Related Experiment Video
Updated: Dec 23, 2025
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma
Sarina A Piha-Paul1, Christine L Hann2, Christopher A French3
1University of Texas MD Anderson Cancer Center, Houston, TX.
Background:
Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors.
Methods:
This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker.
Results:
Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60-100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%-42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3-7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months.
Conclusions:
Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.
Insights
The bromodomain and extra-terminal domain inhibitor molibresib shows promise for treating nuclear protein in testis (NUT) carcinoma. This first-in-human study found molibresib to be well-tolerated with preliminary antitumor activity in NUT carcinoma patients.
Area of Science:
- Epigenetics
- Oncology
- Pharmacology
Background:
- Bromodomain and extra-terminal domain (BET) proteins are key epigenetic regulators and promising targets for anticancer therapies.
- Molibresib (GSK525762) is an orally administered BET inhibitor evaluated in this study.
- Nuclear protein in testis (NUT) carcinoma (NC) is a rare and aggressive cancer with limited treatment options.
Purpose of the Study:
- To assess the safety, tolerability, and pharmacokinetics of molibresib in patients with solid tumors, including NC.
- To determine the recommended Phase II dose (RP2D) of molibresib.
- To evaluate the preliminary antitumor activity and pharmacodynamic effects of molibresib.
Main Methods:
- A Phase I/II, open-label, dose-escalation study using a 3+3 design.
- Molibresib was administered orally once daily, with dose escalation until dose-limiting toxicities were observed.
- Pharmacokinetic parameters and pharmacodynamic biomarker (monocyte chemoattractant protein-1) levels were assessed.
Main Results:
- Sixty-five patients received molibresib; the recommended Phase II dose was determined to be 80 mg once daily.
- The most frequent adverse events included thrombocytopenia and gastrointestinal issues; molibresib demonstrated an acceptable safety profile up to 100 mg.
- Preliminary efficacy in 19 NC patients showed partial responses in 4 patients and stable disease in 8, with 4 patients progression-free for over 6 months.
Conclusions:
- Once-daily oral administration of molibresib is tolerated at doses that achieve target engagement.
- Preliminary data suggest proof-of-concept for molibresib in treating nuclear protein in testis (NUT) carcinoma.
- Molibresib represents a potential new therapeutic strategy for patients with advanced solid tumors, particularly NC.
More Related Videos
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
10:27Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:56Treatment Resistant Cancers
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:43Mouse Models of Cancer Study
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...