Related Experiment Video

Updated: Feb 11, 2026

Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies
08:34

Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies

Published on: February 6, 2019

21.1K

Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients

Jeremy Lewin1, Jean-Charles Soria1, Anastasios Stathis1

  • 1Jeremy Lewin and Lillian L. Siu, Princess Margaret Cancer Center, Toronto, Ontario, Canada; Jean-Charles Soria and Christophe Massard, Institut Gustave Roussy and University Paris-Sud, Villejuif; Jean-Pierre Delord, Institut Claudius Regaud Oncopole, Toulouse; Mohamed Bekradda, Oncology Therapeutic Development, Clichy; Keyvan Rezai, Hôpital René Huguenin, Saint-Cloud, France; Anastasios Stathis, Oncology Institute of Southern Switzerland, Bellinzona; Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ahmad Awada and Philippe G. Aftimos, Université Libre de Bruxelles, Brussels, Belgium; and Zhen Zeng, Azher Hussain, and Susan Perez, Merck & Co, Kenilworth, NJ.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
|May 8, 2018
PubMed
Abstract

Insights

Birabresib (MK-8628/OTX015), a bromodomain inhibitor, showed clinical activity in nuclear protein in testis midline carcinoma (NMC). The recommended phase II dose is 80 mg daily, but intermittent dosing may reduce toxicities.

Area of Science:

  • Oncology
  • Pharmacology

Background:

  • Birabresib (MK-8628/OTX015) is a novel bromodomain inhibitor with demonstrated activity in certain hematologic malignancies.
  • This study investigated the safety, efficacy, and pharmacokinetics of birabresib in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer.

Purpose of the Study:

  • To evaluate the safety and efficacy of birabresib in patients with select solid tumors.
  • To determine the dose-limiting toxicities (DLTs) and establish the recommended phase II dose (RP2D) of birabresib.

Main Methods:

  • A phase Ib, parallel dose-escalation study using a 3+3 design enrolled 47 patients.
  • Patients received birabresib at 80 mg continuously (cohort A) or 100 mg for 7 days (cohort B) in 21-day cycles.
  • The primary objective was to identify DLTs and the RP2D.

Main Results:

  • Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer.
  • Dose-limiting toxicities (DLTs) were observed in cohort A (21% at 80 mg, 67% at 100 mg), primarily thrombocytopenia and elevated liver enzymes.
  • No DLTs occurred in cohort B. Common adverse events included diarrhea, nausea, anorexia, and thrombocytopenia. Partial responses were observed in three NMC patients.
  • Birabresib demonstrated dose-proportional pharmacokinetics with rapid absorption.

Conclusions:

  • The recommended phase II dose (RP2D) for birabresib in select solid tumors is 80 mg once daily with continuous dosing.
  • Birabresib exhibits dose-proportional exposure and a manageable safety profile, with observed clinical activity in NMC.
  • Future research should explore intermittent dosing schedules to potentially mitigate chronic dosing toxicities.

More Related Videos

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b10:20

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

Published on: November 11, 2016

9.0K
Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

11.8K

Related Concept Videos

Phase Transitions02:31

Phase Transitions

Whether solid, liquid, or gas, a substance's state depends on the order and arrangement of its particles (atoms, molecules, or ions). Particles in the solid pack closely together, generally in a pattern. The particles vibrate about their fixed positions but do not move or squeeze past their neighbors. In liquids, although the particles are closely spaced, they are randomly arranged. The position of the particles are not fixed—that is, they are free to move past their neighbors to...
23.3K
Phase Transitions: Sublimation and Deposition02:33

Phase Transitions: Sublimation and Deposition

Some solids can transition directly into the gaseous state, bypassing the liquid state, via a process known as sublimation. At room temperature and standard pressure, a piece of dry ice (solid CO2) sublimes, appearing to gradually disappear without ever forming any liquid. Snow and ice sublimate at temperatures below the melting point of water, a slow process that may be accelerated by winds and the reduced atmospheric pressures at high altitudes. When solid iodine is warmed, the solid sublimes...
20.3K
Phase Diagrams02:39

Phase Diagrams

A phase diagram combines plots of pressure versus temperature for the liquid-gas, solid-liquid, and solid-gas phase-transition equilibria of a substance. These diagrams indicate the physical states that exist under specific conditions of pressure and temperature and also provide the pressure dependence of the phase-transition temperatures (melting points, sublimation points, boiling points). Regions or areas labeled solid, liquid, and gas represent single phases, while lines or curves represent...
50.4K
Molecular and Ionic Solids02:54

Molecular and Ionic Solids

Crystalline solids are divided into four types: molecular, ionic, metallic, and covalent network based on the type of constituent units and their interparticle interactions.
Molecular Solids
Molecular crystalline solids, such as ice, sucrose (table sugar), and iodine, are solids that are composed of neutral molecules as their constituent units. These molecules are held together by weak intermolecular forces such as London dispersion forces, dipole-dipole interactions, or hydrogen bonds, which...
20.2K
Phase Transitions: Melting and Freezing02:39

Phase Transitions: Melting and Freezing

Heating a crystalline solid increases the average energy of its atoms, molecules, or ions, and the solid gets hotter. At some point, the added energy becomes large enough to partially overcome the forces holding the molecules or ions of the solid in their fixed positions, and the solid begins the process of transitioning to the liquid state or melting. At this point, the temperature of the solid stops rising, despite the continual input of heat, and it remains constant until all of the solid is...
15.3K
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.0K