dose for Continuous Treatment.

Study Overview
=================
Brief Summary
-----------------
This is a study in adults with advanced solid tumors including non-small cell lung cancer. The study tests the combination of two medicines called BI 754111 and BI 754091 that may help the immune system to fight the cancer. Such medicines are called immune checkpoint inhibitors. The study has two parts. In the first part, doctors want to find out the highest dose of 2 medicines that people with solid tumors can tolerate. This dose is then used for the second part of the study. In the second part, the combination of the two medicines is tested in patients with non-small cell lung cancer and other types of solid cancer. These patients had gotten treatment with anti-PD-1 or anti-PD-L1 medicines but their tumors have come back. The doctors check whether the combination of BI 754111 and BI 754091 makes tumors shrink. Both medicines are given as an infusion into the vein every 3 weeks. If there is benefit for the patients and if they can tolerate it, the treatment is given for maximum of 1 year. During the entire study doctors will regularly check the health of the patients.

Official Title
-----------------
An Open Label, Phase I Dose-finding Study of BI 754111 in Combination With BI 754091 in Patients With Advanced Solid Cancers Followed by Expansion Cohorts at the Selected Dose of the Combination in Patients With Non-small Cell Lung Cancer and Other Solid Tumors

Conditions
-----------------
Neoplasms, Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
-----------------
* Drug: BI 754111
* Drug: BI 754091


