Study to Explore the Safety, Tolerability and Efficacy of MK-3475 in Combination With INCB024360 in Participants With Selected Cancers

Sponsor
Incyte Corporation (Industry)
Overall Status
Completed
CT.gov ID
NCT02178722
Collaborator
Merck Sharp & Dohme LLC (Industry)
444
24
2
75.7
18.5
0.2

Study Details

Study Description

Brief Summary

The purpose of this study was to assess the safety, tolerability, and efficacy when combining MK-3475 and INCB024360 in participants with certain cancers. This study was conducted in 2 phases, Phase 1 and Phase 2.

Study Design

Study Type:
Interventional
Actual Enrollment :
444 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of MK-3475 in Combination With INCB024360 in Subjects With Selected Cancers (ECHO-202/KEYNOTE-037)
Actual Study Start Date :
Jul 17, 2014
Actual Primary Completion Date :
Nov 26, 2018
Actual Study Completion Date :
Nov 6, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase 1: MK-3475 + INCB024360

Phase 1: MK-3475 + INCB024360 25 mg twice a day (BID) as starting dose, followed by dose escalations (Phase 1) until recommended phase 2 dose of INCB024360 is determined

Drug: MK-3475
IV infusion

Drug: INCB024360
Oral daily dosing

Experimental: Phase 2: MK-3475 + INCB024360

(recommended phase 2 dose)

Drug: MK-3475
IV infusion

Drug: INCB024360
Oral daily dosing

Outcome Measures

Primary Outcome Measures

  1. Phase 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Serious Treatment-Emergent Adverse Events [Approximately 54 months]

    An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after a participant provides informed consent. A TEAE is any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug. Serious adverse event (SAE) is defined as an event that meets 1 of the following criteria: is fatal or life threatening, results in persistent or significant disability or incapacity, constitutes a congenital anomaly or birth defect, is clinically meaningful (i.e. defined as an event that jeopardizes the participant or requires potential medical or surgical intervention to prevent 1 of the outcomes listed above) or requires inpatient hospitalization or prolongation of existing hospitalization.

  2. Phase 2: Objective Response Rate (ORR) [Approximately 54 months]

    ORR was percentage of participants with best overall response [complete response (CR) or partial response (PR)], per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

  1. Phase 2: Duration of Response (DOR) [Up to 54 months]

    Duration of response is the time from the first overall response contributing to an objective response (complete or partial response) for DLBCL to the date of death or the date of first overall response of progressive diseasemeasured (by irRECIST for solid tumors or the Lugano Classification, whichever is earliest.

  2. Phase 2: Progression Free Survival (PFS) [Up to 54 months]

    Progression-free survival is defined as number of days from the first day of taking study drug to the earlier of death or disease progression by irRECIST v1.1 for select solid tumors and modified Lugano Classification for DLBCL.

  3. Phase 2: Duration of Disease Control [Up to 54 months]

    The duration of disease control is the time from the treatment start date to the first objective response of PD (by irRECIST v1.1 or Lugano Classification), death, or last tumor assessment date (if PD/death not present), for subjects with best overall response of SD or better.

  4. Phase 2: Overall Survival (OS) [Up to 54 months]

    Overall survival is determined from the date of first dose until death due to any cause.

  5. Phase 2: Ordinal Categorical Response Score [Up to 54 months]

    Ordinal categorical response score, determined by radiographic disease assessments per irRECIST v1.1. The 5-category ordinal response endpoint is determined at a given timepoint by classifying response into one of the following groups: 1 = Complete response per irRECIST v1.1 2 = Very good response, defined as > 60% tumor reduction 3 = Minor response, defined as > 30% to ≤ 60% tumor reduction 4 = Stable disease per irRECIST v1.1 5 = Progressive disease per irRECIST v1.1

  6. Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Serious Treatment-Emergent Adverse Events [Up to 54 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Subjects with histologically or cytologically non-small cell lung cancer (NSCLC), melanoma, transitional cell carcinoma of the genitourinary (GU) tract, renal cell cancer, triple negative breast cancer, adenocarcinoma of the endometrium or squamous cell carcinoma of the head and neck (Phase 1).

  • Subjects with histologically confirmed melanoma, NSCLC, transitional cell carcinoma of the GU tract, TNBC, SCCHN, ovarian cancer, MSI high colorectal cancer (CRC), RCC, gastric cancer, HCC and DLBCL (Phase 2).

  • Life expectancy > 12 weeks.

  • Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1.

  • Presence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Lugano Classification for subjects with DLBCL.

  • Laboratory and medical history parameters within protocol-defined range.

  • For Phase 1: Subjects who have advanced or metastatic disease as noted above that have received at least one prior therapy or have advanced or metastatic disease for which no curative treatment is available may be enrolled.

  • For Phase 2 expansion cohorts: Subjects with NSCLC, melanoma (checkpoint inhibitor naïve, primary refractory melanoma, relapsed melanoma), transitional cell carcinoma of the GU tract, SCCHN, ovarian cancer, MSI high CRC, RCC, DLBCL, TNBC, gastric cancer, and HCC.

  • Phase 2 expansion: NSCLC

  • Subjects who have received at least 1 prior platinum-based therapy. Subjects who have a non-platinum-based regimen may be enrolled with medical monitor approval.

  • Tumors with epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive treated with a tyrosine kinase inhibitor are permitted; however, subjects should have progressed on or be intolerant to the targeted therapy.

  • Subjects must not have received immunotherapy with programmed death receptor-1 (PD-1) or cytotoxic T-lymphocyte antigen (CTLA-4) targeted therapy.

  • Phase 2 expansion: Melanoma

  • Documentation of V600E-activating BRAF mutation status.

  • Prior systemic therapy requirements.

  • Melanoma immune checkpoint-naïve: Subjects must not have received immunotherapy with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy. Exception: Prior anti-CTLA-4 in the adjuvant setting would be permitted.

  • Primary refractory melanoma: Subjects must have received prior treatment with anti-PD-1 or anti-PD-L1 therapy (alone or as part of a combination) in the advanced or metastatic setting and have progressive disease as their best response to treatment that is confirmed 4 weeks later.

  • Relapsed melanoma: Subjects must have received prior anti-PD-1 or anti-PD-L1 therapy (alone or as part of a combination) in the advanced or metastatic setting and achieved partial response ore complete response but later have confirmed progressive disease.

  • Subjects enrolling in the primary refractory or relapsed melanoma must be willing to undergo mandatory pretreatment and on-treatment biopsies.

  • Ocular melanoma is excluded.

  • Phase 2 expansion: Transitional cell carcinoma of the GU tract

  • Metastatic or locally advanced and not amenable to curative therapy with disease progression on or after platinum-based chemotherapy or alternative therapy if platinum-based therapy is not appropriate.

