A Phase Ia/Ib, Open Label, Dose-escalation Study of the Combination of BI 907828 (Brigimadlin) With BI 754091 (Ezabenlimab) and BI 754111 and the Combination of BI 907828 (Brigimadlin) With BI 754091(Ezabenlimab) Followed by Expansion Cohorts, in Patients With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- ezabenlimab
- Conditions
- Neoplasms
- Sponsor
- Boehringer Ingelheim
- Enrollment
- 119
- Locations
- 44
- Primary Endpoint
- Phase Ib - Objective response (OR)
- Status
- Completed
- Last Updated
- 2 months ago
Overview
Brief Summary
This study has 2 parts. The first part of the study is done. The first part was open to adults with different types of advanced cancer (solid tumors). The second part is open to people with specific types of soft tissue sarcoma, advanced lung cancer, and cancer in the stomach, bladder or bile ducts.
The participants get a combination of 2 medicines called brigimadlin (also called BI 907828) and ezabenlimab (also called BI 754091). Brigimadlin is a so-called MDM2 inhibitor that is being developed to treat cancer. Ezabenlimab is an antibody that may help the immune system fight cancer (immune checkpoint inhibitor). When the study started, some participants got a third medicine called BI 754111 in addition. Treatment with BI 754111 was stopped because data from another study showed no additional effect of BI 754111.
The purpose of the first part of the study was to find out the highest dose of brigimadlin that the participants could tolerate in combination with ezabenlimab. This dose is used in the second part of the study.
The purpose of the second part is to see whether the combination of brigimadlin with ezabenlimab is able to make tumors shrink.
The participants are in the study as long as they benefit from treatment and can tolerate it.
Ezabenlimab treatment is limited to 2 years. During this time, they get infusions of ezabenlimab, and take tablets with brigimadlin every 3 weeks. The doctors check how many participants have health problems during the study. The doctors also monitor the size of the tumor.
Investigators
Eligibility Criteria
Inclusion Criteria
- •All cohorts:
- •Provision of signed and dated, written informed consent form ICF in accordance with International Council on Harmonization-Good Clinical Practice (ICH-GCP)and local legislation prior to any trial-specific procedures, sampling, or analyses.
- •Male or female ≥18 years old at the time of signature of the ICF.
- •ECOG performance status of 0 or
- •Life expectancy of at least 12 weeks after the start of the treatment according to the Investigator's judgement.
- •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.
- •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.
- •Patient must be willing to participate in the blood sampling for the Pharmacokinetics (PK), Pharmacodynamics (PD), biomarker, and PGx analyses.
- •Adequate organ function defined as all of the following (all screening labs should be performed locally within 10 days of treatment initiation):
- •Hematological
Exclusion Criteria
- •Previous administration of BI 907828 or any other MDM2-p53 or MDMX (MDM4)-p53 antagonist
- •In Phase Ib (expansion phase) and Phase Ia expansion cohort only: a documented amino-acid altering mutation in TP53 occurring in the patient's tumor.
- •Symptomatic brain metastases. Note: Patients with previously treated brain metastases may participate but treated lesions should not be used as target lesions
- •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)
- •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).
- •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.
- •Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
- •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.
- •Patients who have not recovered from all clinically significant adverse events from their most recent therapy or intervention prior to study enrolment
- •Known history of human immunodeficiency virus (HIV) infection
Arms & Interventions
Dose Escalation - BI 907828 + ezabenlimab + BI 754111
All neoplasms
Intervention: ezabenlimab
Dose Escalation - BI 907828 + ezabenlimab + BI 754111
All neoplasms
Intervention: BI 754111
Dose Escalation - BI 907828 + ezabenlimab
All neoplasms
Intervention: BI 907828
Dose Escalation - BI 907828 + ezabenlimab
All neoplasms
Intervention: ezabenlimab
Dose Expansion - Cohort 1 BI 907828 + ezabenlimab
Intervention: BI 907828
Dose Expansion - Cohort 1 BI 907828 + ezabenlimab
Intervention: ezabenlimab
Dose Expansion - Cohort 2 - BI 907828 + ezabenlimab
Intervention: BI 907828
Dose Expansion - Cohort 2 - BI 907828 + ezabenlimab
Intervention: ezabenlimab
Dose Escalation - BI 907828 + ezabenlimab + BI 754111
All neoplasms
Intervention: BI 907828
Outcomes
Primary Outcomes
Phase Ib - Objective response (OR)
Time Frame: Up to 24 months
Phase Ia - maximum tolerated dose (MTD) of brigimadlin (BI 907828) in combination with ezabenlimab based on the number of patients with dose limiting toxicities (DLTs) during the first treatment cycle
Time Frame: Up to 21 Days
Phase Ib - Progression free survival
Time Frame: Up to 24 months
Secondary Outcomes
- Phase Ia - Cmax : Maximum measured plasma concentration of brigimadlin (BI 907828) and ezabenlimab (during the first cycle)(Up to 21 Days)
- Phase Ib - Objective Response (OR)(Up to 24 months)
- Phase Ia - Number of patients with DLTs observed during the entire treatment period(Up to 24 months)
- Phase Ib - Disease control (DC)(Up to 24 months)
- Phase Ia - AUC0-tz: Area under the concentration-time curve in plasma for brigimadlin (BI 907828) and ezabenlimab over the time interval from 0 to the last quantifiable time point (during the first cycle)(Up to 21 Days)
- Phase Ib - Number of patients with DLTs(Up to 2 years)
- Phase Ib - Overall survival (OS)(Up to 24 months)