Brightline-3: A Study to Find Out Whether Brigimadlin in Combination With Ezabenlimab Helps People With Advanced Soft Tissue Sarcoma

• ClinicalTrials.gov Identifier: NCT06370871
• Recruitment Status: Not yet recruiting
• First Posted: April 17, 2024
• Last Update Posted: May 14, 2024
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: April 15, 2024
• First Posted Date: April 17, 2024
• Last Update Posted Date: May 14, 2024
• Estimated Study Start Date: June 27, 2024
• Estimated Primary Completion Date: July 3, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 15, 2024)

• Progression-free survival [ Time Frame: up to 4 years. ]
  Progression-free survival is defined as the time from randomization until the earliest of tumor progression according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1, based on blinded central independent review or death from any cause.
• Overall survival [ Time Frame: up to 4 years. ]
  Overall survival, defined as the time from randomization until death from any cause.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 23, 2024)

• Objective response [ Time Frame: up to 4 years. ]
  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 central independent review) from the date of randomization until the earliest of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent.
• Duration of objective response [ Time Frame: up to 4 years. ]
  Duration of objective response (DOR), defined as the time from first documented confirmed OR according to RECIST Version 1.1 until the earliest of disease progression or death among patients with confirmed objective response (based on central independent review).
• Disease control [ Time Frame: up to 4 years. ]
  Disease control (DC), defined as a best overall response of CR, PR, or stable disease (SD), where best overall response is defined according to RECIST Version 1.1 (based on central independent review).
• Duration of disease control [ Time Frame: up to 4 years. ]
  Duration of disease control, defined as the time from randomization until the earliest of disease progression according to RECIST Version 1.1 (based on central independent review) or death from any cause among patients with disease control.
• Occurrence of treatment-emergent adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5 [ Time Frame: up to 4 years. ]
• Occurrence of treatment-emergent AEs leading to study drug discontinuation [ Time Frame: up to 4 years. ]
• Mean change from baseline to Week 12 in the domain fatigue (based on items from the European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30) and the EORTC item library) [ Time Frame: At baseline and at Week 12. ]
  Fatigue will be assessed via 8 items. The score of each item ranges from 0-100 with higher scores indicating higher symptomology.
• Mean change from baseline to Week 12 in the domain fatigability (based on items from the EORTC QLQ-C30 and the EORTC item library) [ Time Frame: At baseline and at Week 12. ]
  Fatigability will be assessed via 12 items. The score of each item ranges from 0-100 with higher scores indicating higher symptomology.
• Mean change from baseline to week 12 in the domain physical functioning (based on items from the EORTC QLQ-C30) [ Time Frame: At baseline and at Week 12. ]
  EORTC QLQ-C30 is a 30-item cancer-specific instrument that assesses participant reported outcomes (PROs). The gloabl health status and the quality of life are 2 of the 30 items and are scored from 1 (1=very poor) to 7 (7=excellent). All other items have 4 possible scores (1= not at all, 2= a little, 3=quite a bit, 4=very much).
• Mean change from baseline to week 12 in the domain pain (based on items from the EORTC QLQ-C30) [ Time Frame: At baseline and at Week 12. ]
  EORTC QLQ-C30 is a 30-item cancer-specific instrument that assesses participant reported outcomes (PROs). The gloabl health status and the quality of life are 2 of the 30 items and are scored from 1 (1=very poor) to 7 (7=excellent). All other items have 4 possible scores (1= not at all, 2= a little, 3=quite a bit, 4=very much).
• Mean change from baseline to week 12 in the domain dyspnea (based on items from the EORTC QLQ-C30) [ Time Frame: At baseline and at Week 12. ]
  EORTC QLQ-C30 is a 30-item cancer-specific instrument that assesses participant reported outcomes (PROs). The gloabl health status and the quality of life are 2 of the 30 items and are scored from 1 (1=very poor) to 7 (7=excellent). All other items have 4 possible scores (1= not at all, 2= a little, 3=quite a bit, 4=very much).
• Mean change from baseline to week 12 in the domain global health status / quality of life (based on items from the EORTC QLQ-C30) [ Time Frame: At baseline and at Week 12. ]
  EORTC QLQ-C30 is a 30-item cancer-specific instrument that assesses participant reported outcomes (PROs). The gloabl health status and the quality of life are 2 of the 30 items and are scored from 1 (1=very poor) to 7 (7=excellent). All other items have 4 possible scores (1= not at all, 2= a little, 3=quite a bit, 4=very much).