  • Prior PD-1 or CTLA-4 targeted therapies are excluded

  • Phase 2 expansion: SCCHN

  • Histologically confirmed metastatic or recurrent squamous cell carcinoma not amenable to local therapy with curative intent (surgery or radiation with or without chemotherapy). Carcinoma of the nasopharynx, salivary gland, or * *Subjects must have received at least 1 prior systemic chemotherapy regimen that must have included a platinum-based therapy.

  • Prior PD-1 or CTLA-4 targeted therapies are excluded.

  • Phase 2 expansion: Ovarian cancer

  • Subjects with FIGO Stage Ic, Stage II, Stage III, Stage IV, recurrent, or persistent (unresectable) histologically confirmed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube carcinoma.

  • Subjects must have received a platinum-taxane-based regimen as first-line therapy.

  • Prior PD-1 or CTLA-4 targeted therapies are excluded.

  • Borderline, low-malignant-potential epithelial carcinoma per histopathology is excluded.

  • Phase 2 expansion: Relapsed or refractory DLBCL

  • Prior allogeneic stem-cell transplantation is excluded.

  • Must have received > or = 1 prior treatment regimen.

  • Not a candidate for curative therapy or hematopoietic stem-cell transplantation (either due to disease burden, fitness, or preference).

  • Prior PD-1 or CTLA-4 targeted therapies are excluded.

  • Phase 2 expansion: TNBC

  • Histologically confirmed breast adenocarcinoma that is unresectable loco regional, or metastatic

  • Pathologically confirmed as triple negative, source documented, defined as both of the following:

  • Estrogen receptor (ER) and progesterone receptor (PgR) negative.

  • Human epidermal growth factor receptor 2 (HER2) negative as per American Society of Clinical Oncology/College of American Pathologists guidelines.

  • Subject must have received at least 1 prior systemic regimen for advanced or metastatic disease

  • Prior PD-1 or CTLA-4 targeted therapies are excluded.

  • Phase 2 expansion: RCC

  • Subjects with histological or cytological confirmation of clear cell RCC.

  • Not curable by surgery.

  • Subjects must have received prior antiangiogenic therapy.

  • Subjects must not have received prior immunotherapy with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy.

  • Phase 2 expansion: MSI high CRC

  • Subjects with histological confirmation of locally advanced unresectable or metastatic MSI high CRC.

  • MSI status is, respectively, determined by examining CRC tumor.

  • Subjects may have received no more than 2 lines of prior therapy for advanced disease.

  • Phase 2 expansion: Gastric Cancer

  • Must have histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma.

  • Must have progression on or after therapy containing platinum/fluoropyrimidine or refused standard therapy.

  • Subjects may have received no more than 2 lines of prior therapy for advanced disease.

  • Prior PD-1 or CTLA-4 targeted therapies are excluded.

  • Phase 2 expansion: HCC

  • Must have histologically or cytologically confirmed diagnosis of HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).

  • Barcelona Clinic Liver Cancer (BCLC) Stage C disease (Llovet et al 1999), or BCLC Stage B disease.

  • Subjects may have received no more than 2 lines of prior therapy for the advanced disease

  • Must have progressed on, refused, or were intolerant of sorafenib.

  • The following are excluded: Subjects with liver transplants, clear invasion of the bile duct or main portal branch(es), or hepatorenal syndrome, or subjects who have required esophageal variceal ablation within 28 days of starting study treatment.

  • Prior PD-1 or CTLA-4 targeted therapies are excluded.

  • Tumor biopsies are required. If a subject has inaccessible lesions, such as in ovarian cancer, HCC, or gastric cancer, or highly vascular lesions, such as RCC, enrollment may be considered with medical monitor approval, and archived tissue may be acceptable.

  • Females of child-bearing potential and males who use adequate birth control through 120 days post dose.

Exclusion Criteria:
  • Subjects who participated in any other study in which receipt of an investigational study drug or device occurred within 2 weeks or 5 half-lives (whichever is longer) prior to first dose.

  • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Exception: Prior anti-CTLA-4 in the adjuvant setting for subjects with melanoma would be permitted.

  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable.

  • Has an active autoimmune disease.

  • Has evidence of noninfectious pneumonitis that required steroids or current pneumonitis.

  • Live vaccine use within 30 days of first dose of study medication.

  • Monoamine oxidase inhibitors.

Contacts and Locations

Locations

Site City State Country Postal Code
1 UC San Diego Moores Cancer Center La Jolla California United States 92093
2 The Angeles Clinic and Research Institute Los Angeles California United States 90025
3 US Davis Cancer Center Sacramento California United States 95817
4 University Of Colorado Cancer Center Aurora Colorado United States 80045
5 University of Connecticut Health Center Carole And Ray Neag Comprehensive Cancer Center Farmington Connecticut United States 06030-1601
6 Miami Cancer Institute at Baptist Health, Inc Miami Florida United States 33176
7 Georgia Cancer Specialists affiliated with Northside Hospital Cancer Institute Atlanta Georgia United States 30342
8 The University of Chicago Medicine Chicago Illinois United States 60637
9 St. Francis Cancer Center Topeka Kansas United States 66618
10 Greater Baltimore Cancer Center Baltimore Maryland United States 21204
11 St. Agnes Hospital Cancer Institute Baltimore Maryland United States 21229
12 The Center for Cancer and Blood Disorders (RCCA MD LLC- Maryland Division) Bethesda Maryland United States 20817
13 University of Michigan Hospital and Health Systems Ann Arbor Michigan United States 48109
14 Health Partners Institute Saint Louis Park Minnesota United States 55426
15 Hackensack University Medical Center - John Theurer Cancer Center Hackensack New Jersey United States 07601
16 The Christ Hospital Hematology Oncology, Lindner Research Center Cincinnati Ohio United States 45219
17 University of Pennsylvania Hospital Philadelphia Pennsylvania United States 19104
18 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111-2497
19 University of Pittsburgh Medical Center Hillman Cancer Center Pittsburgh Pennsylvania United States 15232
20 Greenville Health System Cancer Institute Greenville South Carolina United States 29605
21 West Cancer Center Germantown Tennessee United States 38120
22 Sarah Cannon Research Institute at Tennessee Oncology Nashville Tennessee United States 37203-2173
23 University Of Texas Southwestern Medical Center At Dallas Dallas Texas United States 75390
24 Virginia Cancer Specialists Arlington Virginia United States 22031

