Mouse double minute 2 homolog (MDM2) is a key negative regulator of the tumor suppressor p53. Blocking the MDM2-p53 interaction, and restoring p53 function, is therefore a potential therapeutic strategy in MDM2-amplified, TP53 wild-type tumors. MDM2 is amplified in several tumor types, including biliary tract cancer (BTC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma and bladder cancer, all of which have limited treatment options and poor patient outcomes. Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer.
Trial registration: ClinicalTrials.gov NCT05512377.
Keywords: BI 907828; BTC; MDM2; PDAC; Phase II trial; TP53; brigimadlin; cholangiocarcinoma; gallbladder.
In some types of cancer, including cancers of the bile duct, pancreas, bladder and lung, the number of copies of a gene called MDM2 is abnormally increased (MDM2 amplification). MDM2 usually regulates p53, a protein that stops cancer cells from growing uncontrollably. When MDM2 is amplified, the cell makes too much of the MDM2 protein, which prevents p53 from stopping cancer growth. Blocking the interaction between MDM2 and p53 may allow p53 to do its job again and stop cancer cells from growing. Brightline-2 is a clinical trial that is currently in progress. This trial is assessing the efficacy and safety of an investigational drug, brigimadlin (or BI 907828), in patients with selected advanced or metastatic cancers. To be included, patients must have advanced biliary tract cancer, pancreatic ductal adenocarcinoma, bladder cancer, or lung adenocarcinoma. The tumor must show amplification of MDM2 when tested by a laboratory. Patients will take a 45 mg tablet of brigimadlin by mouth, once every 3 weeks. In this trial, researchers are investigating the ability of the drug to shrink tumors, the side effects of the drug, and the impact of the drug on a patients' quality of life. The goal of this trial is to assess the potential of brigimadlin as a new treatment option for patients with advanced biliary tract cancer, pancreatic ductal adenocarcinoma, bladder cancer, or lung adenocarcinoma. Clinical Trial Registration: NCT05512377 (ClinicalTrials.gov).