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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03964233




Registration number
NCT03964233
Ethics application status
Date submitted
24/05/2019
Date registered
28/05/2019

Titles & IDs
Public title
A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 (Brigimadlin) in Combination With BI 754091 (Ezabenlimab) and BI 754111 or BI 907828 (Brigimadlin) in Combination With BI 754091 (Ezabenlimab)
Scientific title
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
Secondary ID [1] 0 0
2019-001173-84
Secondary ID [2] 0 0
1403-0002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - BI 907828
Treatment: Drugs - ezabenlimab
Treatment: Drugs - BI 754111

Experimental: Dose Escalation - BI 907828 + ezabenlimab - All neoplasms

Experimental: Dose Expansion - Cohort 1 BI 907828 + ezabenlimab -

Experimental: Dose Expansion - Cohort 2 - BI 907828 + ezabenlimab -

Experimental: Dose Escalation - BI 907828 + ezabenlimab + BI 754111 - All neoplasms


Treatment: Drugs: BI 907828
Film-coated tablets

Treatment: Drugs: ezabenlimab
Solution for infusion

Treatment: Drugs: BI 754111
Solution for infusion
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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
Timepoint [1] 0 0
Up to 21 Days
Primary outcome [2] 0 0
Phase Ib - Objective response (OR)
Timepoint [2] 0 0
Up to 24 months
Primary outcome [3] 0 0
Phase Ib - Progression free survival
Timepoint [3] 0 0
Up to 24 months
Secondary outcome [1] 0 0
Phase Ia - Cmax : Maximum measured plasma concentration of brigimadlin (BI 907828) and ezabenlimab (during the first cycle)
Timepoint [1] 0 0
Up to 21 Days
Secondary outcome [2] 0 0
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)
Timepoint [2] 0 0
Up to 21 Days
Secondary outcome [3] 0 0
Phase Ia - Number of patients with DLTs observed during the entire treatment period
Timepoint [3] 0 0
Up to 24 months
Secondary outcome [4] 0 0
Phase Ib - Objective Response (OR)
Timepoint [4] 0 0
Up to 24 months
Secondary outcome [5] 0 0
Phase Ib - Disease control (DC)
Timepoint [5] 0 0
Up to 24 months
Secondary outcome [6] 0 0
Phase Ib - Number of patients with DLTs
Timepoint [6] 0 0
Up to 2 years
Secondary outcome [7] 0 0
Phase Ib - Overall survival (OS)
Timepoint [7] 0 0
Up to 24 months

Eligibility
Key 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 1.
* 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

* Absolute neutrophil count - =1.5 x 10^9/L
* Platelets - =100 x 10^9/L
* Hemoglobin 0 =8.5 g/dL or =5.3 mmol/L or = 85 g/L
* Hepatic

* Total bilirubin = 1,5 times the upper limit of normal (ULN), (patients with Gilbert's syndrome, total bilirubin must be < 3 x ULN)
* Aspartate Transaminase (AST) and Alanine Aminotransferase (ALT) =2.5 x ULN OR =5 x ULN for patients with liver metastases
* Renal

--- 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
* Coagulation --- 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
* Women of childbearing potential (WOCBP, defined as female patients who are premenopausal or who had no cessation of menses within 12 months without an alternative medical cause, but not including female patients who are permanently sterilized) 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. A list of contraception methods meeting these criteria is provided in the patient information.

Phase Ia (dose escalation part):

* Patients with a confirmed diagnosis of unresectable, advanced and/or metastatic solid tumors (any type) irrespective of the TP53 mutation status,
* Patient with either evaluable or non-evaluable disease.
* Availability and willingness to provide a sample of archival Formalin-fixed paraffin embedded (FFPE) tumor tissue material

Phase Ia (Expansion Cohort):

* Patients with MDM2 amplified tumors and TP53 wild type status confirmed on tumor tissue
* 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.

Phase Ib (dose expansion part):

* 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.
* Patients with TP53 wild-type status confirmed on tumor tissue. 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
* Expansion cohorts:

* Cohort 1: Patients with unresectable, advanced and/or metastatic TP53 wt 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)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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
* Any of the following laboratory evidence of hepatitis virus infection:

* Positive results of hepatitis B surface (HBs) antigen
* Presence of HBc antibody together with HBV-DNA
* Presence of hepatitis C RNA
* Known hypersensitivity to the trial drugs or their excipients.
* 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.
* 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.
* 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 to within 30 days after the last study treatment.
* History (including current) of interstitial lung disease or pneumonitis within the last 5 years.
* History of severe hypersensitivity reactions to other monoclonal antibodies
* 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, disease, that requires systemic treatment, i.e. corticosteroids or immunosuppressive drugs, except vitiligo or resolved childhood asthma/atopyatopy, 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.
* Active infection requiring systemic treatment (antibacterial, antiviral, or antifungal therapy) at start of treatment in this trial.
* 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
20/06/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/05/2026
Actual
Sample size
Target
Accrual to date
Final
120
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 0 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Missouri
Country [5] 0 0
United States of America
State/province [5] 0 0
New York
Country [6] 0 0
United States of America
State/province [6] 0 0
Texas
Country [7] 0 0
United States of America
State/province [7] 0 0
Virginia
Country [8] 0 0
Belgium
State/province [8] 0 0
Leuven
Country [9] 0 0
France
State/province [9] 0 0
Bordeaux
Country [10] 0 0
France
State/province [10] 0 0
Lyon
Country [11] 0 0
France
State/province [11] 0 0
Villejuif
Country [12] 0 0
Germany
State/province [12] 0 0
Frankfurt
Country [13] 0 0
Germany
State/province [13] 0 0
Ulm
Country [14] 0 0
Hungary
State/province [14] 0 0
Budapest
Country [15] 0 0
Japan
State/province [15] 0 0
Tokyo, Chuo-ku
Country [16] 0 0
Netherlands
State/province [16] 0 0
Groningen
Country [17] 0 0
Singapore
State/province [17] 0 0
Singapore
Country [18] 0 0
Spain
State/province [18] 0 0
Barcelona
Country [19] 0 0
Spain
State/province [19] 0 0
Madrid
Country [20] 0 0
United Kingdom
State/province [20] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Boehringer Ingelheim
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
After the study is completed and the primary manuscript is accepted for publishing, researchers can use this 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". Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing.

com/ to find information in order to 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. The data shared are the raw clinical study data sets.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Clinical study report (CSR)
When will data be available (start and end dates)?
After all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication.
Available to whom?
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 both the independent review panel and the sponsor, including checking that the planned analysis does not compete with sponsor's publication plan); 2. and upon signing of a 'Data Sharing Agreement'.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://www.mystudywindow.com/msw/datasharing


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03964233