A phase Ia/Ib, open label, dose-escalation study of the combination of BI 907828 with BI 754091 (ezabenlimab) and BI 754111 and the combination of BI 907828 with BI 754091 (ezabenlimab) followed by expansion cohorts, in patients with advanced solid tumors

1. Provision of signed and dated, written informed consent form ICF in
accordance with ICH-GCP and local legislation prior to any trial-specific
procedures, sampling, or analyses.
2. Male or female >=18 years old at the time of signature of the ICF.
3. ECOG performance status of 0 or 1.
4. Life expectancy of at least 12 weeks after the start of the treatment
according to the Investigator*s judgement.
5. Patients with radiologically documented disease progression or relapse
during or after all standard of care treatments. Patients who are not eligible
to receive standard of care treatments, and for whom no proven treatments
exist, are eligible.
6. Previous treatment with an anti-PD-1/PD-L1 mAb is allowed as long as the
last administration of the anti-PD-1/PD-L1 mAb on the previous treatment
occurred a minimum of 28 days prior to the first administration of study
treatment.
7. Patient must be willing to participate in the blood sampling for the PK, PD,
and tumor mutation analysis.
8. Adequate organ function defined as all of the following (all screening labs
should be performed locally within 10 days of treatment initiation):
Absolute neutrophil count >=1.5 x 10^9/L (or >= 1.5×10^3/µL or >= 1500/mm^3)
Platelets >=100 x 10^9/L (or >= 100×10^3/µL or >= 100×10^3/mm^3)
Hemoglobin >=8.5 g/dL or >=5.3 mmol/L (red blood cell transfusion allowed to meet
eligibility criteria) or >= 85 g/L
Total bilirubin <= 1.5 times the upper limit of normal (ULN), (patients with
Gilbert*s syndrome, total bilirubin must be <=3 x ULN)
AST and ALT <=2.5 x ULN OR <=5 x ULN for patients with liver metastases
Creatinine <=1.5 x ULN
Patients may enter if creatinine is >1.5 x ULN and estimated glomerular
filtration rate (eGFR) >50 mL/min (assessed by Chronic Kidney Disease
Epidemiology [CKDEPI] Collaboration equation); confirmation of eGFR is only
required when creatinine is >1.5 X ULN
International Normalised Ratio (INR) or Prothrombin Time (PT). Activated
Partial Thromboplastin Time (aPTT) <=1.5 x institutional ULN. Patients taking
low dose warfarin must have their INR
followed closely and according to institutional guidelines.
9. Women of childbearing potential (WOCBP), and men able to father a child must
be ready and able to use two medically acceptable 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 beginning at screening, during trial
participation and until certain time has passed after the last administration
of trial medication:
- Women: 6 months and 12 days after end of BI 907828; 6 months after end of
ezabenlimab.
- Men: 102 days after end of BI 907828; 6 months after end of ezabenlimab.
A list of contraception methods meeting these criteria is provided in the
patient information.

Inclusion criteria 10-14 are only applicable to Phase I a.

The following inclusion criteria are only applicable to Phase I b:
15. At least one target lesion that can be accurately measured per RECIST 1.1.
In patients who only have one target lesion, the baseline imaging must be
performed at least two weeks after any biopsy of the target lesion.
16. Patients with TP53 wild-type status confirmed on tumor tissue.
17. Provision of fresh tissue biopsy at screening (may be omitted if patient
has archival tissue within 12 months prior to enrolment) and willingness to
provide fresh tissue biopsy on study, if safe and feasible on either occasion.
18. Patients with the following tumor types:
- Cohort 1: Patients with unresectable, advanced and/or metastatic TP53 wt
selected subtypes of soft tissue sarcomas as listed below, who received at
least one line of systemic medical treatment in the advanced and/or metastatic
setting:
- Liposarcoma excluding dedifferentiated liposarcoma
- Undifferentiated pleomorphic sarcoma
- Myxofibrosarcoma
- Synovial sarcoma
- Leiomyosarcoma
- Cohort 2: Patients with unresectable, advanced and/or metastatic TP53 wt
MDM2-amplified tumors as listed below, who received at least one line of
systemic medical treatment in the advanced and/or metastatic setting:
- NSCLC (patients with NSCLC harboring genomic aberrations for which approved
targeted therapy is approved and available, must have received such prior
treatment)
- Gastric adenocarcinoma
- Urothelial carcinoma
- Biliary tract carcinoma (including cholangiocarcinoma, intra-and extrahepatic
biliary tree, gall bladder and ampulla of vater)

See protocol section 3.3.2.

