Abstract：
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.
Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced BTC, PDAC, or other solid tumorsIn 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).
Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced BTC, PDAC, or other solid tumorsIn 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).
摘要：
小鼠双分2同源物(MDM2)是肿瘤抑制因子p53的关键负调控因子。阻断MDM2-p53相互作用，恢复p53功能，因此是MDM2扩增的潜在治疗策略，TP53野生型肿瘤。MDM2在几种肿瘤类型中扩增，包括胆道癌（BTC），胰腺导管腺癌（PDAC），肺腺癌和膀胱癌，所有这些都有有限的治疗选择和不良的患者结局.Brigimadlin（BI907828）是一种高效的MDM2-p53拮抗剂，在临床前和早期临床研究中显示出有希望的活性。该手稿描述了正在进行的IIa/IIbBrightline-2期试验的基本原理和设计，该试验评估了brigimadlin作为晚期/转移性BTC患者的二线治疗，PDAC,肺腺癌,或者膀胱癌.
在某些类型的癌症中，包括胆管癌,胰腺,膀胱和肺，称为MDM2的基因的拷贝数异常增加（MDM2扩增）。MDM2通常调节p53，这是一种阻止癌细胞不受控制地生长的蛋白质。当MDM2被扩增时，细胞产生过多的MDM2蛋白，阻止p53阻止癌症生长。阻断MDM2和p53之间的相互作用可能使p53再次发挥作用并阻止癌细胞生长。Brightline-2是一项正在进行的临床试验。该试验正在评估研究药物的有效性和安全性，brigimadlin（或BI907828），在选定的晚期或转移性癌症患者中。要包括在内，患者必须患有晚期胆道癌，胰腺导管腺癌,膀胱癌,或者肺腺癌.当通过实验室测试时,肿瘤必须显示MDM2的扩增。患者将口服45毫克的brigimadlin片剂，每三周一次。在这次审判中,研究人员正在研究这种药物缩小肿瘤的能力，药物的副作用，以及药物对患者生活质量的影响。这项试验的目的是评估brigimadlin作为晚期胆道癌患者的新治疗选择的潜力，胰腺导管腺癌,膀胱癌,或者肺腺癌.临床试验注册：NCT05512377（ClinicalTrials.gov）。
在某些类型的癌症中，包括胆管癌,胰腺,膀胱和肺，称为MDM2的基因的拷贝数异常增加（MDM2扩增）。MDM2通常调节p53，这是一种阻止癌细胞不受控制地生长的蛋白质。当MDM2被扩增时，细胞产生过多的MDM2蛋白，阻止p53阻止癌症生长。阻断MDM2和p53之间的相互作用可能使p53再次发挥作用并阻止癌细胞生长。Brightline-2是一项正在进行的临床试验。该试验正在评估研究药物的有效性和安全性，brigimadlin（或BI907828），在选定的晚期或转移性癌症患者中。要包括在内，患者必须患有晚期胆道癌，胰腺导管腺癌,膀胱癌,或者肺腺癌.当通过实验室测试时,肿瘤必须显示MDM2的扩增。患者将口服45毫克的brigimadlin片剂，每三周一次。在这次审判中,研究人员正在研究这种药物缩小肿瘤的能力，药物的副作用，以及药物对患者生活质量的影响。这项试验的目的是评估brigimadlin作为晚期胆道癌患者的新治疗选择的潜力，胰腺导管腺癌,膀胱癌,或者肺腺癌.临床试验注册：NCT05512377（ClinicalTrials.gov）。