Original Secondary Outcome Measures (submitted: April 15, 2024)

• Objective response [ Time Frame: up to 4 years. ]
  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 central independent review) from the date of randomization until the earliest of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent.
• Duration of objective response [ Time Frame: up to 4 years. ]
  Duration of objective response (DOR), defined as the time from first documented confirmed OR according to RECIST Version 1.1 until the earliest of disease progression or death among patients with confirmed objective response (based on central independent review).
• Disease control [ Time Frame: up to 4 years. ]
  Disease control (DC), defined as a best overall response of CR, PR, or stable disease (SD), where best overall response is defined according to RECIST Version 1.1 (based on central independent review).
• Duration of disease control [ Time Frame: up to 4 years. ]
  Duration of disease control, defined as the time from randomization until the earliest of disease progression according to RECIST Version 1.1 (based on central independent review) or death from any cause among patients with disease control.
• Occurrence of treatment-emergent adverse events (AEs) according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5 [ Time Frame: up to 4 years. ]
• Occurrence of treatment-emergent AEs leading to study drug discontinuation [ Time Frame: up to 4 years. ]
• Mean change from baseline to Week 12 in the domain fatigue (based on items from the European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30) and the EORTC item library) [ Time Frame: At baseline and at Week 12. ]
  Fatigue will be assessed via 8 items. The score of each item ranges from 0-100 with higher scores indicating higher symptomology.
• Mean change from baseline to Week 12 in the domain fatigability (based on items from the EORTC QLQ-C30 and the EORTC item library) [ Time Frame: At baseline and at Week 12. ]
  Fatigue will be assessed via 12 items. The score of each item ranges from 0-100 with higher scores indicating higher symptomology.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Brightline-3: A Study to Find Out Whether Brigimadlin in Combination With Ezabenlimab Helps People With Advanced Soft Tissue Sarcoma
• Official Title: Brightline-3: A Phase III, Randomized, Open-label, Multi-center Trial of Brigimadlin + Ezabenlimab Compared to Gemcitabine + Docetaxel for Second-line Treatment of Patients With Advanced TP53 Wild-type Soft Tissue Sarcoma Subtypes

Brief Summary

This study is open to adults with specific types of advanced soft tissue sarcoma. People with undifferentiated pleomorphic sarcoma (UPS) or myxofibrosarcoma (MFS) can join the study if they have a normal version of the TP53 gene. This is a study for people whose earlier treatment isn't working anymore, and their doctors suggest a new treatment to stop the sarcoma from getting worse.

The purpose of this study is to compare a medicine called brigimadlin in combination with another medicine called ezabenlimab with chemotherapy. Brigimadlin is a so-called MDM2-p53 antagonist that is being developed to treat cancer. Ezabenlimab is an antibody that may help the immune system fight cancer.

Participants are put into 3 groups by chance:

• Ezabenlimab group: Participants receive ezabenlimab as an infusion into a vein every 3 weeks
• Brigimadlin + ezabenlimab group: Participants take brigimadlin as tablets and receive ezabenlimab as an infusion into a vein every 3 weeks
• Chemotherapy group: Participants get chemotherapy as an infusion into a vein on 2 days every 3 weeks. Chemotherapy is a combination of gemcitabine and docetaxel which is often used in the treatment of sarcoma.

There are twice as many participants in the brigimadlin + ezabenlimab group and in the chemotherapy group, compared to those in the ezabenlimab group.

