PMID- 35949290
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221122
IS  - 2235-1795 (Print)
IS  - 1664-5553 (Electronic)
IS  - 1664-5553 (Linking)
VI  - 11
IP  - 3
DP  - 2022 Jun
TI  - First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with 
      GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers.
PG  - 268-277
LID - 10.1159/000522418 [doi]
AB  - INTRODUCTION: GNS561/Ezurpimtrostat is a first-in-class, orally bioavailable, 
      small molecule that blocks cancer cell proliferation by inhibiting late-stage 
      autophagy and dose-dependent build-up of enlarged lysosomes by interacting with 
      the palmitoyl-protein thioesterase 1 (PPT1). METHODS: This phase I, open-label, 
      dose-escalation trial (3 + 3 design) explored two GNS561 dosing schedules: one 
      single oral intake 3 times a week (Q3W) and twice daily (BID) continuous oral 
      administration in patients with advanced hepatocellular carcinoma, 
      cholangiocarcinoma, and pancreatic adenocarcinoma or colorectal adenocarcinomas 
      with liver metastasis. The primary objective was to determine GNS561 recommended 
      phase II dose (RP2D) and schedule. Secondary objectives included evaluation of 
      the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor 
      activity of GNS561. RESULTS: Dose escalation ranged from 50 to 400 mg Q3W to 
      200-300 mg BID. Among 26 evaluable patients for safety, 20 were evaluable for 
      efficacy and no dose-limiting toxicity was observed. Adverse events (AEs) 
      included gastrointestinal grade 1-2 events, primarily nausea and vomiting 
      occurred in 13 (50%) and 14 (54%) patients, respectively, and diarrhea in 11 
      (42%) patients. Seven grade 3 AEs were reported (diarrhea, decreased appetite, 
      fatigue, alanine aminotransferase, and aspartate aminotransferase increased). Q3W 
      administration was associated with limited exposure and the BID schedule was 
      preferred. At 200 mg BID GNS561, plasma and liver concentrations were comparable 
      to active doses in animal models. Liver trough concentrations were much higher 
      than in plasma a median time of 28 days of administration with a mean liver to 
      plasma ratio of 9,559 (Min 149-Max 25,759), which is in accordance with rat 
      preclinical data observed after repeated administration. PPT1 expression in 
      cancer tissues in the liver was reduced upon GNS561 exposure. There was no 
      complete or partial response. Five patients experienced tumor stable diseases 
      (25%), including one minor response (-23%). CONCLUSION: Based on a favorable 
      safety profile, exposure, and preliminary signal of activity, oral GNS561 RP2D 
      was set at 200 mg BID. Studies to evaluate the antitumor activity of GNS561 in 
      hepatocarcinoma cells and intrahepatic cholangiocarcinoma are to follow 
      NCT03316222.
CI  - Copyright (c) 2022 by S. Karger AG, Basel.
FAU - Harding, James J
AU  - Harding JJ
AD  - Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
AD  - Department of Medicine, Weill Medical College at Cornell University, New York, 
      New York, USA.
FAU - Awada, Ahmad
AU  - Awada A
AD  - Department of Oncology, Institute Jules Bordet, Brussels, Belgium.
FAU - Roth, Gael
AU  - Roth G
AD  - Department of Hepatology and Gastroenterology, CHU Grenoble Alpes, Institute for 
      Advanced Biosciences Research Center Inserm U 1209/CNRS 5309, University Grenoble 
      Alpes, Grenoble, France.
FAU - Decaens, Thomas
AU  - Decaens T
AD  - Department of Hepatology and Gastroenterology, CHU Grenoble Alpes, Institute for 
      Advanced Biosciences Research Center Inserm U 1209/CNRS 5309, University Grenoble 
      Alpes, Grenoble, France.
FAU - Merle, Philippe
AU  - Merle P
AD  - Department of Hepatology and Gastroenterology, Hospices Civils de Lyon, Lyon, 
      France.
FAU - Kotecki, Nuria
AU  - Kotecki N
AD  - Department of Oncology, Institute Jules Bordet, Brussels, Belgium.
FAU - Dreyer, Chantal
AU  - Dreyer C
AD  - Department of Oncology, Hospital Saint Joseph, Paris, France.
FAU - Ansaldi, Christelle
AU  - Ansaldi C
AD  - Genoscience Pharma, Marseille, France.