Sponsors and Collaborators

  • Incyte Corporation
  • Merck Sharp & Dohme LLC

Investigators

  • Study Director: Mark Jones, MD, Incyte Corporation

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Incyte Corporation
ClinicalTrials.gov Identifier:
NCT02178722
Other Study ID Numbers:
  • INCB 24360-202/ ECHO-202
First Posted:
Jul 1, 2014
Last Update Posted:
Feb 14, 2022
Last Verified:
Feb 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details Participants took part in the study at 22 investigative sites in the United States from 17July 2014 to 06 November 2020.
Pre-assignment Detail Prior to 17May18 study amended/discontinued, 444 participants were enrolled. Survival follow up and monotherapy option after discontinuation of combination were removed so anyone in survival follow up were discontinued the study and were assigned to "study terminated by sponsor" because completed was not an option in the database for those in survival follow up. 1 patient on combo treatment did not move to the monotherapy so they were also assigned to this reason for discontinuing.
Arm/Group Title Phase 1: Epacadostat 25 mg BID Phase 1: Epacadostat 50 mg BID Phase 1: Epacadostat 100 mg BID Phase 1: Epacadostat 300 mg BID Phase 2: Epacadostat 100 mg BID
Arm/Group Description Epacadostat 25 mg tablet orally twice daily (BID) starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 50 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 300 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 200 mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 100 mg tablet orally BID in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W).
Period Title: Overall Study
STARTED 4 20 18 20 382
COMPLETED 0 0 0 0 0
NOT COMPLETED 4 20 18 20 382

Baseline Characteristics

Arm/Group Title Phase 1: Epacadostat 25 mg BID Phase 1: Epacadostat 50 mg BID Phase 1: Epacadostat 100 mg BID Phase 1: Epacadostat 300 mg BID Phase 2: Epacadostat 100 mg BID Total
Arm/Group Description Epacadostat 25 mg tablet orally twice daily (BID) starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 50 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 300 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 200 mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 100 mg tablet orally BID in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W). Total of all reporting groups
Overall Participants 4 20 18 20 382 444
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
48.8
(18.01)
60.8
(12.97)
63.2
(13.67)
59.2
(13.06)
62.7
(11.60)
62.3
(11.92)
Sex: Female, Male (Count of Participants)
Female
3
75%
9
45%
6
33.3%
9
45%
181
47.4%
208
46.8%
Male
1
25%
11
55%
12
66.7%
11
55%
201
52.6%
236
53.2%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian
1
25%
20
100%
18
100%
17
85%
337
88.2%
393
88.5%
Black/African-American
1
25%
0
0%
0
0%
2
10%
19
5%
22
5%
Asian
1
25%
0
0%
0
0%
1
5%
15
3.9%
17
3.8%
Native Hawaiian/Pacific Islander
1
25%
0
0%
0
0%
0
0%
0
0%
1
0.2%
Other
0
0%
0
0%
0
0%
0
0%
9
2.4%
9
2%
Missing
0
0%
0
0%
0
0%
0
0%
2
0.5%
2
0.5%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino
0
0%
0
0%
1
5.6%
1
5%
16
4.2%
18
4.1%
Not Hispanic or Latino
4
100%
20
100%
17
94.4%
19
95%
353
92.4%
413
93%
Unknown
0
0%
0
0%
0
0%
0
0%
10
2.6%
10
2.3%
Other
0
0%
0
0%
0
0%
0
0%
2
0.5%
2
0.5%
Missing
0
0%
0
0%
0
0%
0
0%
1
0.3%
1
0.2%

Outcome Measures

1. Primary Outcome
Title Phase 1: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Serious Treatment-Emergent Adverse Events
Description An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after a participant provides informed consent. A TEAE is any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug. Serious adverse event (SAE) is defined as an event that meets 1 of the following criteria: is fatal or life threatening, results in persistent or significant disability or incapacity, constitutes a congenital anomaly or birth defect, is clinically meaningful (i.e. defined as an event that jeopardizes the participant or requires potential medical or surgical intervention to prevent 1 of the outcomes listed above) or requires inpatient hospitalization or prolongation of existing hospitalization.
Time Frame Approximately 54 months

Outcome Measure Data

Analysis Population Description
The safety evaluable population included all participants enrolled in the study who received at least 1 dose of study drug (epacadostat or pembrolizumab).
Arm/Group Title Phase 1: Epacadostat 25 mg BID Phase 1: Epacadostat 50 mg BID Phase 1: Epacadostat 100 mg BID Phase 1: Epacadostat 300 mg BID
Arm/Group Description Epacadostat 25 mg tablet orally twice daily (BID) starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 50 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 300 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 200 mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1.
Measure Participants 4 20 18 20
SAE
0
0%
40.0
200%
50.0
277.8%
45.0
225%
TEAS
100.
2500%
95.0
475%
94.4
524.4%
100.
500%
2. Primary Outcome
Title Phase 2: Objective Response Rate (ORR)
Description ORR was percentage of participants with best overall response [complete response (CR) or partial response (PR)], per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame Approximately 54 months

Outcome Measure Data

Analysis Population Description
The efficacy evaluable population included all participants enrolled in the study who received at least 1 dose of study drug (epacadostat or pembrolizumab). Number analyzed indicated participants analyzed in the respective tumor type.
Arm/Group Title Epacadostat 100 mg BID+ Pembrolizumab 200 mg Q3W
Arm/Group Description Epacadostat 100 mg tablet orally BID in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W).
Measure Participants 382
Triple negative breast cancer
11.1
277.5%
Microsatellite-instability high colorectal cancer
43.8
1095%
Gastric cancer
22.2
555%
Hepatocellular carcinoma
16.7
417.5%
Melanoma - immune checkpoint-naïve
60.5
1512.5%
Non-small cell lung cancer (NSCLC) (tumor proportion score (TPS) < 50% or indeterminate)
30.8
770%
NSCLC programmed cell death ligand (PD-L1) low negative (TPS < 50%)
24.4
610%
Ovarian cancer
8.1
202.5%
Renal cell carcinoma
32.4
810%
Squamous cell carcinoma of the head and neck
33.3
832.5%
Transitional carcinoma of the genitourinary (GU) tract
30.6
765%
Diffuse large B-cell lymphoma
19.2
480%
Primary Refractory Melanoma
0.0
0%
Relapsed Melanoma
0.0
0%
3. Secondary Outcome
Title Phase 2: Duration of Response (DOR)
Description Duration of response is the time from the first overall response contributing to an objective response (complete or partial response) for DLBCL to the date of death or the date of first overall response of progressive diseasemeasured (by irRECIST for solid tumors or the Lugano Classification, whichever is earliest.
Time Frame Up to 54 months

Outcome Measure Data

Analysis Population Description
The efficacy evaluable population included all participants enrolled in the study who received at least 1 dose of study drug (epacadostat or pembrolizumab). Number analyzed indicated participants analyzed in the respective tumor type and those who responded.
Arm/Group Title Epacadostat 100 mg BID+ Pembrolizumab 200 mg Q3W
Arm/Group Description Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 200 mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1.
Measure Participants 105
Hepatocellular Carcinoma
NA
Triple Negative Breast Cancer
NA
Immune Checkpoint-naïve Melanoma
NA
NSCLC high positive (PD-L1 TPS ≥ 50%)
12.44
NSCLC low/negative or indeterminate (PD-L1 TPS < 50% or indeterminate)
11.93
NSCLC (TPS 0%)
NA
NSCLC Unknown
10.84
Renal Cell Carcinoma
16.95
Squamous Cell Carcinoma of the Head and Neck
11.33
Transitional Cell Carcinoma of the GU Tract
NA
Ovarian Cancer
NA
Gastric Cancer
NA
MSI high Colorectal Cancer
NA
DLBCL
3.66
4. Secondary Outcome
Title Phase 2: Progression Free Survival (PFS)
Description Progression-free survival is defined as number of days from the first day of taking study drug to the earlier of death or disease progression by irRECIST v1.1 for select solid tumors and modified Lugano Classification for DLBCL.
Time Frame Up to 54 months