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of signed and dated, written Informed consent form (ICF) prior to any trial-specific procedures, sampling, or analyses Patients ≥18 years of age at the time of signature of the ICF Part I (dose escalation): --Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic solid tumours (any type) For whom no therapy of proven efficacy exists, or who are not amenable to standard therapies. Must have measurable lesions according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 Previous treatment with an anti-programmed cell death 1 (receptor) (PD-1) monoclonal antibody (mAb) is allowed as long as the last administration of the anti-PD-1 mAb on the previous treatment is a minimum of 60 days prior to starting treatment in this trial. Part II (dose expansion): Patients must have measurable disease per RECIST v1.1 criteria, must have at least 1 tumour lesion amenable to biopsy, and must be medically fit and willing to undergo a biopsy before first treatment (if adequate archival tissue is not available) and, unless clinically contraindicated, after 6 weeks on therapy. Dose Expansion Cohorts: Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic solid tumours of one of the following types: Second and 3rd line Non-small cell lung cancer (NSCLC) patients: Must have progressed on anti-PD-1 or anti-programmed cell death ligand 1 (PD-L1) treatment after having achieved radiologically confirmed benefit (minimum of stable disease) Must have had a minimum duration of benefit of 4 months and minimum treatment duration of 2 months on the previous anti- PD-1 or anti-PD-L1 treatment without experiencing disease progression during that period. The anti-PD-1- or anti-PD-L1-containing treatment must have been the latest treatment regimen prior to enrolling in this trial Must be within >4 and <12 weeks since the latest treatment and their first dose in this trial. Patients who have had anti-PD-1 or anti-PD-L1 monotherapy as their first-line NSCLC treatment regimen must have a PD-L1 expression level of ≥1% at baseline (local validated testing). Anti-PD-1 or anti-PD-L1 treatment-naïve patients with microsatellite stable Metastatic colorectal Cancer (mCRC): Patients must have had ≥ 1 line treatment Must have microsatellite stable disease (identified using any validated test) Must be anti-PD-1 and anti-PD-L1 treatment naïve Anti-PD-1 or anti-PD-L1 pretreated patients with any high Tumour mutational burden (TMB) (≥10 mutations/Mb) and/or Microsatellite instability high (MSI-H) and/or DNA MMRd solid tumours Patients must have high TMB (≥ 10 mutations/Mb) and/or MSI-H and/or DNA mismatch repair deficient (MMRd) (measured using any validated test). Patients must have received 1 prior anti-PD-1 or anti-PD-L1 treatment regimen. 1st-line squamous or non-squamous NSCLC patients: Patients must be treatment naïve Must be epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild type (only applicable to patients with non-squamous NSCLC) Regardless of PD-L1 expression level. However, the number of patients with high level of PD-L1 expression (≥50% PD-L1) will be limited to a maximum of 10 patients Eastern Cooperative Oncology Group (ECOG, R01-0787) score: 0 to 1 Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement Male or female patients. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control (that result in a low failure rate of less than 1% per year when used consistently and correctly) during trial participation and for at least 6 months after the last administration of trial medication. A list of contraception methods meeting these criteria is provided in the patient information. Exclusion Criteria: Major surgery (major according to the Investigator's assessment) performed within 12 weeks prior to first trial treatment or planned within 12 months after screening, e.g., hip replacement Patients who must or wish to continue the intake of restricted medications (see Section 4.2.2.2) or any drug considered likely to interfere with the safe conduct of the trial Previous enrolment in this trial Any investigational or anti-tumour treatment, except BI 754091, within 4 weeks or within 5 half-life periods (whichever is shorter) prior to the initiation of trial treatment. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 neuropathy due to prior platinum-based therapy Prior treatment with anti-Lymphocyte-activation gene 3 (LAG-3) agents Patients with NSCLC that has EGFR mutations or ALK rearrangements (only applicable to patients with non-squamous NSCLC). Presence of other active invasive cancers other than the one treated in this trial within 5 years prior to screening, with the exception of appropriately treated basal-cell carcinoma of the skin, in situ carcinoma of the uterine cervix, or other local tumours considered cured by local treatment Untreated brain metastasis(es) that may be considered active. Patients with previously treated brain metastases may participate provided they are stable (i.e., without evidence of PD by imaging for at least 4 weeks prior to the first dose of trial treatment, and any neurologic symptoms have returned to baseline), and there is no evidence of new or enlarging brain metastases. Inadequate organ function or bone marrow reserve as demonstrated by the laboratory values presented in Table 3.3.3: 1. Any of the following cardiac criteria: Mean resting corrected QT interval (QTc) >470 msec Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval Patients with an ejection fraction (EF) <55% or the lower limit of normal of the institutional standard will be excluded. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition scan). A historic measurement of EF no older than 6 months prior to first administration of study drug can be accepted provided that there is clinical evidence that the EF value has not worsened since this measurement in the opinion of the Investigator or of the treating physician or both. History of pneumonitis within the last 5 years History of severe hypersensitivity reactions to other mAbs Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of study treatment. Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal therapy) at start of treatment in this trial Known history of human immunodeficiency virus infection or an active hepatitis B or C virus infection Interstitial lung disease Chronic alcohol or drug abuse or any condition that, in the Investigator's opinion, makes him/her an unreliable trial subject, unlikely to complete the trial, or unable to comply with the protocol procedures.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I - Dose--Escalation<br> | Drug: BI 754111<br>* Day 1 of 3 week cycle<br>Drug: BI 754091<br>* Day 1 of 3 week cycle<br>|
| Experimental: Part II - Dose-Expansion<br> | Drug: BI 754111<br>* Day 1 of 3 week cycle<br>Drug: BI 754091<br>* Day 1 of 3 week cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I - Maximum-tolerated dose (MTD) of the BI 754111 plus BI 754091 combination |  | Up to 3 weeks | 
| Part I - Number of patients experiencing Dose-limiting toxicity (DLTs) during the combination Maximum-tolerated dose (MTD) evaluation period (first cycle of BI 754111 plus BI 754091 combination therapy) in patients with solid tumours |  | Up to 3 weeks | 
| Part II - Objective response (OR) - confirmed complete response (CR) and partial response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 as assessed by the Investigator during the entire treatment |  | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I - Cmax: maximum measured concentration of BI 754111/ BI 754091 in plasma |  | Up to 1 year and 30 days | 
| Part I - AUC 0-504: Area under the Concentration Time Curve (AUC 0-504) of BI 754111/ BI 754091 in plasma over the time interval |  | Up to 504 hours | 
| Part I - Number of patients experiencing Dose-limiting toxicity (DLTs) from start of treatment until end of treatment (in all cycles) |  | Up to 1 year and 30 days | 
| Part I - Objective response (OR) for patients with solid tumours: confirmed complete response (CR) and partial response (PR) according to RECIST Version 1.1 as assessed by the Investigator during the entire treatment period |  | Up to 1 year | 
| Part II - Duration of response is the duration from the date of first documented PR or CR according to RECIST Version 1.1 as assessed by the Investigator to the date of Progression of disease [PD] or death |  | Up to 1 year | 
| Part II - Disease control (CR, PR, or stable disease (SD) according to RECIST Version 1.1) as assessed by the Investigator |  | Up to 1 year | 
| Part II - Progression-free survival (PFS) is the duration from the date of first treatment to the date of PD or death |  | Up to 1 year | 
| Part II - Number of patients experiencing DLTs from start of treatment until end of treatment |  | Up to 1 year |