Cancer Therapy: Clinical
First-in-Human Phase I Study of the Oral Inhibitor
of Indoleamine 2,3-Dioxygenase-1 Epacadostat
(INCB024360) in Patients with Advanced Solid
Malignancies
Gregory L. Beatty
1,2
, Peter J. O'Dwyer
1,2
, Jason Clark
3
, Jack G. Shi
3
, Kevin J. Bowman
3
,
Peggy A. Scherle
3
, Robert C. Newton
3
, Richard Schaub
3
, Janet Maleski
3
, Lance Leopold
3
,
and Thomas F. Gajewski
4
Abstract
Purpose: Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the
degradation of tryptophan to N-formyl-kynurenine. Overex-
pressed in many solid malignancies, IDO1 can promote tumor
escape from host immunosurveillance. This first-in-human phase
I study invest igated the maximum tolerated dose, safety, phar-
macokinetics, pharmacodynamics, and antitumor activity of epa-
cadostat (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 þ 3 design and evaluated in 28-day cycles.
Treatment was continued until disease progression or unaccept-
able 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, 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 wel l tol erated,
effectively normalized kynurenine levels, and produced max-
imal inhibition of IDO1 activity at doses of 100 mg BID.
Studies investigating epacadostat in combination with othe r
immunomodulatory drugs are ongoing.
Clin Cancer Res; 23(13);
3269–76. 2017 AACR.
Introduction
Recently, immunotherapy with checkpoint inhibitors has pro-
duced potent long-lasting antitumor activity in patients with
advanced cancer (1–4). However, the majority of patients across
a wide range of malignancies do not respond (5). This observation
emphasizes the likely existence of additional immunoregulatory
pathways that control the effectiveness of immunosurveillance in
cancer (6, 7). Strategies designed to derail these pathways may be
critical for broadening the application of cancer immunotherapy.
Indoleamine 2,3-dioxygenase-1 (IDO1) is a heme-containing,
monomeric oxidoreductase rate-limiting enzyme that catalyzes
the degradation of the amino acid tryptophan to kynurenine (8).
IDO has been shown to play an important role in immune
regulation. During fetal development, IDO inhibition using the
competitive inhibitor 1-methyltryptophan leads to fetal rejection
by maternal T cells (9). In autoimmunity, IDO appears to be a key
regulator involved in suppressing T-cell responses toward apo-
ptotic cell-associated antigens (10) and in controlling T-cell
activity at sites of graft-versus-host disease (11). In cancer, IDO1
expression can block the development of a productive antitumor
immune response (12–16).
Indoleamine 2,3-dioxygenase-1 is expressed by various cell
types, including malignant epithelial and myeloid cells such as
dendritic cells and macrophages that localize in tumor sites and
within tumor-draining lymph nodes. IDO1 expression by malig-
nant and nonmalignant cells can inhibit T-cell immune
responses, leading to immune evasion and tumor outgrowth
(17–19). Tryptophan metabolites such as kynurenine, produced
by IDO1, inhibit immunosurveillance in cancer by arresting T
cells in the G
1
phase of the cell cycle (18), promoting T-cell and
1
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylva-
nia.
2
Division of Hematology-Oncology, Department of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania.
3
Incyte Corporation, Wilmington,
Delaware.
4
Section of Hematology/Oncology, Department of Medicine, Univer-
sity of Chicago, Chicago, Illinois.
Note: Trial registration ID: NCT01195311.
Prior presentation: This article presents original results of a phase I study o f
epacadostat (INCB024360) in patients with advanced solid malignancies.
Results were presented in part at the Annual Meeting of the American Society
of Clinical Oncology (J Clin Oncol 30, 2012 suppl; abstr 2500; J Clin Oncol 31, 2013
suppl; abstr 3025).
Corresponding Author: Gregory L. Beatty, Abramson Cancer Center of the
University of Pennsylvania, Smilow Center for Translational Research, Room
8-112, 3400 Civic Cente r Boulevard, Building 421, Philadelphia, PA 19104-5156.