Outcome Measure Data

Analysis Population Description
The efficacy evaluable population included all participants enrolled in the study who received at least 1 dose of study drug (epacadostat or pembrolizumab). Number analyzed indicated participants analyzed in the respective tumor type.
Arm/Group Title Epacadostat 100 mg BID+ Pembrolizumab 200 mg Q3W
Arm/Group Description Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 200 mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1.
Measure Participants 382
Hepatocellular Carcinoma
5.49
Triple Negative Breast Cancer
1.97
Immune Checkpoint-naïve Melanoma
16.69
Primary Refractory Melanoma
1.69
Relapsed Melanoma
2.60
NSCLC
4.09
Renal Cell Carcinoma
4.50
Squamous Cell Carcinoma of the Head and Neck
4.37
Transitional Cell Carcinoma of the GU Tract
4.40
Ovarian Cancer
2.10
Gastric Cancer
1.97
MSI high Colorectal Cancer
6.11
DLBCL
2.63
5. Secondary Outcome
Title Phase 2: Duration of Disease Control
Description The duration of disease control is the time from the treatment start date to the first objective response of PD (by irRECIST v1.1 or Lugano Classification), death, or last tumor assessment date (if PD/death not present), for subjects with best overall response of SD or better.
Time Frame Up to 54 months

Outcome Measure Data

Analysis Population Description
The Efficacy Evaluable Population included all participants enrolled in the study who received at least 1 dose of study drug (epacadostat or pembrolizumab). Number analyzed indicated participants analyzed in the respective tumor type. The median time and the 90% CI were estimated using Kaplan-Meier method.
Arm/Group Title Epacadostat 100 mg BID+ Pembrolizumab 200 mg Q3W
Arm/Group Description Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 200 mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1.
Measure Participants 191
Hepatocellular Carcinoma
10.38
Triple Negative Breast Cancer
11.47
Immune Checkpoint-naïve Melanoma
30.29
Relapsed Melanoma
4.21
NSCLC Total
14.42
Renal Cell Carcinoma
13.39
Squamous Cell Carcinoma of the Head and Neck
9.18
Transitional Cell Carcinoma of the GU Tract
15.36
Ovarian Cancer
5.08
Gastric Cancer
NA
MSI high Colorectal Cancer
NA
DLBCL
7.29
6. Secondary Outcome
Title Phase 2: Overall Survival (OS)
Description Overall survival is determined from the date of first dose until death due to any cause.
Time Frame Up to 54 months

Outcome Measure Data

Analysis Population Description
The Efficacy Evaluable Population included all participants enrolled in the study who received at least 1 dose of study drug. Number analyzed indicated participants analyzed in the respective tumor type. The median time and the 90% CI were estimated using Kaplan-Meier method.
Arm/Group Title Epacadostat 100 mg BID+ Pembrolizumab 200 mg Q3W
Arm/Group Description Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 200 mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1.
Measure Participants 382
Hepatocellular Carcinoma
NA
Triple Negative Breast Cancer
5.16
Immune Checkpoint-naïve Melanoma
NA
Primary Refractory Melanoma
NA
Relapsed Melanoma
NA
NSCLC
14.62
Renal Cell Carcinoma
NA
Squamous Cell Carcinoma of the Head and Neck
8.34
Transitional Cell Carcinoma of the GU Tract
13.44
Ovarian Cancer
13.11
Gastric Cancer
4.04
MSI high Colorectal Cancer
NA
DLBCL
11.79
7. Secondary Outcome
Title Phase 2: Ordinal Categorical Response Score
Description Ordinal categorical response score, determined by radiographic disease assessments per irRECIST v1.1. The 5-category ordinal response endpoint is determined at a given timepoint by classifying response into one of the following groups: 1 = Complete response per irRECIST v1.1 2 = Very good response, defined as > 60% tumor reduction 3 = Minor response, defined as > 30% to ≤ 60% tumor reduction 4 = Stable disease per irRECIST v1.1 5 = Progressive disease per irRECIST v1.1
Time Frame Up to 54 months

Outcome Measure Data

Analysis Population Description
The Efficacy Evaluable Population included all participants enrolled in the study who received at least 1 dose of study drug (epacadostat or pembrolizumab). Number analyzed indicated participants analyzed in the respective tumor type.
Arm/Group Title Epacadostat 100 mg BID+ Pembrolizumab 200 mg Q3W
Arm/Group Description Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 200 mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1.
Measure Participants 382
Complete Response - Score 1
0
0%
Very Good Response - Score 2
2
50%
Minor Response - Score 3
2
50%
Stable Disease - Score 4
11
275%
Progressive Disease - Score 5
8
200%
Unable to Evaluable
1
25%
Complete Response - Score 1
1
25%
Very Good Response - Score 2
1
25%
Minor Response - Score 3
2
50%
Stable Disease - Score 4
7
175%
Progressive Disease - Score 5
19
475%
Unable to Evaluable
6
150%
Complete Response - Score 1
3
75%
Very Good Response - Score 2
17
425%
Minor Response - Score 3
6
150%
Stable Disease - Score 4
5
125%
Progressive Disease - Score 5
10
250%
Unable to Evaluable
2
50%
Complete Response - Score 1
0
0%
Very Good Response - Score 2
0
0%
Minor Response - Score 3
0
0%
Stable Disease - Score 4
0
0%
Progressive Disease - Score 5
2
50%
Unable to Evaluable
1
25%
Complete Response - Score 1
3
75%
Very Good Response - Score 2
4
100%
Minor Response - Score 3
5
125%
Stable Disease - Score 4
8
200%
Progressive Disease - Score 5
10
250%
Unable to Evaluable
6
150%
Complete Response - Score 1
4
100%
Very Good Response - Score 2
3
75%
Minor Response - Score 3
8
200%
Stable Disease - Score 4
15
375%
Progressive Disease - Score 5
24
600%
Unable to Evaluable
4
100%
Complete Response - Score 1
2
50%
Very Good Response - Score 2
6
150%
Minor Response - Score 3
4
100%
Stable Disease - Score 4
10
250%
Progressive Disease - Score 5
13
325%
Unable to Evaluable
2
50%
Complete Response - Score 1
3
75%
Very Good Response - Score 2
4
100%
Minor Response - Score 3
5
125%
Stable Disease - Score 4
8
200%
Progressive Disease - Score 5
10
250%
Unable to Evaluable
6
150%
Complete Response - Score 1
2
50%
Very Good Response - Score 2
4
100%
Minor Response - Score 3
5
125%
Stable Disease - Score 4
10
250%
Progressive Disease - Score 5
11
275%
Unable to Evaluable
4
100%
Complete Response - Score 1
1
25%
Very Good Response - Score 2
0
0%
Minor Response - Score 3
2
50%
Stable Disease - Score 4
11
275%
Progressive Disease - Score 5
16
400%
Unable to Evaluable
7
175%
Complete Response - Score 1
0
0%
Very Good Response - Score 2
1
25%
Minor Response - Score 3
5
125%
Stable Disease - Score 4
1
25%
Progressive Disease - Score 5
11
275%
Unable to Evaluable
9
225%
Complete Response - Score 1
1
25%
Very Good Response - Score 2
3
75%
Minor Response - Score 3
3
75%
Stable Disease - Score 4
3
75%
Progressive Disease - Score 5
5
125%
Unable to Evaluable
1
25%
8. Secondary Outcome
Title Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) and Serious Treatment-Emergent Adverse Events
Description
Time Frame Up to 54 months

