Brightline-1: A Study to Compare Brigimadlin (BI 907828) With Doxorubicin in People With a Type of Cancer Called Dedifferentiated Liposarcoma

Study Overview
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Brief Summary
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This study is open to people with a type of cancer called dedifferentiated liposarcoma. People with advanced liposarcoma aged 18 or older who are not receiving any other cancer treatment can participate. The purpose of this study is to compare a medicine called brigimadlin (BI 907828) with doxorubicin in people with liposarcoma. Brigimadlin (BI 907828) is a so-called MDM2 inhibitor that is being developed to treat cancer. Doxorubicin is a medicine already used to treat cancer including liposarcoma. During the study, participants get either brigimadlin (BI 907828) or doxorubicin. Every 3 weeks, participants take brigimadlin (BI 907828) as tablets or doxorubicin as an infusion into a vein. Participants can switch to brigimadlin (BI 907828) treatment if they did not benefit from doxorubicin treatment. Participants can continue treatment in the study as long as they benefit from it and can tolerate it. Doctors regularly check the size of the tumour and check whether it has spread to other parts of the body. The doctors also regularly check participants' health and take note of any unwanted effects.

Official Title
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Brightline-1: A Phase II/III, Randomized, Open-label, Multi-center Study of Brigimadlin (BI 907828) Compared to Doxorubicin as First Line Treatment of Patients With Advanced Dedifferentiated Liposarcoma

Conditions
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Liposarcoma, Dedifferentiated

Intervention / Treatment
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* Drug: Brigimadlin (BI 907828)
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Male or female patients ≥18 years old at the time of signature of the informed consent form (ICF). Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use 2 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 6 months and 12 days after last dose for women and 102 days after last dose for men. A list of contraception methods meeting these criteria is provided in the patient information. Histologically proven locally advanced or metastatic, unresectable (surgery morbidity would outweigh potential benefits), progressive or recurrent dedifferentiated liposarcoma (DDLPS). Locally performed histopathological diagnosis will be accepted for entry into this trial but will be confirmed by independent pathological review while the patients receive treatment in this trial. Written pathology report indicating the diagnosis of DDLPS with positive mouse double minute 2 homolog (MDM2) immunohistochemistry or MDM2 amplification as demonstrated by fluorescence in situ hybridization or next generation sequencing (NGS) must be available. Formalin fixed paraffin embedded tumor blocks or slides must be available for retrospective histopathological central review. Presence of at least one measurable target lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. In patients who only have one target lesion, the baseline imaging must be performed at least 2 weeks after any biopsy of the target lesion. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patient must be willing to donate blood samples for the pharmacokinetics, pharmacodynamics, and tumor mutation analysis. Patient willing to undergo a mandatory tumor biopsy at the time point specified in the flowchart unless exempt. Adequate organ function. Exclusion Criteria: Known mutation in the TP53 gene (screening for TP53 status is not required). Major surgery (major according to the investigator's assessment) performed within 4 weeks prior to randomization or planned within 6 months after screening. Prior systemic therapy for liposarcoma in any setting (including adjuvant, neoadjuvant, maintenance, palliative). Previous or concomitant malignancies other than DDLPS or WDLPS, treated within the previous 5 years, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ, or other malignancy that is considered cured by local treatment. Previous treatment with anthracyclines in any setting (systemic treatment with other anticancer agents is allowed if completed at least 5 years prior to study entry with the exception of hormone therapy). Patients who must or intend 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 30 days since ending another investigational device or drug trial(s) or receiving other investigational treatment(s). Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator's opinion, makes the patient an unreliable trial participant). 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brigimadlin (BI 907828) low dose<br>Phase II | Drug: Brigimadlin (BI 907828)<br>* Brigimadlin (BI 907828)<br>* Other names: Brigimadlin;|
| Experimental: Brigimadlin (BI 907828) high dose<br>Phase II | Drug: Brigimadlin (BI 907828)<br>* Brigimadlin (BI 907828)<br>* Other names: Brigimadlin;|
| Experimental: Brigimadlin (BI 907828) arm<br>Phase III | Drug: Brigimadlin (BI 907828)<br>* Brigimadlin (BI 907828)<br>* Other names: Brigimadlin;|
| Active Comparator: Doxorubicin arm<br>Phase II/III | Drug: Doxorubicin<br>* doxorubicin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | defined as the time interval from randomization until tumor progression according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (solely based on blinded central independent review) or death from any cause, whichever occurs first. | Up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response (OR) | defined as a best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.1 (based on blinded central independent review) from the date of randomization until disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent, whichever occurs first. | Up to 30 months | 
| Duration of objective response (DOR) | defined as the time interval from first documented confirmed OR until disease progression or death among patients with confirmed objective response (based on blinded central independent review), whichever occurs first. | Up to 30 months | 
| Overall survival (OS) | defined as the time interval from randomization until death from any cause | Up to 50 months | 
| Disease control (DC) | defined as a best overall response of CR, PR, or stable disease (SD) according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 (based on blinded central independent review). | Up to 30 months | 
| Change from baseline in QLQ-C30 (Quality of Life questionnaire C30) | The QLQ C30 rates the overall quality of life in cancer participants. 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function, symptoms and financial difficulties and 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Includes scores for physical functioning, fatigue, pain, global health status. | Up to week 18 | 
| Change from baseline in EQ-5D5L (European Quality of Life 5 dimensions 5 level) | The EQ-5D-5L is a standardized instrument to assess of health outcome through 5 Likert scale items. In the EQ-5D-5L VAS, the participant rates his or her general state of health at the time of the assessment on a scale from 0 to 100. | Up to week 18 | 
| Change from baseline in fatigue | Fatigue symptoms are assessed through 25 items selected from the European Organization for Research and Treatment of Cancer (EORTC) item library. Items use a 4-point scale (1=not at all to 4=very much) similar to the C30. | Up to week 18 | 
| Change from baseline in pain | Pain symptoms are assessed through 18 items selected from the EORTC item library. Items use a 4-point scale (1=not at all to 4=very much) similar to the C30. | Up to week 18 | 
| Occurrence of treatment-emergent adverse events (AEs) |  | Up to 30 months | 
| Occurrence of treatment-emergent AEs leading to study drug discontinuation |  | Up to 30 months |