| Abstrakt: |
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. Plain language summary Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced BTC, PDAC, or other solid tumors 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) Executive summary Background Patients with advanced or metastatic biliary tract cancer (BTC) or pancreatic ductal adenocarcinoma (PDAC) generally have a poor prognosis, with a median survival of ≈1 year. Patients with lung adenocarcinomas or bladder cancer have similarly poor survival rates. Current first- and second-line treatments for these conditions include chemotherapy; however, the benefit – especially for second-line chemotherapy – is modest. The MDM2 gene encodes a negative regulator of the p53 tumor suppressor protein. Antagonism of Mouse double minute 2 homolog (MDM2) can restore p53 activity and represents a novel therapeutic strategy. MDM2 is amplified in various solid tumors, including BTC (5–8%), PDAC (1%), lung adenocarcinoma (5%) and bladder cancer (8%). Brigimadlin (BI 907828) Brigimadlin (or BI 907828) is an oral, MDM2–p53 antagonist that inhibits the interaction between MDM2 and p53. In a subgroup of ten patients with advanced MDM2-amplified BTC from two ongoing phase Ia/Ib trials, brigimadlin (with or without the anti-PD-1 inhibitor ezabenlimab) showed early signs of activity, with 50% of patients demonstrating a partial response. In these two phase Ia/Ib trials, brigimadlin was associated with a manageable safety profile, both as monotherapy and in combination with ezabenlimab. Brightline-2 trial This is an ongoing phase IIa/IIb, open-label, single-arm, multicenter trial with brigimadlin in patients with BTC, PDAC, or other solid tumors. Eligible patients are adults with locally advanced or metastatic MDM2-amplified, TP53 wild-type BTC, PDAC, lung adenocarcinoma, or bladder cancer with at least one measurable target lesion, Eastern Cooperative Oncology Group performance status of 0 or 1, and who have received appropriate prior standard of care therapy. The phase IIa part of the trial will include five cohorts with the following estimated patient numbers: Cohort 1 (BTC; n = 30), Cohort 1-CN (BTC in mainland China; n = 25), Cohort 2 (PDAC; n = 10), Cohort 3 (lung adenocarcinoma; n = 15) and Cohort 4 (bladder cancer; n = 15). All patients will receive brigimadlin 45 mg orally once every 3 weeks, with up to two dose reductions allowed. An interim futility analysis will be performed for the first 30 patients in Cohort 1 only. A non-binding futility boundary of objective response rate = 20% is planned for the interim futility analysis. The total sample size for Cohort 1 will be ∼90 patients. The primary end point is objective response rate based on central independent review. Secondary end points include duration of response, progression-free survival, overall survival, disease control, patient-reported outcomes, treatment-emergent adverse events and the occurrence of treatment-emergent adverse events leading to discontinuation of brigimadlin. [ABSTRACT FROM AUTHOR] |
