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

  • Sophie Cousin
    Medical Oncology Department Institut Bergonié Bordeaux France
  • Jean‐Yves Blay
    Medical Oncology Department Centre Léon Bérard Lyon France
  • Irene Braña Garcia
    Medical Oncology Department Vall d'Hebron University Hospital, Vall d'Hebron Institut of Oncology (VHIO) Barcelona Spain
  • Johann S. de Bono
    The Institute of Cancer Research and Royal Marsden Hospital London UK
  • Christophe Le Tourneau
    Department of Drug Development and Innovation (D3i), INSERM U900 Research Unit Institut Curie, Paris‐Saclay University Paris and Saint‐Cloud France
  • Victor Moreno
    Medical Oncology, START Madrid‐FJD Fundación Jiménez Díaz Hospital Madrid Spain
  • Jose Trigo
    Medical Oncology Department Hospital Universitario Virgen de la Victoria y Regional, IBIMA Málaga Spain
  • Christine L. Hann
    Johns Hopkins University School of Medicine Baltimore Maryland USA
  • Arun A. Azad
    Peter MacCallum Cancer Centre Victoria Australia
  • Seock‐Ah Im
    Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine Seoul Republic of Korea
  • Philippe A. Cassier
    Medical Oncology Department Centre Léon Bérard Lyon France
  • Christopher A. French
    Department of Pathology Brigham and Women's Hospital Boston Massachusetts USA
  • Antoine Italiano
    Early Phase Trials and Sarcoma Units Institut Bergonié Bordeaux France
  • Vicki L. Keedy
    Department of Medicine, Hematology and Oncology Vanderbilt‐Ingram Cancer Center Nashville Tennessee USA
  • Ruth Plummer
    Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne UK
  • Marie‐Paule Sablin
    Department of Drug Development and Innovation (D3i), INSERM U900 Research Unit Institut Curie, Paris‐Saclay University Paris and Saint‐Cloud France
  • Matthew L. Hemming
    Department of Medical Oncology, Dana‐Farber Cancer Institute and Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA
  • Geraldine Ferron‐Brady
    GSK Collegeville Pennsylvania USA
  • Anastasia Wyce
    GSK Collegeville Pennsylvania USA
  • Ahmed Khaled
    GSK Collegeville Pennsylvania USA
  • Antara Datta
    GSK Collegeville Pennsylvania USA
  • Shawn W. Foley
    GSK Collegeville Pennsylvania USA
  • Michael T. McCabe
    GSK Collegeville Pennsylvania USA
  • Yuehui Wu
    GSK Collegeville Pennsylvania USA
  • Thierry Horner
    GSK Collegeville Pennsylvania USA
  • Brandon E. Kremer
    GSK Collegeville Pennsylvania USA
  • Arindam Dhar
    GSK Collegeville Pennsylvania USA
  • Peter J. O'Dwyer
    Abramson Cancer Center University of Pennsylvania Philadelphia Pennsylvania USA
  • Geoffrey I. Shapiro
    Department of Medical Oncology, Dana‐Farber Cancer Institute and Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA
  • Sarina A. Piha‐Paul
    Department of Investigational Cancer Therapeutics University of Texas MD Anderson Cancer Center Houston Texas USA

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<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

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