Phone: 215-746-7764; Fax: 215-573-8590; E-mail:
gregory.beatty@uphs.upenn.edu
doi: 10.1158/107 8-0432.CCR-16-2272
2017 American Association for Cancer Research.
Clinical
Cancer
Research
www.aacrjournals.org
3269
Downloaded from http://aacrjournals.org/clincancerres/article-pdf/23/13/3269/2300480/3269.pdf by guest on 26 August 2022
dendritic cell apoptosis, and supporting regulatory T-cell gener-
ation (12, 19–22). In addition, tryptophan metabolites have been
found to negatively affect natural killer cell function (23, 24).
Indoleamine 2,3-dioxygenase-1 is increased in tumors that are
actively infiltrated by effector T cells (13). This enhanced tumor
expression of IDO1 is thought to be driven by IFNg (12). In
patients with advanced cancer, IDO1 activity is increased
with elevated levels of tryptophan metabolites detected in
the serum and is associated with a poor prognosis (12, 25–29).
Based on these findings, IDO1 inhibition using epacadostat
(INCB024360), a selective small-molecule inhibitor of IDO1,
was initially evaluated in a mouse model of cancer, where it was
found to induce T-celldependent antitumor immunity (12).
This activity was related to the ability of epacadostat to block
regulatory T-cell activity and promote dendritic cell maturation
and function. Here, we report on the safety and activity of single-
agent epacadostat in patients with advanced solid malignancies.
The primary objective was to define the safety, tolerability, and
maximum tolerated dose (MTD) of epacadostat. Secondary objec-
tives were to evaluate clinical activity, pharmacokinetics (PK),
pharmacodynamics, and the effect on blood biomarkers of
inflammation.
Patients and Methods
Patients
Fifty-two patients with a neoplastic disease that was refractory
to currently available therapies or for which no effective treatment
was available were enrolled at the Abramson Cancer Center,
University of Pennsylvania (Philadelphia, PA), and the University
of Chicago (Chicago, IL). Inclusion criteria were age 18 years,
Eastern Cooperative Oncology Group (ECOG) performance sta-
tus of 0 to 2, life expectancy 12 weeks, and adequate end organ
function. Exclusion criteria included receipt of an investigational
study drug within 28 days (42 days for monoclonal antibodies)
before study entry and prior anticancer medication within 21 days
of the first dose of study medication or 6 weeks for mitomycin-C
or nitrosoureas. Hormonal treatments were allowed and could be
continued, and there were no restrictions on the number of prior
lines of therapy. Additional exclusion criteria were active viral
hepatitis or other active chronic or acute systemic infection, active
autoimmune disorder, receipt of any compound known to be a
potent inducer or inhibitor of CYP3A4, prior bone marrow or
solid organ transplant, receipt of serotonin reuptake inhibitor
within 3 weeks before study entry, major surgery within 4 weeks of
study entry, active cardiovascular disease, history of gastrointes-
tinal condition causing malabsorption or obstruction, history of
brain metastases or spinal cord compression, and active infection.
All patients provided written informed consent. The study was
approved by the institutional review boards of the participating
institutions.
Study design and treatment
This was an open-label, multicenter, phase I dose-escalation
study using a 3 þ 3 design. The primary objective was to determine
safety, tolerability, and MTD of epacadostat. Secondary objectives
were to characterize PK, pharmacodynamics, biomarkers, and
tumor response rates.
Epacadostat was supplied by Incyte Corp oration (Wilming-
ton, DE ; 25-, 100-, and 300-mg tablets) and was administered
orally once or twic e daily after a 2-hour fast [50 m g once daily
or 50, 100 , 300, 400, 50 0, 6 00, or 700 mg twice daily (BID)] in
28-day cycles. The p redetermi ned doses of 50, 100, and 300 mg
BID were predicted bas ed on preclinical studies to achieve 50%,
75%, and 90 % inhibi tory concentrations (IC
50
,IC
75
,andIC
90
)
of IDO1 at trough serum levels in humans . The starting dose of
50 mg daily was proposed to minimize risk while stil l provid-
ing some inhibitory effect. Patients were instructed to fast for an
additional hour following dosing. Additionally, the foo d effect
of a standardized high-fat meal on steady-stat e PK was eva lu-
ated for the epacadostat 600 mg BID grou p on cy cle 2, day 1.
Patients continued treatment until disease progression or unac-
ceptable toxicity.
