Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study

Int J Cancer. 2022 Mar 15;150(6):993-1006. doi: 10.1002/ijc.33861. Epub 2021 Nov 26.


Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted.

Trial registration: NCT01587703.

Keywords: BET inhibitor; NUT carcinoma; castration-resistant prostate cancer; molibresib.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / adverse effects
  • Benzodiazepines / pharmacokinetics
  • Benzodiazepines / therapeutic use*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism*
  • Receptors, Cell Surface / antagonists & inhibitors
  • Testicular Neoplasms / drug therapy*
  • Young Adult


  • DNER protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Receptors, Cell Surface
  • Benzodiazepines
  • molibresib

Associated data