| Reference | 1. Clin Cancer Res. 2017 Jul 1;23(13):3269-3276. doi: 10.1158/1078-0432.CCR-16-2272.
Epub 2017 Jan 4. <br />
<br />
First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine
2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid
Malignancies. <br />
<br />
Beatty GL(1)(2), O/’Dwyer PJ(3)(2), Clark J(4), Shi JG(4), Bowman KJ(4), Scherle
PA(4), Newton RC(4), Schaub R(4), Maleski J(4), Leopold L(4), Gajewski TF(5).
Author information: <br />
(1)Abramson Cancer Center, University of Pennsylvania, Philadelphia,
Pennsylvania. [email protected].
(2)Division of Hematology-Oncology, Department of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania.
(3)Abramson Cancer Center, University of Pennsylvania, Philadelphia,
Pennsylvania.
(4)Incyte Corporation, Wilmington, Delaware.
(5)Section of Hematology/Oncology, Department of Medicine, University of Chicago,
Chicago, Illinois. <br />
Purpose: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of
tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1
can promote tumor escape from host immunosurveillance. This first-in-human phase
I study investigated the maximum tolerated dose, safety, pharmacokinetics,
pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent
and selective inhibitor of IDO1.Experimental Design: Fifty-two patients with
advanced solid malignancies were treated with epacadostat [50 mg once daily or
50, 100, 300, 400, 500, 600, or 700 mg twice daily (BID)] in a dose-escalation 3
+ 3 design and evaluated in 28-day cycles. Treatment was continued until disease
progression or unacceptable toxicity.Results: One dose-limiting toxicity (DLT)
occurred at the dose of 300 mg BID (grade 3, radiation pneumonitis); another DLT
occurred at 400 mg BID (grade 3, fatigue). The most common adverse events in >20%
of patients overall were fatigue, nausea, decreased appetite, vomiting,<br />
constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. Treatment
produced significant dose-dependent reductions in plasma kynurenine levels and in
the plasma kynurenine/tryptophan ratio at all doses and in all patients. Near
maximal changes were observed at doses of ≥100 mg BID with >80% to 90% inhibition
of IDO1 achieved throughout the dosing period. Although no objective responses
were detected, stable disease lasting ≥16 weeks was observed in 7 of 52
patients.Conclusions: Epacadostat was generally well tolerated, effectively
normalized kynurenine levels, and produced maximal inhibition of IDO1 activity at
doses of ≥100 mg BID. Studies investigating epacadostat in combination with other
immunomodulatory drugs are ongoing. Clin Cancer Res; 23(13); 3269-76. ©2017 AACR. <br />
<br />
2. ACS Med Chem Lett. 2017 Mar 6;8(5):486-491. doi: 10.1021/acsmedchemlett.6b00391.
eCollection 2017 May 11. <br />
<br />
INCB24360 (Epacadostat), a Highly Potent and Selective
Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology. <br />
<br />
Yue EW(1), Sparks R(1), Polam P(1), Modi D(1), Douty B(1), Wayland B(1), Glass
B(1), Takvorian A(1), Glenn J(1), Zhu W(1), Bower M(1), Liu X(1), Leffet L(1),
Wang Q(1), Bowman KJ(1), Hansbury MJ(1), Wei M(1), Li Y(1), Wynn R(1), Burn
TC(1), Koblish HK(1), Fridman JS(1), Emm T(1), Scherle PA(1), Metcalf B(1), Combs
AP(1). <br />
Author information: <br />
(1)Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United
States. <br />
A data-centric medicinal chemistry approach led to the invention of a potent and
selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of
INCB24360 contains several previously unknown or underutilized functional groups
in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide.
These moieties taken together in a single structure afford a compound that falls
outside of /drug-like/ space. Nevertheless, the in vitro ADME data is consistent
with the good cell permeability and oral bioavailability observed in all species
(rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed
in the small molecule crystal structure of 4f is believed to significantly
contribute to the observed permeability and PK. Epacadostat in combination with
anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial
in patients with unresectable or metastatic melanoma. <br />
<br />
3. Oncotarget. 2016 Jun 21;7(25):37762-37772. doi: 10.18632/oncotarget.9326. <br />
<br />
The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity
and lytic ability of tumor antigen-specific T cells. <br />
<br />
Jochems C(1), Fantini M(1), Fernando RI(1), Kwilas AR(1), Donahue RN(1), Lepone
LM(1), Grenga I(1), Kim YS(2), Brechbiel MW(2), Gulley JL(3), Madan RA(3), Heery
CR(1), Hodge JW(1), Newton R(4), Schlom J(1), Tsang KY(1). <br />
Author information: <br />
(1)Laboratory of Tumor Immunology and Biology, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
(2)Radioimmune Inorganic Chemistry Section, Radiation Oncology Branch, Center for
Cancer Research, National Cancer Institute, National Institutes of Health,
Bethesda, MD, USA.
(3)Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD, USA.
(4)Incyte Corporation, Wilmington, DE, USA. <br />
Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that
suppresses systemic tryptophan catabolism and is currently being evaluated in
ongoing clinical trials. We investigated the effects of epacadostat on (a) human
dendritic cells (DCs) with respect to maturation and ability to activate human
tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis
of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral
blood mononuclear cells (PBMCs) in vitro. Simultaneous treatment with epacadostat
and IFN-γ plus lipopolysaccharide (LPS) did not change the phenotype of matured
human DCs, and as expected decreased the tryptophan breakdown and kynurenine
production. Peptide-specific T-cell lines stimulated with DCs pulsed with peptide
produced significantly more IFN-γ, TNFα, GM-CSF and IL-8 if the DCs were treated
with epacadostat. These T cells also displayed higher levels of tumor cell lysis
on a per cell basis. Epacadostat also significantly decreased Treg proliferation
induced by IDO production from IFN-γ plus LPS matured human DCs, although the
Treg phenotype did not change. Multicolor flow cytometry was performed on human
PBMCs treated with epacadostat; analysis of 123 discrete immune cell subsets
revealed no changes in major immune cell types, an increase in activated CD83+
conventional DCs, and a decrease in immature activated Tim3+ NK cells. These
studies show for the first time several effects of epacadostat on human DCs, and
subsequent effects on CTL and Tregs, and provide a rationale as to how
epacadostat could potentially increase the efficacy of immunotherapeutics,
including cancer vaccines. <br />
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