Safety and efficacy assessments
All patients who received at least 1 dose of epacadostat were
evaluated for safety and efficacy. Safety assessments included the
incidence of all adverse events (AE), irrespective of relationship to
study drug, according to the National Cancer Institute Common
Terminology Criteria for Adverse Events, version 4.0, and the
incidence of patients experiencing dose modifications and/or
premature discontinuation of study drug. AEs were monitored
at screening; on days 1, 8, 15, and 22 during cycle 1; and on days 1
and 15 for all subsequent cycles. A dose-limiting toxicity (DLT)
was defined as a treatment-related grade 4 hematologic toxicity
of any duration except for grade 4 neutropenia without fever
lasting less than 7 days or any grade 3 nonhematologic toxicity
that occurred during the first 28 days of treatment (cycle 1). The
MTD was estimated as the dose level below that at which one third
or more patients in a group (minimum 6) experienced DLTs
related to treatment with epacadostat. Tumor response was
assessed by computed tomography at baseline and every 8 weeks
according to Response Evaluation Criteria in Solid Tumors, ver-
sion 1.1.
Pharmacokinetics assessment
Plasma samples were collected on days 1 and 15 (steady state)
of cycle 1 before dosing and at defined time points after dosing.
Samples were analyzed for epacadostat by a validated liquid
chromatography with tandem mass spectrometry (LC/MS/MS)
Translational Relevance
Immunotherapy has emerged as a promising treatment
option for advanced cancer; however, many patients do not
receive adequate benefit, possibly because of immune check-
point pathway redundancies. Here, we report results of a first-
in-human study of epacadostat, an oral selective inhibitor of
indoleamine 2,3-dioxygenase (IDO1), in patients with treat-
ment-refractory advanced carcinoma. IDO1 is a rate-limiting
enzyme that catalyzes the degradation of the amino acid
tryptophan to kynurenine and, in doing so, can inhibit anti-
tumor immune activity. In this phase I study, epacadostat was
generally well tolerated and was associated with stable disease
lasting 16 weeks in 7 of 52 patients. Reductions in plasma
kynurenine levels and the kynurenine/tryptophan ratio were
found to be relevant blood-based biomarkers for monitoring
IDO1 inhibition in vivo. Our findings support further evalu-
ation of epacadostat in combination with other treatment
approaches for improving antitumor immune activity in
patients with advanced cancer.
Beatty et al.
Clin Cancer Res; 23(13) July 1, 2017 Clinical Cancer Research3270
Downloaded from http://aacrjournals.org/clincancerres/article-pdf/23/13/3269/2300480/3269.pdf by guest on 26 August 2022
assay, with a lower limit of quantitation of 2 nmol/L (30).
Noncompartmental PK analysis was performed using Phoenix
WinNonlin (Certara USA, Inc.). Where available, the actual sam-
ple collection times were used for PK analysis. For a small number
of samples for which actual collection times were not recorded,
the scheduled collection times were used instead.
Pharmacodynamic assessments
Plasma levels of tryptophan and kynurenine at different time
points were evaluated by LC/MS/MS. In addition, whole blood
samples, collected at times correlating with PK assessments, were
evaluated for IDO1 inhibition by stimulating the blood with IFNg
(100 ng/mL) and lipopolysaccharide (LPS; 100 ng/mL) for 18
hours and then analyzing the plasma from the samples for
tryptophan and kynurenine levels by LC/MS/MS as previously
described (30). For each patient, the percentage inhibition of
IDO1, as determined by the decrease in kynurenine levels, was
calculated by comparing predose values with values obtained at
different times after dosing.
Changes in the plasma levels of proteins related to immunity or
inflammation were monitored using Evidence Investigator Bio-
chip Array technology, a custom-designed multiplex biochip array
based on sandwich chemiluminescent immunoassays (Randox
Laboratories).
Statistical analysis
Descriptive statistical analyses were used to evaluate all appli-
cable outcomes.
Results
Patient characteristics
Fifty-two patients with advanced solid malignancies were
enrolled (Table 1). The predominant tumor sites were colorectal
(n ¼ 29, 55.8%) and melanoma (n ¼ 6, 11.5%), and the most
frequently reported locations of metastatic disease were lung,
liver, and lymph nodes. Each patient had received at least 1 prior
treatment for metastatic disease before study entry, and all
patients except 1 had ECOG performance status of 0 or 1.