Patients must not enter the trial if any of the following exclusion criteria
are fulfilled:
1. Previous administration of BI 907828 or any other MDM2-p53 or MDMX
(MDM4)-p53 antagonist.
2. In Phase Ib (expansion phase) and Phase Ia expansion cohort only: a
documented aminoacid altering mutation in TP53 occurring in the patient*s tumor.
3. Symptomatic brain metastases.
Note: Patients with previously treated brain metastases may participate but
treated lesions should not be used as target lesions.
4. Exclusion criterion 4 is not applicable for patients enrolled after protocol
version 4 is approved.
5. Active bleeding, significant risk of haemorrhage (e.g. previous severe
gastrointestinal bleeding, previous haemorrhagic stroke at any time), or
current bleeding disorder (e.g. haemophilia, von Willebrand disease).
6. Major surgery (major according to the Investigator*s assessment) performed
within 12 weeks prior to start of study treatment or planned within 12 months
after screening (e.g. hip replacement).
7. Any other documented active or suspected malignancy or history of malignancy
within 3 years prior to screening, except appropriately treated basal cell
carcinoma of the skin or in situ carcinoma of uterine cervix, or other local
tumors considered cured by local treatment.
8. Patients who must or wish to continue the intake of restricted medications
(see Section 4.2.2.1) or any drug considered likely to interfere with the safe
conduct of the trial.
9. Currently enrolled in another investigational device or drug trial, or less
than 4 weeks since receiving other investigational treatments. Patients who are
in follow-up/observation for another clinical trial are eligible.
10. Exclusion criterion 10 is not applicable for patients enrolled after
protocol version 4 is approved.
11. Patients who have not recovered from all clinically significant adverse
events from their most recent therapy or intervention prior to study enrolment.
12. Known history of human immunodeficiency virus (HIV) infection.
13. Any of the following known laboratory evidence of hepatitis virus infection:
o Positive results of hepatitis B surface (HBs) antigen
o Presence of HBc antibody together with HBV-DNA
o Presence of hepatitis C RNA
14. Known hypersensitivity to the trial drugs or their excipients.
15. Serious concomitant disease or medical condition affecting compliance with
trial requirements or which are considered relevant for the evaluation of the
efficacy or safety of the trial drug, such as neurologic, psychiatric,
infectious disease or active ulcers (gastro-intestinal tract, skin) or
laboratory abnormality that may increase the risk associated with trial
participation or trial drug administration, and in the judgment of the
Investigator, would make the patient inappropriate for entry into the trial.
16. Chronic alcohol or drug abuse or any condition that, in the Investigator*s
opinion, makes them an unreliable trial patient or unlikely to complete the
trial.
17. Women who are pregnant, nursing, or who plan to become pregnant while in
the trial; female patients who do not agree to the interruption of breast
feeding from the start of study treatment until 6 months and 12 days after last
dose of study treatment.
18. History of (including current) interstitial lung disease or pneumonitis
within the last 5 years.
19. History of severe hypersensitivity reactions to other monoclonal antibodies
20. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or
equivalent) within 4 weeks prior to the first dose of study treatment.
21. Active autoimmune disease or a documented history of autoimmune disease,
that requires systemic treatment, i.e. corticosteroids or immunosuppressive
drugs, except vitiligo or resolved childhood asthma/atopy, alopecia, or any
chronic skin condition that does not require systemic therapy; patients with
autoimmune-related hypothyroidism on a stable dose of thyroid replacement
hormone and/or controlled Type 1 diabetes mellitus on a stable insulin regimen
are eligible.
22. Active infection requiring systemic treatment (antibacterial, antiviral, or
antifungal therapy) at start of treatment in this trial.
23. 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 factor that increases 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) <50% 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.

See protocol section 3.3.3.