Unlabelled: Brigimadlin (BI 907828) is an oral MDM2-p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively).
Significance: We report phase Ia data indicating that the oral MDM2-p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10401071 | PMC |
| http://dx.doi.org/10.1158/2159-8290.CD-23-0153 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Investigating the P53-dependent anti-cancer effect of ibutamoren in human cancer cell lines.
Basic Clin Pharmacol Toxicol
January 2025
Department of Molecular Biology and Genetics, Graduate School of Natural and Applied Sciences, Mugla Sitki Kocman University, Mugla, Turkey.
The MDM2-p53 pathway plays a pivotal role in regulating cell cycle and apoptosis, with its dysfunction contributing to approximately 50% of human malignancies. MDM2, an E3 ubiquitin ligase, targets the tumour suppressor p53 for degradation, thereby promoting uncontrolled cell growth in cancers. Inhibiting the MDM2-p53 interaction represents a promising therapeutic strategy for reactivating p53's tumour-suppressive functions.
View Article and Find Full Text PDFTherapy-relevant amplification in cholangiocarcinomas in Caucasian patients.
Ther Adv Med Oncol
November 2024
Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany.
Article Synopsis
- Cholangiocarcinomas (CCA) are aggressive and poorly prognosed cancers, influenced by genetic changes such as MDM2 mutations; targeted therapies like Brigimadlin show potential benefits for specific patient groups.
- This study focused on 52 CCA patients to explore the relationship between MDM2 status and patient outcomes, using methods like FISH and IHC to analyze tumor samples.
- Results indicated that 5.8% of patients had MDM2 amplification, mostly in intrahepatic CCA, where improved survival rates were observed for those with amplification compared to those without.
An update patent review of MDM2-p53 interaction inhibitors (2019-2023).
Expert Opin Ther Pat
December 2024
Institute of Molecular and Industrial Biotechnology, Lodz University of Technology, Lodz, Poland.
Article Synopsis
- The p53 tumor suppressor protein is commonly disrupted in cancers through TP53 mutations or MDM2 overexpression, leading to interest in inhibitors that can release p53 for cancer therapy.
- The article reviews patents and patent applications from 2019 to 2023 for MDM2-p53 interaction inhibitors, categorizing newly discovered compounds into five groups based on their chemical structure.
- Despite two decades of research and various clinical evaluations, no MDM2-p53 inhibitors have been approved for market use yet, though over ten are still undergoing clinical trials, including some with promising FDA designations.
Targeting MDM2-mediated suppression of p53 with idasanutlin: a promising therapeutic approach for acute lymphoblastic leukemia.
Invest New Drugs
December 2024
Biotechnology Application and Research Centre, Bilecik Şeyh Edebali University, 11100, Bilecik, Turkey.
Despite available treatments for acute lymphoblastic leukemia (ALL), the disease's high clinical variability necessitates new therapeutic strategies, particularly for patients with high-risk features. The tumor suppressor protein p53, encoded by the TP53 gene and known as the guardian of the genome, plays a crucial role in preventing tumor development. Over 90% of ALL cases initially harbor wild-type TP53.
View Article and Find Full Text PDFDiscovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules.
Mol Cancer Ther
December 2024
Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria.
Article Synopsis
- * MDM2-p53 antagonists can restore p53 activity but have dose-limiting toxicities such as thrombocytopenia and neutropenia; to reduce these side effects, less frequent dosing is being explored with drugs like brigimadlin.
- * Brigimadlin, a new MDM2-p53 antagonist, has shown promise in preclinical models by effectively restoring p53 function and inhibiting tumor growth in cancers with TP53 mutations, supporting its further testing in cancer
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!