Dose-limiting toxicities
Two patients experienced DLTs: grade 3 radiation pneumonitis
and grade 3 fatigue occurred in 1 patient each at the 300- and 400-
mg BID dose levels, respectively. In light of the projection from
preclinical animal modeling data (30) that all BID doses admin-
istered during dose escalation (50–700 mg) would be efficacious,
no other DLT occurred with dosing up to 700 mg BID; thus, the
MTD was not established for epacadostat.
Safety and tolerability
The median (range) duration of epacadostat exposure was 51.5
(7–284) days with a median (range) total daily dose of 800 (43.2–
1400) mg. Irrespective of association with therapy, the most
common AEs (all grades) occurring throughout the study period
were fatigue (69.2%), nausea (65.4%), decreased appetite
(53.8%), and vomiting (42.3%; Table 2). These AEs were man-
aged by investigators using routine supportive care measures.
Seven patients (13.5%) discontinued therapy because of AEs
(50 mg once daily, n ¼ 1; 100 mg BID, n ¼ 1; 300 mg BID,
n ¼ 2; 400 mg BID, n ¼ 3), including pain, hepatic infection,
pneumonia, radiation recall pneumonitis (DLT), fatigue (DLT),
dyspnea and hypoxia, and nausea and vomiting. Only radiation
pneumonitis and fatigue were considered DLTs and possibly
related, but these dose levels were expanded and determined to
not exceed the MTD. Liver enzymes were monitored closely
throughout treatment in all patients. No grade 4 elevations were
observed in aspartate aminotransferase (AST) or alanine amino-
transferase (ALT) levels. Grade 3 AST/ALT elevation was observed
in 1 patient but was attributed to biliary duct obstruction con-
sistent with progressive disease. A second patient also experienced
grade 3 AST/ALT elevations, but this was determined to be most
likely related to acetaminophen ingestion over the maximum
recommended daily dose for tumor fevers.
Pharmacokinetics
Following oral d ose administratio n in t he fasted state, the PK
of epacadostat was characterized by a time of maximu m
observed concentration at approximately 2 hours and a bip has-
ic disposition with an apparent terminal-phase dispositio n
half-life of 2.9 hours, which appeared to be dose-i ndep endent.
Systemic accumulatio n followi ng BID dosi ng increased mea n
epacadostat maximum observed concentration (C
max
)andarea
under the concentration versu s time curve over 1 steady- state
dosing interval ( AUC
0t
) by 16% and 33 %, respe ctively , s ug-
gesting a relatively longer effective half-life of 4 to 6 ho urs.
Increases in epacadostat C
max
and AUC
0t
were slig htly less
Table 1. Patient demographics and disease characteristics at baseline
Total
Characteristic (N ¼ 52)
Age, y
Median 59.5
Min, max 38.0, 78.0
65 y, n (%) 36 (69.2)
Gender, n (%)
Male 31 (59.6)
Female 21 (40.4)
Race, n (%)
White 45 (86.5)
Black/African American 4 (7.7)
Asian 2 (3.8)
Native Hawaiian/Other Pacific Islander 1 (1.9)
ECOG status, n (%)
0 20 (38.5)
1 31 (59.6)
2 1 (1.9)
Tumor site, n (%)
Colorectal 29 (55.8)
Melanoma 6 (11.5)
Renal cell carcinoma 3 (5.8)
Other 14 (26.9)
Locally advanced disease, n (%)
Yes 33 (63.5)
No 19 (36.5)
Locations of metastatic disease, n (%)
Lung 38 (73.1)
Liver 30 (57.7)
Lymph nodes 27 (51.9)
Bone 6 (11.5)
Ascites 3 (5.8)
Skin or subcutaneous tissue 2 (3.8)
Pancreas 1 (1.9)
Pleural effusion 1 (1.9)
Other
a
22 (42.3)
Abbreviation: ECOG, Eastern Cooperati ve Oncology Group.
a
Includes lesions detected in or invading the spleen, adrenals, abdominal wall,
ovary, peritoneum, kidney, small bowel, mesentery, bladder, chest wall, medi-
astinum, pleura, pelvis, uterus, and ureters.
