PMID- 34724226
OWN - NLM
STAT- MEDLINE
DCOM- 20220218
LR  - 20220218
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 150
IP  - 6
DP  - 2022 Mar 15
TI  - 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.
PG  - 993-1006
LID - 10.1002/ijc.33861 [doi]
AB  - 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.
CI  - (c) 2021 UICC.
FAU - Cousin, Sophie
AU  - Cousin S
AUID- ORCID: 0000-0002-4847-6329
AD  - Medical Oncology Department, Institut Bergonie, Bordeaux, France.
FAU - Blay, Jean-Yves
AU  - Blay JY
AUID- ORCID: 0000-0001-7190-120X
AD  - Medical Oncology Department, Centre Leon Berard, Lyon, France.
FAU - Garcia, Irene Brana
AU  - Garcia IB
AD  - Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron 
      Institut of Oncology (VHIO), Barcelona, Spain.
FAU - de Bono, Johann S
AU  - de Bono JS
AD  - The Institute of Cancer Research and Royal Marsden Hospital, London, UK.
FAU - Le Tourneau, Christophe
AU  - Le Tourneau C
AD  - Department of Drug Development and Innovation (D3i), INSERM U900 Research Unit, 
      Institut Curie, Paris-Saclay University, Paris and Saint-Cloud, France.
FAU - Moreno, Victor
AU  - Moreno V
AD  - Medical Oncology, START Madrid-FJD, Fundacion Jimenez Diaz Hospital, Madrid, 
      Spain.
FAU - Trigo, Jose
AU  - Trigo J
AD  - Medical Oncology Department, Hospital Universitario Virgen de la Victoria y 
      Regional, IBIMA, Malaga, Spain.
FAU - Hann, Christine L
AU  - Hann CL
AD  - Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
FAU - Azad, Arun A
AU  - Azad AA
AD  - Peter MacCallum Cancer Centre, Victoria, Australia.
FAU - Im, Seock-Ah
AU  - Im SA
AUID- ORCID: 0000-0002-5396-6533
AD  - Seoul National University Hospital, Cancer Research Institute, Seoul National 
      University College of Medicine, Seoul, Republic of Korea.
FAU - Cassier, Philippe A
AU  - Cassier PA
AD  - Medical Oncology Department, Centre Leon Berard, Lyon, France.
FAU - French, Christopher A
AU  - French CA
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, 
      USA.
FAU - Italiano, Antoine
AU  - Italiano A
AUID- ORCID: 0000-0002-8540-5351
AD  - Early Phase Trials and Sarcoma Units, Institut Bergonie, Bordeaux, France.
FAU - Keedy, Vicki L
AU  - Keedy VL
AD  - Department of Medicine, Hematology and Oncology, Vanderbilt-Ingram Cancer Center, 
      Nashville, Tennessee, USA.
FAU - Plummer, Ruth
AU  - Plummer R
AD  - Translational and Clinical Research Institute, Newcastle University, Newcastle 
      upon Tyne, UK.
FAU - Sablin, Marie-Paule
AU  - Sablin MP
AD  - Department of Drug Development and Innovation (D3i), INSERM U900 Research Unit, 
      Institut Curie, Paris-Saclay University, Paris and Saint-Cloud, France.
FAU - Hemming, Matthew L
AU  - Hemming ML
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute and Department of 
      Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 
      Massachusetts, USA.
FAU - Ferron-Brady, Geraldine
AU  - Ferron-Brady G
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Wyce, Anastasia
AU  - Wyce A
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Khaled, Ahmed
AU  - Khaled A
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Datta, Antara
AU  - Datta A
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Foley, Shawn W
AU  - Foley SW
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - McCabe, Michael T
AU  - McCabe MT
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Wu, Yuehui
AU  - Wu Y
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Horner, Thierry
AU  - Horner T
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Kremer, Brandon E
AU  - Kremer BE
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - Dhar, Arindam
AU  - Dhar A
AD  - GSK, Collegeville, Pennsylvania, USA.
FAU - O'Dwyer, Peter J
AU  - O'Dwyer PJ
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, 
      USA.
FAU - Shapiro, Geoffrey I
AU  - Shapiro GI
AUID- ORCID: 0000-0002-3331-4095
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute and Department of 
      Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 
      Massachusetts, USA.
FAU - Piha-Paul, Sarina A
AU  - Piha-Paul SA
AUID- ORCID: 0000-0001-9455-1660
AD  - Department of Investigational Cancer Therapeutics, University of Texas MD 
      Anderson Cancer Center, Houston, Texas, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01587703
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211126
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (DNER protein, human)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 12794-10-4 (Benzodiazepines)
RN  - 5QIO6SRZ2R (molibresib)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Benzodiazepines/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Nerve Tissue Proteins/antagonists & inhibitors
MH  - Nuclear Proteins/*metabolism
MH  - Receptors, Cell Surface/antagonists & inhibitors
MH  - Testicular Neoplasms/*drug therapy
MH  - Young Adult
OTO - NOTNLM
OT  - BET inhibitor
OT  - NUT carcinoma
OT  - castration-resistant prostate cancer
OT  - molibresib
EDAT- 2021/11/02 06:00
MHDA- 2022/02/19 06:00
CRDT- 2021/11/01 17:00
PHST- 2021/07/01 00:00 [revised]
PHST- 2021/01/26 00:00 [received]
PHST- 2021/07/13 00:00 [accepted]
PHST- 2021/11/02 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2021/11/01 17:00 [entrez]
AID - 10.1002/ijc.33861 [doi]
PST - ppublish
SO  - Int J Cancer. 2022 Mar 15;150(6):993-1006. doi: 10.1002/ijc.33861. Epub 2021 Nov 
      26.