Evaluation of BI 907828 Monotherapy in Patients with MDM2-Amplified, TP53 Wild-Type Biliary Tract, Pancreatic, Lung, and Urothelial Bladder Cancers
- Trial ID
- 2023-506369-79-00
- Protocol
- 1403-0011
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the study is to assess the **efficacy**, safety, and tolerability of BI 907828 monotherapy in patients with specific types of cancer. The study focuses on four cohorts: Cohort 1 includes patients with biliary tract adenocarcinoma, encompassing cholangiocarcinoma, gallbladder cancer, and ampullary cancer. Cohort 2 involves patients with pancreatic ductal adenocarcinoma. Cohort 3 targets those with lung adenocarcinoma, and Cohort 4 includes patients with urothelial bladder cancer. Evaluating the efficacy of BI 907828 is clinically relevant as it may offer a new therapeutic option for these malignancies, which are often associated with poor prognosis and limited treatment options.
Participants
The clinical trial involves a total of **119 participants** diagnosed with various types of cancer, including **biliary tract adenocarcinoma**, **pancreatic ductal adenocarcinoma**, **urothelial bladder cancer**, and **lung adenocarcinoma**. The study population comprises both male and female subjects aged 18 years and older. Participants were selected based on their diagnosis of locally advanced or metastatic disease that is unresectable and have received all available conventional therapies known to confer clinical benefit. The trial includes individuals with an **Eastern Cooperative Oncology Group (ECOG) performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have adequate organ function and a life expectancy of at least three months. The trial population includes a vulnerable group, and all participants must provide informed consent. Lifestyle factors such as diet and physical activity are not specified, but participants must adhere to medically acceptable methods of birth control. The selection criteria ensure that participants have measurable target lesions and meet specific molecular profiling requirements, including **MDM2 amplification** and **TP53 wild-type status**. The sponsor has not provided additional information regarding specific lifestyle considerations or other demographic details.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy, safety, and tolerability of **BI 907828** monotherapy in patients with locally advanced or metastatic, MDM2 amplified, TP53 wild-type solid tumors, including biliary tract adenocarcinoma, pancreatic ductal adenocarcinoma, lung adenocarcinoma, and urothelial bladder cancer. This is a Phase IIa/IIb, open-label, single-arm, multi-center trial. The trial is expected to run from November 22, 2022, to March 25, 2027, with a maximum treatment period of 48 weeks for each participant. The study involves oral administration of the investigational product in the form of film-coated tablets, with varying maximum daily doses of 20 mg, 30 mg, or 45 mg, depending on the cohort.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as the presence of a measurable target lesion, adequate organ function, and a life expectancy of at least three months. Following the screening, participants will attend regular follow-up visits to monitor treatment response and safety, as well as to collect pharmacokinetic, pharmacodynamic, and biomarker data. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participant involvement is expected to last up to 48 weeks, with conditions for early termination including the occurrence of treatment-emergent adverse events leading to trial drug discontinuation, disease progression, or withdrawal of consent. The primary endpoint of the trial is the objective response based on central independent review, while secondary endpoints include duration of objective response, progression-free survival, overall survival, disease control, and changes in quality of life scores. The trial aims to provide comprehensive data on the potential benefits and risks of BI 907828 in the specified patient populations.
Treatment
The clinical trial involves the administration of the experimental medication **BI 907828**, which is provided in the form of a **film-coated tablet**. The active substance in BI 907828 is chemically derived and identified as (3S,3'S,3A'S,10A'S)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-6'-methyl-2-oxo-1,2,3',3A',10',10A'-hexahydro-1'H-spiro[indole-3,2'-pyrrolo[2',3':4,5]pyrrolo[1,2-b]indazole]-7'-carboxylic acid. The medication is administered orally, with a maximum daily dose of 20 mg, 30 mg, or 45 mg, depending on the specific treatment regimen. The total maximum dose amounts to 1435 mg, 2115 mg, or 3150 mg over a treatment period of up to 48 weeks. The pharmaceutical form and administration route are consistent across all dosing regimens.
In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the efficacy, safety, and tolerability of BI 907828 monotherapy. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the therapeutic potential of BI 907828 in patients with locally advanced or metastatic, MDM2 amplified, TP53 wild-type biliary tract adenocarcinoma, pancreatic ductal adenocarcinoma, or other selected solid tumors.
Efficacy
The efficacy of the clinical trial involving BI 907828 will be assessed using several primary and secondary endpoints. The primary endpoint is the **Objective Response (OR)**, which will be evaluated based on a central independent review. Secondary endpoints include the **Duration of Objective Response (DOR)**, **Progression-Free Survival (PFS)**, and **Overall Survival (OS)**, all of which will also be assessed through central independent review. Additionally, the trial will measure **Disease Control (DC)** and the occurrence of treatment-emergent adverse events (AEs) during the on-treatment period, as well as AEs leading to trial drug discontinuation.