IDO1 Inhibitor in Advanced Solid Cancers
www.aacrjournals.org Clin Cancer Res; 23(13) July 1, 2017 3271
Downloaded from http://aacrjournals.org/clincancerres/article-pdf/23/13/3269/2300480/3269.pdf by guest on 26 August 2022
than proporti onal to dose within the r ange of 5 0 to 700 mg
BID. Moderate inter subject v ariabil ity was observed for ep aca-
dostat plasma e xposure s (Table 3). Administration of a high-fat
meal with e pacados tat 600 mg BID decreased t he geometric
mean C
max
by approximately 10% and increased the geometric
mean area under the curve from 0 to 12 hours (AUC
012h
)by
22%. The 90% C Is of the geometric mean rat io point estimates
for C
max
and AUC
012h
were 0.645 to 1.25 and 0.952 to 1.57,
respectively, bo th including the value of 1 and indica ting that
the effect on epacadostat plasma exposu res from a high-fat
meal was not s tatis tically significant.
Pharmacodynamics
Treatment with epacadostat did not produce any significant
changes in plasma proteins related to immune function, includ-
ing IL-4, IL-10, IL12, CCL22 (macrophage-derived chemokine), or
CCL5 (RANTES). In addition, no changes were observed with
treatment in plasma proteins related to inflammation, including
C-reactive protein, intercellular adhesion molecule 1, IL-6, tumor
necrosis factor (TNF)-a, TNF receptor 2, and vascular cell adhe-
sion protein 1.
In the published literature, kynurenine levels are generally
elevated in patients with cancer (12), suggesting activation of the
Table 2. Treatment-emergent adverse events
50 mg 50 mg 100 mg 300 mg 400 mg 500 mg 600 mg 700 mg
QD BID BID BID BID BID BID BID Total
AE, n (%) (n ¼ 3) (n ¼ 4) (n ¼ 5) (n ¼ 6) (n ¼ 11) (n ¼ 5) (n ¼ 14) (n ¼ 4) (N ¼ 52)
All-grade AEs in 10% of patients
Fatigue 2 (66.7) 2 (50.0) 4 (80.0) 3 (50.0) 10 (90.9) 5 (100.0) 8 (57.1) 2 (50.0) 36 (69.2)
Nausea 3 (100.0) 4 (100.0) 3 (60.0) 4 (66.7) 5 (45.5) 4 (80.0) 8 (57.1) 3 (75.0) 3 4 (65.4)
Decreased appetite 0 2 (50.0) 1 (20.0) 3 (50.0) 7 (63.6) 4 (80.0) 8 (57.1) 3 (75.0) 28 (53.8)
Vomiting 2 (66.7) 2 (50.0) 0 3 (50.0) 3 (27.3) 2 (40.0) 8 (57.1) 2 (50.0) 22 (42.3)
Constipation 1 (33.3) 2 (50.0) 1 (20.0) 4 (66.7) 2 (18.2) 0 6 (42.9) 3 (75.0) 19 (36.5)
Abdominal pain 1 (33.3) 1 (25.0) 0 2 (33.3) 5 (45.5) 1 (20.0) 4 (28.6) 1 (25.0) 15 (28.8)
Diarrhea 1 (33.3) 2 (50.0) 1 (20.0) 1 (16.7) 4 (36.4) 1 (20.0) 3 (21.4) 1 (25.0) 14 (26.9)
Back pain 1 (33.3) 0 0 3 (50.0) 3 (27.3) 0 4 (28.6) 2 (50.0) 13 (25.0)
