Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies

Purpose: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose–escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). Patients and Methods: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. Results: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. Conclusions: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.

[1]  Jun Yu Li,et al.  The Novel Bromodomain and Extraterminal Domain Inhibitor INCB054329 Induces Vulnerabilities in Myeloma Cells That Inform Rational Combination Strategies , 2018, Clinical Cancer Research.

[2]  G. Borthakur,et al.  Bromodomain inhibitors: what does the future hold? , 2018, Clinical advances in hematology & oncology : H&O.

[3]  C. Britten,et al.  Phase ib/2a study of PLX51107, a small molecule BET inhibitor, in subjects with advanced hematological malignancies and solid tumors. , 2018 .

[4]  I. Flinn,et al.  A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma , 2018 .

[5]  M. Dawson,et al.  A Phase I Study of GSK525762, a Selective Bromodomain (BRD) and Extra Terminal Protein (BET) Inhibitor: Results from Part 1 of Phase I/II Open Label Single Agent Study in Patients with Acute Myeloid Leukemia (AML) , 2017 .

[6]  K. Hoang-Xuan,et al.  Targeted therapies in 54 patients with Erdheim-Chester disease, including follow-up after interruption (the LOVE study). , 2017, Blood.

[7]  P. LoRusso,et al.  BET inhibitors: a novel epigenetic approach , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  B. Ruggeri,et al.  Abstract 5080: BET inhibitors INCB054329 and INCB057643 display significant activity in androgen-independent prostate cancer models , 2017 .

[9]  R. Wynn,et al.  Abstract 5071: Preclinical characterization of the potent and selective BET inhibitor INCB057643 in models of hematologic malignancies , 2017 .

[10]  Y. Taniguchi.  The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins , 2016, International journal of molecular sciences.

[11]  H. Dombret,et al.  Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. , 2016, The Lancet. Haematology.

[12]  G. Salles,et al.  Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. , 2016, The Lancet. Haematology.

[13]  L. Ouyang,et al.  Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery , 2015, Oncotarget.

[14]  H. Dombret,et al.  A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Advanced Acute Leukemia , 2014 .

[15]  S. Knapp,et al.  Targeting bromodomains: epigenetic readers of lysine acetylation , 2014, Nature Reviews Drug Discovery.

[16]  S. Robson,et al.  Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia , 2011, Nature.

[17]  P. Sandy,et al.  Targeting MYC dependence in cancer by inhibiting BET bromodomains , 2011, Proceedings of the National Academy of Sciences.

[18]  R. Young,et al.  BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc , 2011, Cell.

[19]  Joel P. Mackay,et al.  Structural Basis and Specificity of Acetylated Transcription Factor GATA1 Recognition by BET Family Bromodomain Protein Brd3 , 2011, Molecular and Cellular Biology.

[20]  Shwu‐Yuan Wu,et al.  The Double Bromodomain-containing Chromatin Adaptor Brd4 and Transcriptional Regulation* , 2007, Journal of Biological Chemistry.