Outcome Measure Data

Analysis Population Description
The safety evaluable population included all participants enrolled in the study who received at least 1 dose of study drug (epacadostat or pembrolizumab). Treatment groups for this population were determined according to the actual treatment the participant receives on Day 1. All safety analyses were conducted using the safety evaluable population.
Arm/Group Title Phase 2: Epacadostat 100 mg BID
Arm/Group Description Epacadostat 100 mg tablet orally BID in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W).
Measure Participants 382
Treatment-Emergent Adverse Events (TEAE)
100
2500%
Serious Treatment-Emergent Adverse Events
51.0
1275%

Adverse Events

Time Frame Approximately 54 months
Adverse Event Reporting Description The safety evaluable population included all participants enrolled in the study who received at least 1 dose of study drug (epacadostat or pembrolizumab).
Arm/Group Title Phase 1: Epacadostat 25 mg BID Phase 1: Epacadostat 50 MG BID Phase 1: Epacadostat 100 MG BID Phase 1: Epacadostat 300 MG BID Phase 2: Epacadostat 100 MG BID Total
Arm/Group Description Epacadostat 25 mg tablet orally twice daily (BID) starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 50 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1. Epacadostat 100 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1 Epacadostat 300 mg tablet orally BID starting on Cycle 1 Day 1 in combination with pembrolizumab 2 mg/kg or 200mg administered intravenously every 3 weeks (Q3W) starting on Cycle 1 Day 1 Epacadostat 100 mg tablet orally BID in combination with pembrolizumab 200 mg intravenously every 3 weeks (Q3W). Total
All Cause Mortality
Phase 1: Epacadostat 25 mg BID Phase 1: Epacadostat 50 MG BID Phase 1: Epacadostat 100 MG BID Phase 1: Epacadostat 300 MG BID Phase 2: Epacadostat 100 MG BID Total
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/4 (50%) 13/20 (65%) 12/18 (66.7%) 14/20 (70%) 209/382 (54.7%) 250/444 (56.3%)
Serious Adverse Events
Phase 1: Epacadostat 25 mg BID Phase 1: Epacadostat 50 MG BID Phase 1: Epacadostat 100 MG BID Phase 1: Epacadostat 300 MG BID Phase 2: Epacadostat 100 MG BID Total
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/4 (0%) 8/20 (40%) 9/18 (50%) 9/20 (45%) 195/382 (51%) 221/444 (49.8%)
Blood and lymphatic system disorders
Anaemia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 5/382 (1.3%) 5 6/444 (1.4%) 6
Lymphadenopathy 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Thrombocytopenia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 2 1/444 (0.2%) 2
Cardiac disorders
Acute coronary syndrome 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Acute myocardial infarction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Atrial fibrillation 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 2 1/444 (0.2%) 2
Atrial flutter 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Cardiac arrest 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Cardiac failure 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Cardiac failure congestive 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Cardiac tamponade 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Myocardial infarction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Myocarditis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Pericardial effusion 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 6/382 (1.6%) 6 6/444 (1.4%) 6
Pulseless electrical activity 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Sinus bradycardia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Tachycardia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Endocrine disorders
Hypercalcaemia of malignancy 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Eye disorders
Macular degeneration 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Gastrointestinal disorders
Abdominal distension 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Abdominal pain 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 12/382 (3.1%) 13 14/444 (3.2%) 15
Abdominal pain upper 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Ascites 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Colitis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 6/382 (1.6%) 6 7/444 (1.6%) 7
Constipation 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 4/382 (1%) 4 5/444 (1.1%) 5
Diarrhoea 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 5/382 (1.3%) 5 6/444 (1.4%) 6
Diverticulum intestinal haemorrhagic 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Duodenal ulcer haemorrhage 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Duodenitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Gastrointestinal haemorrhage 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Gastrointestinal vascular malformation haemorrhagic 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Gastrointestinal wall thickening 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Gastrooesophageal reflux disease 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Intestinal perforation 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Lower gastrointestinal haemorrhage 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Nausea 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 12/382 (3.1%) 13 13/444 (2.9%) 14
Pancreatitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Rectal haemorrhage 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Retching 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Retroperitoneal haemorrhage 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Small intestinal obstruction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 11/382 (2.9%) 12 11/444 (2.5%) 12
Volvulus 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Vomiting 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 9/382 (2.4%) 10 10/444 (2.3%) 11
General disorders
Asthenia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Chest pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Death 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Disease progression 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 9/382 (2.4%) 9 10/444 (2.3%) 10
Facial pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Fatigue 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 4 4/444 (0.9%) 4
Non-cardiac chest pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Oedema 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Physical deconditioning 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Pyrexia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 6/382 (1.6%) 6 6/444 (1.4%) 6
Hepatobiliary disorders
Acute hepatic failure 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Autoimmune hepatitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Bile duct obstruction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Bile duct stenosis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Cholecystitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Hepatic pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Hepatorenal syndrome 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Hyperbilirubinaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Immune-mediated hepatitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Infections and infestations
Arthritis bacterial 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Bacteraemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Cellulitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Cellulitis of male external genital organ 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Clostridium difficile colitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Clostridium difficile infection 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Cystitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Diverticulitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Enterobacter bacteraemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Gastroenteritis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Gastroenteritis viral 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Influenza 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Meningitis aseptic 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Pneumonia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 15/382 (3.9%) 16 16/444 (3.6%) 17
Pneumonia bacterial 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Pyelonephritis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 3 2/444 (0.5%) 3