Patient-reported outcomes will be evaluated using changes from baseline in the EORTC QLQ-C30 and QLQ-BIL21 scores, specifically focusing on physical functioning, fatigue, role functioning, and tiredness domains. These assessments will provide insights into the impact of the treatment on patients' quality of life. The trial is designed to include multiple cohorts of patients with locally advanced or metastatic, MDM2 amplified, TP53 wild-type solid tumors, including biliary tract adenocarcinoma, pancreatic ductal adenocarcinoma, lung adenocarcinoma, and urothelial bladder cancer. The trial is expected to conclude by March 2027.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosis of a solid tumour which meets the criteria for an open trial cohort: o Cohort 1 (biliary tract adenocarcinoma): Locally advanced or metastatic biliary tract adenocarcinoma (intra- and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary cancer). Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards; or (in the opinion of the investigator) patients are unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy. o Cohort 2 (pancreatic ductal adenocarcinoma): Locally advanced or metastatic pancreatic ductal adenocarcinoma. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards. o Cohort 3 (lung adenocarcinoma): Locally advanced or metastatic lung adenocarcinoma. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards. o Cohort 4 (urothelial bladder cancer): Locally advanced or metastatic urothelial bladder cancer. Patients must have unresectable disease and have received all available conventional therapies known to confer clinical benefit for their disease based on local approved standards.
- Written pathology report / molecular profiling report indicating MDM2 amplification or a copy number ≥8, and TP53 wild-type status. This must have been confirmed with a tissue-based test. A test with liquid biopsy is not accepted.
- Archival tissue (formalin fixed paraffin embedded [FFPE] tumour blocks or slides) must be provided for retrospective confirmation of MDM2 amplification and TP53 status.
- Presence of at least 1 measurable target lesion according to RECIST version 1.1.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
- Patient must be willing to donate mandatory blood samples for the pharmacokinetics, pharmacodynamics, and biomarker analyses.
- Adequate organ function, as specified in the protocol.
- All toxicities related to previous anti-cancer therapies have resolved to ≤CTCAE Grade 1 prior to trial treatment administration (except for alopecia and amenorrhea / menstrual disorders which can be of any grade and peripheral neuropathy which must be ≤CTCAE Grade 2).
- Life expectancy ≥3 months at the start of treatment in the opinion of the investigator.
- 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 ICF. Women of childbearing potential 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.
Exclusion Criteria
- Previous administration of BI 907828 or any other MDM2-p53 or MDMX (MDM4)-p53 antagonist.
- 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 4 weeks prior to start of trial treatment or planned within 6 months after screening (e.g. hip replacement).
- Clinically significant previous or concomitant malignancies in the opinion of the investigator affecting the efficacy and/or outcome of the trial.
- 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.
- Any history of, or concomitant condition that, in the opinion of the investigator, would compromise the patient’s ability to comply with the trial or interfere with the evaluation of the safety and efficacy of the trial drug.
- 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).
- 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 breastfeeding from the start of trial treatment until 6 months and 12 days after last dose of trial treatment.
- Patients with known history of human immunodeficiency virus (HIV) infection who meet 1 or more of the following criteria: o CD4+ count <350 cells/μL o Viral load >400 copies/mL (local laboratory assessment) o Not receiving antiretroviral therapy o Receiving established antiretroviral therapy for <4 weeks prior to the start of trial treatment o History of AIDS-defining opportunistic infections within 12 months prior to start of trial treatment Patients with a history of HIV who do not meet any of the criteria above are eligible to participate but the patient must be under the care of a HIV/Infectious Diseases specialist or a HIV/Infectious Diseases specialist must be consulted prior to inclusion.
- Patients with a history of HCV infection who meet 1 or more of the following criteria: o Currently receiving curative antiviral treatment o Not yet achieved sustained viral response (SVR) o HCV viral load is above the limit of quantification (HCV RNA positive)
- Patients with chronic HBV infection with active disease who meet the criteria for anti- HBV therapy (according to local / institutional standard) and who have not been treated with suppressive antiviral therapy prior to initiation of trial treatment.
- Further exclusion criteria apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 22 Nov 2022 | 2 |
 Belgium | Not Recruiting | 22 Nov 2022 | 5 |
 France | Not Recruiting | 22 Nov 2022 | 12 |
 Germany | Not Recruiting | 22 Nov 2022 | 8 |
 Spain | Not Recruiting | 22 Nov 2022 | 11 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BI 907828 | Test | FILM-COATED TABLET | ORAL USE | 20 | 48 | PRD10565901 |
BI 907828 | Test | FILM-COATED TABLET | ORAL USE | 45 | 48 | PRD10565911 |
BI 907828 | Test | FILM-COATED TABLET | ORAL USE | 30 | 48 | PRD10565907 |