Phase 1 study of molibresib (GSK525762), a bromodomain and extra-terminal domain protein inhibitor, in NUT carcinoma and other solid tumors

Sarina A. Piha-Paul, Christine L. Hann, Christopher A. French, Sophie Cousin, Irene Braña, Phillippe A. Cassier, Victor Moreno, Johann S. de Bono, Sara Duckworth Harward, Geraldine Ferron-Brady, Olena Barbash, Anastasia Wyce, Yuehui Wu, Thierry Horner, Meg Annan, Nigel J. Parr, Rabinder K. Prinjha, Christopher L. Carpenter, John Hilton, David S. HongNaomi B. Haas, Mark C. Markowski, Arindam Dhar, Peter J. O’Dwyer, Geoffrey I. Shapiro

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28 Scopus citations


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 þ 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.

Original languageEnglish (US)
Article numberPKZ093
JournalJNCI Cancer Spectrum
Issue number2
StatePublished - 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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