Pyelonephritis acute 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Renal abscess 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Respiratory syncytial virus infection 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Sepsis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 2/20 (10%) 4 8/382 (2.1%) 8 10/444 (2.3%) 12
Upper respiratory tract infection 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 2 1/444 (0.2%) 2
Urinary tract infection 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 6/382 (1.6%) 6 6/444 (1.4%) 6
Urinary tract infection bacterial 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Urosepsis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Vestibular neuronitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Wound infection 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Injury, poisoning and procedural complications
Craniocerebral injury 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Fall 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Femoral neck fracture 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Femur fracture 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Hip fracture 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Infusion related reaction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Pelvic fracture 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Subdural haematoma 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Urinary tract stoma complication 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Investigations
Blood creatinine increased 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Ejection fraction decreased 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
White blood cell count increased 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Metabolism and nutrition disorders
Adult failure to thrive 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Dehydration 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 6/382 (1.6%) 6 6/444 (1.4%) 6
Failure to thrive 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 5/382 (1.3%) 5 5/444 (1.1%) 5
Hypercalcaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Hyperglycaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Hyperkalaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 4 4/444 (0.9%) 4
Hypernatraemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Hypoglycaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Hypokalaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 3 2/444 (0.5%) 3
Hyponatraemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 4 3/444 (0.7%) 4
Malnutrition 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Musculoskeletal and connective tissue disorders
Arthralgia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Back pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Flank pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Gouty arthritis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Muscular weakness 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Myositis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Neck pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Osteoarthritis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Pain in extremity 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Cancer pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Choroid melanoma 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Chronic myeloid leukaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Diffuse large B-cell lymphoma 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Malignant neoplasm progression 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 33/382 (8.6%) 33 35/444 (7.9%) 35
Malignant pleural effusion 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 2 1/382 (0.3%) 1 2/444 (0.5%) 3
Metastases to bone 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Metastases to central nervous system 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Metastases to peritoneum 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Metastases to spine 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Metastatic lymphoma 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Metastatic squamous cell carcinoma 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Neoplasm progression 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Non-small cell lung cancer 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Non-small cell lung cancer stage I 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Tumour haemorrhage 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Tumour pain 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 2 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 2
Nervous system disorders
Aphasia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Brain oedema 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 2 2/444 (0.5%) 3
Cognitive disorder 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Cranial nerve disorder 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Encephalopathy 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Generalised tonic-clonic seizure 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Haemorrhage intracranial 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Headache 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Hemiparesis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Memory impairment 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Nervous system disorder 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Peripheral sensory neuropathy 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Seizure 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Spinal cord haemorrhage 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Syncope 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 3/444 (0.7%) 3
Transient ischaemic attack 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Product Issues
Device occlusion 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Psychiatric disorders
Anxiety 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Confusional state 0/4 (0%) 0 1/20 (5%) 2 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 3
Delirium 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Mental status changes 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Psychotic disorder 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Renal and urinary disorders
Acute kidney injury 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 7/382 (1.8%) 8 7/444 (1.6%) 8
Chronic kidney disease 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Hydronephrosis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 2/444 (0.5%) 2
Nephrolithiasis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Polyuria 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Ureteric obstruction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Ureterolithiasis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Urinary retention 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Urinary tract obstruction 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Reproductive system and breast disorders
Scrotal oedema 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 5/382 (1.3%) 6 5/444 (1.1%) 6
Atelectasis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Bronchial obstruction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Chronic obstructive pulmonary disease 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 5 2/444 (0.5%) 5
Cough 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Dyspnoea 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 9/382 (2.4%) 9 11/444 (2.5%) 11
Haemoptysis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Hypoxia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 4 4/444 (0.9%) 4
Laryngeal haemorrhage 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Pharyngeal haemorrhage 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Pleural effusion 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 11/382 (2.9%) 11 12/444 (2.7%) 12
Pneumonia aspiration 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 4/382 (1%) 4 5/444 (1.1%) 5
Pneumonitis 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 4 5/444 (1.1%) 5
Pneumothorax 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Productive cough 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Pulmonary embolism 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 7/382 (1.8%) 7 7/444 (1.6%) 7