Dyspnea 1 (33.3) 1 (25.0) 1 (20.0) 1 (16.7) 2 (18.2) 1 (20.0) 5 (35.7) 1 (25.0) 13 (25.0)
Cough 1 (33.3) 0 2 (40.0) 2 (33.3) 1 (9.1) 2 (40.0) 3 (21.4) 0 11 (21.2)
Hypokalemia 0 2 (50.0) 2 (40.0) 1 (16.7) 2 (18.2) 0 2 (14.3) 1 (25.0) 10 (19.2)
Weight decreased 2 (66.7) 0 1 (20.0) 1 (16.7) 3 (27.3) 0 2 (14.3) 1 (25.0) 10 (19.2)
Pain 1 (33.3) 1 (25.0) 0 1 (16.7) 1 (9.1) 2 (40.0) 1 (7.1) 2 (50.0) 9 (17.3)
Pyrexia 1 (33.3) 1 (25.0) 0 1 (16.7) 3 (27.3) 0 2 (14.3) 0 8 (15.4)
Dehydration 0 1 (25.0) 0 1 (16.7) 3 (27.3) 0 2 (14.3) 0 7 (13.5)
Dizziness 1 (33.3) 0 0 0 1 (9.1) 0 2 (14.3) 2 (50.0) 6 (11.5)
Dysgeusia 0 0 1 (20.0) 1 (16.7) 1 (9.1) 0 2 (14.3) 1 (25.0) 6 (11.5)
Grade 3 or 4 AEs occurring in 2 patients
Fatigue 0 0 0 0 1 (9.1) 1 (20.0) 3 (21.4) 1 (25.0) 6 (11.5)
Abdominal pain 0 1 (25.0) 0 0 3 (27.3) 0 1 (7.1) 0 5 (9.6)
Hypokalemia 0 1 (25.0) 1 (20.0) 0 1 (9.1) 0 1 (7.1) 1 (25.0) 5 (9.6)
Nausea 0 1 (25.0) 0 1 (16.7) 1 (9.1) 0 2 (14.3) 0 5 (9.6)
Dehydration 0 1 (25.0) 0 1 (16.7) 1 (9.1) 0 0 0 3 (5.8)
Dyspnea 0 0 0 0 1 (9.1) 0 2 (14.3) 0 3 (5.8)
Hypotension 0 0 1 (20.0) 1 (16.7) 1 (9.1) 0 0 0 3 (5.8)
Vomiting 0 1 (25.0) 0 0 1 (9.1) 0 1 (7.1) 0 3 (5.8)
ALT increased 0 1 (25.0) 0 0 0 0 1 (7.1) 0 2 (3.8)
Anemia 0 0 1 (20.0) 0 1 (9.1) 0 0 0 2 (3.8)
Back pain 0 0 0 0 1 (9.1) 0 1 (7.1) 0 2 (3.8)
Bacterial infection 0 0 0 0 0 0 2 (14.3) 0 2 (3.8)
Hyponatremia 0 0 0 0 0 0 2 (14.3) 0 2 (3.8)
Pneumonia 0 0 0 1 (16.7) 0 0 1 (7.1) 0 2 (3.8)
Small intestinal obstruction 0 2 (50.0) 0 0 0 0 0 0 2 (3.8)
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; BID, twice daily; QD, once daily.
Table 3. Summary of epacadostat steady-state (day 15) pharmacokinetic parameters
Mean SD
Dose group C
max
, mmol/L t
max
,h
a
t
1/2
, h AUC
0t
, mmol/L h
50 mg QD (n ¼ 3) 0.396 0.172 2.0 (1.0–4.0) 2.4 0.26 1.58 0.31
50 mg BID (n ¼ 4) 0.742 0.212 2.0 (1.0–3.9) 2.4 0.56 3.05 1.36
100 mg BID (n ¼ 5) 1.23 0.348 2.0 (1.0–2.2) 3.3 0.75 5.77 2.34
300 mg BID (n ¼ 5) 2.48 0.515 2.0 (1.0–2.0) 3.9 2.1 9.78 0.86
400 mg BID (n ¼ 8) 4.39 2.02 2.0 (1.0–6.0) 2.7 0.62 19.6 7.43
500 mg BID (n ¼ 5) 4.82 2.26 2.0 (2.0–2.4) 2.4 0.37 20.6 6.82
600 mg BID (n ¼ 12) 4.82 2.16 2.0 (1.0–2.1) 3.3 0.97 22.9 10.0
700 mg BID (n ¼ 4) 6.23 2.09 3.0 (2.0–4.5) 3.0 1.2 35.8 15.5
Abbreviations: AUC
0t
, area under the concentration versus time curve over 1 steady-state dosing interval; BID, twice daily; C
max
, maximum observed concentration;
QD, once daily; t
1/2
, half-life; t
max
, time of maximum observed concentration.
a
t
max
is reported as median (range).