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 tumor 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. Participants in this study use an app on a mobile phone to regularly answer questions about their health and well-being. This is to find out if their quality of life is changing.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Soft Tissue Sarcoma
• Undifferentiated Pleomorphic Sarcoma (UPS)
• Myxofibrosarcoma (MFS)

Intervention

• Drug: Brigimadlin
  Brigimadlin
  Other Name: BI 907828
• Drug: Ezabenlimab
  Ezabenlimab
  Other Name: BI 754091
• Drug: Gemcitabine
  Solution for infusion
• Drug: Docetaxel
  Solution for infusion

Study Arms

• Experimental: Arm A: Ezabenlimab
  Intervention: Drug: Ezabenlimab
• Experimental: Arm B: Brigimadlin + ezabenlimab
  Interventions:

  • Drug: Brigimadlin
  • Drug: Ezabenlimab
• Active Comparator: Arm C: Gemcitabine + docetaxel
  Interventions:

  • Drug: Gemcitabine
  • Drug: Docetaxel

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: April 15, 2024): 263
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 13, 2028
• Estimated Primary Completion Date: July 3, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Provision of signed and dated, written informed consent form (ICF) in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good clinical practice (ICH-GCP) and local legislation prior to any trial-specific procedures, sampling, or analyses
2. Male or female patients ≥18 years old at the time of signature of the ICF

3. Histologically proven diagnosis of one of the following:

   • Undifferentiated pleomorphic sarcoma (UPS) with TP53 wild-type status
   • Myxofibrosarcoma (MFS) with TP53 wild-type status
4. Written pathology report indicating the diagnosis of UPS or MFS must be available
5. Written report from the trial central laboratory indicating TP53 wild-type status
6. One prior systemic regimen for advanced disease with documented progressive disease as per serial radiologic imaging. If prior systemic cytotoxic treatment for soft tissue sarcoma was given in a neoadjuvant, adjuvant or perioperative setting that treatment would count as one line of therapy in case of radiological progression during that treatment or within 3 months after completing that systemic therapy. If progression or relapse occurred after >3 months after completing that systemic therapy, the pre-, post or perioperative treatment would not count as a line of treatment for advanced disease
7. Patient must be willing to donate mandatory blood and tissue samples for the pharmacokinetics, pharmacodynamics, and biomarker analyses
8. Presence of at least one target lesion according to RECIST Version 1.1 Further inclusion criteria apply

Exclusion Criteria:

1. Prior treatment with immunotherapy in the context of anticancer therapy
2. Previous administration of gemcitabine, taxanes, brigimadlin or any other mouse double minute 2 homolog-p53 (MDM2-p53) or MDMX (MDM4)-p53 antagonist
3. Previous or concomitant malignancies other than the one treated in this trial within the previous 2 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
4. Patient unable to swallow the trial medication
5. Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the trial drug (e.g., nausea, vomiting, Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) in the opinion of the investigator
6. Active bleeding, significant risk of hemorrhage (e.g., previous severe gastrointestinal bleeding, previous hemorrhagic stroke at any time), or current bleeding disorder (e.g., hemophilia, von Willebrand disease)
7. Known history of severe hypersensitivity reactions to other monoclonal antibodies or known hypersensitivity or known contraindication to the trial medications or their excipients
8. Active autoimmune disease or a documented history of autoimmune disease, that requires systemic treatment, i.e., corticosteroids or immunosuppressive drugs, except for 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 hormone replacement and/or controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible Further exclusion criteria apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Boehringer Ingelheim; 1-800-243-0127; clintriage.rdg@boehringer-ingelheim.com

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT06370871
• Other Study ID Numbers: 1403-0006; 2022-502985-26-00 ( Registry Identifier: CTIS (EU) ); U1111-1292-9594 ( Registry Identifier: WHO Registry )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Once the criteria in section "Time Frame" are fulfilled, researchers can use the following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement".

Furthermore, researchers can request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: One year after the approval has been granted by major Regulatory Authorities and after the primary manuscript has been accepted for publication, or after termination of the development program.
• Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by the sponsor and/or the independent review panel, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a legal agreement.
• URL: https://www.mystudywindow.com/msw/datasharing

• Current Responsible Party: Boehringer Ingelheim
• Original Responsible Party: Same as current
• Current Study Sponsor: Boehringer Ingelheim
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Boehringer Ingelheim
• Verification Date: May 2024