Respiratory arrest 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Respiratory failure 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 5/382 (1.3%) 5 5/444 (1.1%) 5
Stridor 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Rash 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Vascular disorders
Deep vein thrombosis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 3/382 (0.8%) 3 4/444 (0.9%) 4
Haemorrhage 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Hypotension 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 5/382 (1.3%) 6 6/444 (1.4%) 7
Hypovolaemic shock 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Superior vena cava syndrome 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Thrombosis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 1/444 (0.2%) 1
Other (Not Including Serious) Adverse Events
Phase 1: Epacadostat 25 mg BID Phase 1: Epacadostat 50 MG BID Phase 1: Epacadostat 100 MG BID Phase 1: Epacadostat 300 MG BID Phase 2: Epacadostat 100 MG BID Total
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 4/4 (100%) 18/20 (90%) 17/18 (94.4%) 20/20 (100%) 375/382 (98.2%) 434/444 (97.7%)
Blood and lymphatic system disorders
Anaemia 0/4 (0%) 0 2/20 (10%) 3 2/18 (11.1%) 6 3/20 (15%) 4 48/382 (12.6%) 65 55/444 (12.4%) 78
Increased tendency to bruise 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 4/444 (0.9%) 4
Iron deficiency anaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Lymphadenitis 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Neutropenia 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 6 5/444 (1.1%) 7
Thrombocytopenia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 4/382 (1%) 5 5/444 (1.1%) 6
Cardiac disorders
Atrial fibrillation 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 6/382 (1.6%) 7 7/444 (1.6%) 8
Bradycardia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 3/444 (0.7%) 3
Sinus tachycardia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 5/382 (1.3%) 6 6/444 (1.4%) 7
Tachycardia 0/4 (0%) 0 2/20 (10%) 2 3/18 (16.7%) 4 0/20 (0%) 0 11/382 (2.9%) 13 16/444 (3.6%) 19
Ear and labyrinth disorders
Ear discomfort 1/4 (25%) 1 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 5/444 (1.1%) 5
Hypoacusis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 1/382 (0.3%) 1 3/444 (0.7%) 3
Tinnitus 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 5 5/444 (1.1%) 6
Vertigo 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 4/444 (0.9%) 4
Endocrine disorders
Hypogonadism 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Hypothalamo-pituitary disorder 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Hypothyroidism 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 2/20 (10%) 2 29/382 (7.6%) 30 32/444 (7.2%) 33
Eye disorders
Diplopia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 3/382 (0.8%) 3 4/444 (0.9%) 4
Dry eye 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 4 5/444 (1.1%) 5
Eye pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 3/444 (0.7%) 3
Eye pruritus 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 4/444 (0.9%) 4
Lacrimation increased 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Ocular hyperaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Vision blurred 0/4 (0%) 0 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 14/382 (3.7%) 14 16/444 (3.6%) 16
Visual acuity reduced 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Vitreous floaters 0/4 (0%) 0 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 5/444 (1.1%) 5
Xerophthalmia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Gastrointestinal disorders
Abdominal discomfort 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 11/382 (2.9%) 12 12/444 (2.7%) 13
Abdominal distension 0/4 (0%) 0 3/20 (15%) 3 0/18 (0%) 0 3/20 (15%) 3 19/382 (5%) 19 25/444 (5.6%) 25
Abdominal pain 1/4 (25%) 1 0/20 (0%) 0 2/18 (11.1%) 3 3/20 (15%) 4 53/382 (13.9%) 60 59/444 (13.3%) 68
Abdominal pain lower 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 6/382 (1.6%) 6 7/444 (1.6%) 7
Abdominal pain upper 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 23/382 (6%) 25 25/444 (5.6%) 27
Cheilitis 1/4 (25%) 2 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 3
Constipation 3/4 (75%) 4 8/20 (40%) 13 4/18 (22.2%) 4 3/20 (15%) 5 86/382 (22.5%) 94 104/444 (23.4%) 120
Diarrhoea 3/4 (75%) 6 5/20 (25%) 9 7/18 (38.9%) 12 5/20 (25%) 10 99/382 (25.9%) 142 119/444 (26.8%) 179
Dry mouth 1/4 (25%) 1 2/20 (10%) 2 4/18 (22.2%) 4 2/20 (10%) 2 24/382 (6.3%) 26 33/444 (7.4%) 35
Dyspepsia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 11/382 (2.9%) 12 12/444 (2.7%) 13
Dysphagia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 13/382 (3.4%) 13 14/444 (3.2%) 14
Epigastric discomfort 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 0/382 (0%) 0 2/444 (0.5%) 2
Faeces hard 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Flatulence 1/4 (25%) 1 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 10/382 (2.6%) 12 12/444 (2.7%) 14
Gastritis 0/4 (0%) 0 1/20 (5%) 2 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 3
Gastrooesophageal reflux disease 1/4 (25%) 2 2/20 (10%) 2 1/18 (5.6%) 1 2/20 (10%) 3 13/382 (3.4%) 13 19/444 (4.3%) 21
Glossodynia 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Hypoaesthesia oral 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Large intestine polyp 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Mouth haemorrhage 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Mouth ulceration 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Nausea 3/4 (75%) 6 9/20 (45%) 20 5/18 (27.8%) 5 11/20 (55%) 18 115/382 (30.1%) 143 143/444 (32.2%) 192
Odynophagia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 4/382 (1%) 4 5/444 (1.1%) 5
Oesophagitis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 4/382 (1%) 4 5/444 (1.1%) 5
Oral disorder 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Stomatitis 2/4 (50%) 3 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 3 11/382 (2.9%) 13 15/444 (3.4%) 20
Toothache 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 5/382 (1.3%) 5 7/444 (1.6%) 7
Upper gastrointestinal haemorrhage 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Vomiting 1/4 (25%) 2 4/20 (20%) 5 4/18 (22.2%) 8 10/20 (50%) 13 78/382 (20.4%) 99 97/444 (21.8%) 127
General disorders
Asthenia 1/4 (25%) 1 2/20 (10%) 3 1/18 (5.6%) 1 4/20 (20%) 4 27/382 (7.1%) 28 35/444 (7.9%) 37
Chest discomfort 1/4 (25%) 1 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 7/382 (1.8%) 7 10/444 (2.3%) 10
Chills 0/4 (0%) 0 4/20 (20%) 4 2/18 (11.1%) 3 3/20 (15%) 3 36/382 (9.4%) 40 45/444 (10.1%) 50
Early satiety 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 3/382 (0.8%) 3 4/444 (0.9%) 4
Face oedema 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Fatigue 3/4 (75%) 5 13/20 (65%) 17 9/18 (50%) 10 13/20 (65%) 20 185/382 (48.4%) 220 223/444 (50.2%) 272
Foreign body reaction 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Influenza like illness 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 15/382 (3.9%) 15 17/444 (3.8%) 17
Malaise 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 4/382 (1%) 4 5/444 (1.1%) 5
Mass 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Medical device pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Mucosal inflammation 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Non-cardiac chest pain 0/4 (0%) 0 1/20 (5%) 1 2/18 (11.1%) 2 0/20 (0%) 0 31/382 (8.1%) 32 34/444 (7.7%) 35
Oedema 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 5/382 (1.3%) 5 7/444 (1.6%) 7
Oedema peripheral 1/4 (25%) 1 3/20 (15%) 4 3/18 (16.7%) 5 2/20 (10%) 2 40/382 (10.5%) 46 49/444 (11%) 58
Pain 0/4 (0%) 0 1/20 (5%) 1 2/18 (11.1%) 3 1/20 (5%) 1 17/382 (4.5%) 19 21/444 (4.7%) 24
Peripheral swelling 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 8/382 (2.1%) 8 10/444 (2.3%) 10
Pyrexia 0/4 (0%) 0 3/20 (15%) 5 3/18 (16.7%) 4 9/20 (45%) 10 58/382 (15.2%) 74 73/444 (16.4%) 93
Swelling 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Swelling face 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Temperature intolerance 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 3/382 (0.8%) 3 4/444 (0.9%) 4
Hepatobiliary disorders
Hyperbilirubinaemia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Immune system disorders
Multiple allergies 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 4/444 (0.9%) 4
Seasonal allergy 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 7/382 (1.8%) 7 9/444 (2%) 9
Infections and infestations