Beatty et al.
Clin Cancer Res; 23(13) July 1, 2017 Clinical Cancer Research3272
Downloaded from http://aacrjournals.org/clincancerres/article-pdf/23/13/3269/2300480/3269.pdf by guest on 26 August 2022
IDO1 pathway. Treatment with epacadostat reduced plasma
kynurenine levels by 2 hours (data not shown) and, at doses
100 mg BID, was shown to reduce kynurenine levels to within
the range observed in normal, healthy volunteers (median value
of healthy subjects, 1499 nmol/L; Fig. 1A). In patients treated with
epacadostat, plasma kynurenine levels were found to decrease at
all doses, with near maximal inhibition achieved at doses 100
mg BID (Fig. 1B). Similar findings were also observed for kynur-
enine to tryptophan ratios (data not shown).
Basal kynurenine levels in the plasma can be influenced by both
IDO1 and tryptophan 2,3-dioxygenase (TDO), a liver enzyme that
controls dietary tryptophan catabolism (31). To determine the
ability of epacadostat to inhibit IDO1 activity in vivo and mini-
mize the TDO component, whole blood was stimulated for 18
hours with IFNg and LPS to induce IDO1 expression and then
assayed for kynurenine levels. Within 2 hours of dosing, a rapid
onset of IDO1 inhibition was seen with >90% inhibition achieved
at all dose levels. Maximal inhibition at trough was observed at
doses 100 mg BID (Fig. 1C). The 90% inhibitory concentration
was achievable at plasma concentrations greater than 500 nmol/L
(Fig. 1D), which is consistent with the in vitro potency of epacado-
stat (12).
Efficacy
The overall objective response rates are summarized in Table 4.
Stable disease, seen in 18 patients (34.6%), was the best overall
response. Eleven patients (21.2%), including 2 melanoma
patients who had progressed on ipilimumab immunotherapy
before study entry, showed prolonged stable disease compared
with their last prior therapy (Fig. 2). Stable disease lasting 16
weeks was seen in 7 patients (13.5%).
A
DC
B
Baseline
Day 15 (Predose)
Average Kyn, nmol/L
0
1,000
2,000
3,000
4,000
5,000
50 mg
BID
100 mg
BID
300 mg
BID
400 mg
BID
500 mg
BID
600 mg
BID
700 mg
BID
8007001000 200 300 400 500 600
Average percentage decrease in Kyn levels
from baseline at day 15
0
25
50
75
Dose, mg BID
210
Kyn, % Inhibition
0
10
20
30
40
50
60
70
80
90
100
Epacadostat plasma concentration, mmol/L
Average Kyn, % Inhibition
Time, h
0
20
2406
40
60
100
80
120
50 mg BID
100 mg BID
300 mg BID
400 mg BID
500 mg BID
600 mg BID
700 mg BID
Figure 1.
Pharmacodynamic effects of epacadostat BID dosing in vivo. A, Kyn levels by dose group at baseline and day 15. The dashed line represents the median Kyn
value observed in normal, healthy volunteers (1,499 nmol/L). B, Percentage decrease in Kyn levels from baseline by dose. C, Average Kyn inhibition over
time by dose on day 15 (relative to day 1) following IDO1 induction with IFNg and LPS. Time 0 represents the trough levels before the next dose of epacadostat
treatment. D, Epacadostat plasma concentrations relative to percentage Kyn inhibition. BID, twice daily; IDO1, indoleamine 2,3-dioxygenase-1; IFNg, interferon
gamma; Kyn, kynurenine; LPS, lipopolysaccharide.
Table 4. Best overall tumor response by RECIST, version 1.1
Total
n (%) (N ¼ 52)
Complete response 0
Partial response 0
Stable disease 18 (34.6)
Progressive disease 22 (42.3)
Not evaluable 12 (23.1)
Abbreviation: RECIST, Response Evaluation Criteria in Solid Tumors.
IDO1 Inhibitor in Advanced Solid Cancers
www.aacrjournals.org Clin Cancer Res; 23(13) July 1, 2017 3273
Downloaded from http://aacrjournals.org/clincancerres/article-pdf/23/13/3269/2300480/3269.pdf by guest on 26 August 2022