FAU - Rachid, Madani
AU  - Rachid M
AD  - Genoscience Pharma, Marseille, France.
FAU - Mezouar, Soraya
AU  - Mezouar S
AD  - Genoscience Pharma, Marseille, France.
FAU - Menut, Agnes
AU  - Menut A
AD  - Genoscience Pharma, Marseille, France.
FAU - Bestion, Eloine Nadeige
AU  - Bestion EN
AD  - Genoscience Pharma, Marseille, France.
FAU - Paradis, Valerie
AU  - Paradis V
AD  - Department of Pathology, Hospital Beaujon, Paris, France.
FAU - Halfon, Philippe
AU  - Halfon P
AD  - Genoscience Pharma, Marseille, France.
FAU - Abou-Alfa, Ghassan K
AU  - Abou-Alfa GK
AD  - Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, New 
      York, USA.
AD  - Department of Medicine, Weill Medical College at Cornell University, New York, 
      New York, USA.
FAU - Raymond, Eric
AU  - Raymond E
AD  - Department of Oncology, Hospital Saint Joseph, Paris, France.
AD  - Genoscience Pharma, Marseille, France.
LA  - eng
SI  - ClinicalTrials.gov/NCT03316222
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20220215
PL  - Switzerland
TA  - Liver Cancer
JT  - Liver cancer
JID - 101597993
PMC - PMC9218623
OTO - NOTNLM
OT  - Autophagy
OT  - Cholangiocarcinoma
OT  - GNS561/ezurpimtrostat
OT  - Hepatocellular carcinoma
OT  - Lysosome
OT  - Palmitoyl-protein thioesterase 1
OT  - Phase 1 trial
COIS- J.J.H. received research support from Bristol Myers Squibb and consulting fees 
      from Bristol Myers Squibb, Merck, Eli Lilly, Eisai, Exelexis, CytomX, Imvax, 
      Adaptiimmune, QED, and Zymeworks. G.K.A. receives research support from Arcus, 
      Agios, Astra Zeneca, Bayer, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, 
      Genoscience, Incyte, Polaris, Puma, QED, Sillajen, and Yiviva and consulting fees 
      from Adicet, Agios, Astra Zeneca, Alnylam, Autem, Bayer, Beigene, Berry Genomics, 
      Cend, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, 
      Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck, MINA, Nerviano, 
      QED, Redhill, Rafael, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, 
      Twoxar, Vector, and Yiviva. A.A. received consulting fees from Roche, Lilly, 
      Amgen, Eisai, BMS, Pfizer, Novartis, MSD, Genomic Health, Ipsen, AstraZeneca, 
      Bayer, Leo Pharma, Merck, and Daiichi. G.R. received consulting fees and 
      honoraria from Accord Healthcare, Abbvie, Amgen, Ipsen, Sanofi, and Servier. T.D. 
      received research support from Genoscience, ArQule; and consulting fees from 
      Bristol Myers Squibb, IPSEN, Becton Dickinson, AstraZeneca, Bayer, Roche, Eisai, 
      Sirtex, BTG, AbbVie, Gilead, Merck, Guerbet, and Sanofi. P.M. received grants 
      from NXEO and IPSEN and consulting/AdBoards fees from Bayer Schering Pharma, 
      Ipsen, Eisai, Bristol Myers Squibb, Merck, Eli Lilly, AstraZeneca, Roche, and 
      Merck. N.K. received consulting fees and honoraria from Innate, Erytech, 
      Leopharma, and Seattle genetics. E.R. received consulting fees from Genoscience, 
      SCOR, StromaCare and own shares from SCOR, Genoscience, and Axoltis.
EDAT- 2022/08/12 06:00
MHDA- 2022/08/12 06:01
PMCR- 2022/02/15
CRDT- 2022/08/11 02:15
PHST- 2021/09/27 00:00 [received]
PHST- 2022/01/29 00:00 [accepted]
PHST- 2022/08/11 02:15 [entrez]
PHST- 2022/08/12 06:00 [pubmed]
PHST- 2022/08/12 06:01 [medline]
PHST- 2022/02/15 00:00 [pmc-release]
AID - lic-0011-0268 [pii]
AID - 10.1159/000522418 [doi]
PST - epublish
SO  - Liver Cancer. 2022 Feb 15;11(3):268-277. doi: 10.1159/000522418. eCollection 2022 
      Jun.