Acute sinusitis 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Body tinea 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Bronchitis 1/4 (25%) 1 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 9/382 (2.4%) 9 11/444 (2.5%) 11
Candida infection 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 6/382 (1.6%) 6 8/444 (1.8%) 8
Conjunctivitis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Cystitis 0/4 (0%) 0 2/20 (10%) 2 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 4/444 (0.9%) 4
Fungal infection 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Gastroenteritis 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Herpes zoster 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 5/382 (1.3%) 5 7/444 (1.6%) 7
Influenza 1/4 (25%) 2 1/20 (5%) 2 0/18 (0%) 0 0/20 (0%) 0 9/382 (2.4%) 11 11/444 (2.5%) 15
Lower respiratory tract infection 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Nasopharyngitis 1/4 (25%) 1 4/20 (20%) 12 0/18 (0%) 0 1/20 (5%) 1 24/382 (6.3%) 24 30/444 (6.8%) 38
Onychomycosis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Oral herpes 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 2 0/20 (0%) 0 4/382 (1%) 4 5/444 (1.1%) 6
Pneumonia 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 10/382 (2.6%) 11 12/444 (2.7%) 13
Postoperative wound infection 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Rash pustular 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Rhinitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 2 3/382 (0.8%) 3 4/444 (0.9%) 5
Sinusitis 0/4 (0%) 0 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 21/382 (5.5%) 25 23/444 (5.2%) 27
Tinea pedis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Upper respiratory tract infection 0/4 (0%) 0 3/20 (15%) 6 2/18 (11.1%) 2 2/20 (10%) 2 31/382 (8.1%) 38 38/444 (8.6%) 48
Urinary tract infection 1/4 (25%) 2 2/20 (10%) 8 0/18 (0%) 0 1/20 (5%) 1 28/382 (7.3%) 36 32/444 (7.2%) 47
Viral pharyngitis 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Injury, poisoning and procedural complications
Arthropod bite 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 2/382 (0.5%) 2 4/444 (0.9%) 4
Epicondylitis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 3/444 (0.7%) 3
Fall 0/4 (0%) 0 1/20 (5%) 1 2/18 (11.1%) 2 0/20 (0%) 0 23/382 (6%) 24 26/444 (5.9%) 27
Hip fracture 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Incision site pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Incision site pruritus 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Infusion related reaction 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Joint injury 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Ligament sprain 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Procedural pain 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 7/382 (1.8%) 7 9/444 (2%) 9
Skin laceration 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 5/382 (1.3%) 5 6/444 (1.4%) 6
Stoma site haemorrhage 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Tooth fracture 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Wrist fracture 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Investigations
Alanine aminotransferase increased 0/4 (0%) 0 2/20 (10%) 3 3/18 (16.7%) 4 1/20 (5%) 1 36/382 (9.4%) 46 42/444 (9.5%) 54
Amylase increased 1/4 (25%) 1 0/20 (0%) 0 1/18 (5.6%) 5 2/20 (10%) 3 35/382 (9.2%) 45 39/444 (8.8%) 54
Aspartate aminotransferase increased 0/4 (0%) 0 2/20 (10%) 3 4/18 (22.2%) 6 1/20 (5%) 1 44/382 (11.5%) 56 51/444 (11.5%) 66
Blood alkaline phosphatase increased 0/4 (0%) 0 2/20 (10%) 2 2/18 (11.1%) 2 1/20 (5%) 1 31/382 (8.1%) 37 36/444 (8.1%) 42
Blood bilirubin increased 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 7/382 (1.8%) 7 8/444 (1.8%) 8
Blood calcium decreased 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Blood creatinine increased 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 2 25/382 (6.5%) 29 27/444 (6.1%) 32
Blood iron decreased 0/4 (0%) 0 0/20 (0%) 0 2/18 (11.1%) 2 0/20 (0%) 0 4/382 (1%) 4 6/444 (1.4%) 6
Blood thyroid stimulating hormone increased 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 2 0/20 (0%) 0 5/382 (1.3%) 5 6/444 (1.4%) 7
Body temperature increased 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 4/382 (1%) 4 5/444 (1.1%) 5
Electrocardiogram QT prolonged 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Gamma-glutamyltransferase increased 0/4 (0%) 0 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 5/444 (1.1%) 5
Lipase decreased 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Lipase increased 0/4 (0%) 0 0/20 (0%) 0 3/18 (16.7%) 13 3/20 (15%) 6 48/382 (12.6%) 80 54/444 (12.2%) 99
Platelet count decreased 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 2 9/382 (2.4%) 11 10/444 (2.3%) 13
Red blood cell count decreased 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 2 1/382 (0.3%) 1 2/444 (0.5%) 3
Troponin increased 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Weight decreased 0/4 (0%) 0 0/20 (0%) 0 4/18 (22.2%) 4 1/20 (5%) 1 35/382 (9.2%) 37 40/444 (9%) 42
Weight increased 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 8/382 (2.1%) 9 10/444 (2.3%) 11
White blood cell count decreased 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 14/382 (3.7%) 16 15/444 (3.4%) 17
Metabolism and nutrition disorders
Decreased appetite 0/4 (0%) 0 4/20 (20%) 4 1/18 (5.6%) 1 9/20 (45%) 9 95/382 (24.9%) 103 109/444 (24.5%) 117
Dehydration 1/4 (25%) 1 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 32/382 (8.4%) 34 34/444 (7.7%) 36
Hypercalcaemia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 14/382 (3.7%) 14 16/444 (3.6%) 16
Hyperglycaemia 0/4 (0%) 0 1/20 (5%) 2 2/18 (11.1%) 4 3/20 (15%) 5 23/382 (6%) 31 29/444 (6.5%) 42
Hyperkalaemia 0/4 (0%) 0 0/20 (0%) 0 3/18 (16.7%) 5 2/20 (10%) 3 21/382 (5.5%) 26 26/444 (5.9%) 34
Hypermagnesaemia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Hyperphosphataemia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 2/382 (0.5%) 4 3/444 (0.7%) 5
Hyperuricaemia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 15/382 (3.9%) 17 16/444 (3.6%) 18
Hypoalbuminaemia 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 2/20 (10%) 2 14/382 (3.7%) 14 17/444 (3.8%) 17
Hypocalcaemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 2/20 (10%) 2 9/382 (2.4%) 9 11/444 (2.5%) 11
Hypoglycaemia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 2 1/20 (5%) 1 6/382 (1.6%) 6 8/444 (1.8%) 9
Hypokalaemia 0/4 (0%) 0 0/20 (0%) 0 2/18 (11.1%) 2 2/20 (10%) 2 30/382 (7.9%) 39 34/444 (7.7%) 43
Hypomagnesaemia 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 12/382 (3.1%) 17 14/444 (3.2%) 19
Hyponatraemia 0/4 (0%) 0 0/20 (0%) 0 3/18 (16.7%) 5 1/20 (5%) 1 39/382 (10.2%) 57 43/444 (9.7%) 63
Hypophosphataemia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 2/20 (10%) 6 17/382 (4.5%) 25 19/444 (4.3%) 31
Hypovolaemia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Vitamin D deficiency 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Musculoskeletal and connective tissue disorders
Arthralgia 4/4 (100%) 7 9/20 (45%) 12 4/18 (22.2%) 6 6/20 (30%) 8 64/382 (16.8%) 88 87/444 (19.6%) 121
Back pain 1/4 (25%) 2 4/20 (20%) 4 7/18 (38.9%) 8 5/20 (25%) 6 48/382 (12.6%) 58 65/444 (14.6%) 78
Bursitis 0/4 (0%) 0 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 2/444 (0.5%) 2
Flank pain 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 2/20 (10%) 2 17/382 (4.5%) 19 21/444 (4.7%) 23
Groin pain 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 7/382 (1.8%) 8 9/444 (2%) 10
Joint contracture 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Joint swelling 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 4/382 (1%) 4 5/444 (1.1%) 5
Limb discomfort 0/4 (0%) 0 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 2/444 (0.5%) 2
Muscle spasms 2/4 (50%) 2 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 23/382 (6%) 31 25/444 (5.6%) 33
Muscle tightness 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Muscle twitching 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 4 4/444 (0.9%) 5
Muscular weakness 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 1/20 (5%) 1 16/382 (4.2%) 16 19/444 (4.3%) 19
Musculoskeletal chest pain 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 13/382 (3.4%) 16 15/444 (3.4%) 18
Musculoskeletal pain 1/4 (25%) 1 3/20 (15%) 3 1/18 (5.6%) 1 3/20 (15%) 4 28/382 (7.3%) 30 36/444 (8.1%) 39
Musculoskeletal stiffness 0/4 (0%) 0 2/20 (10%) 3 1/18 (5.6%) 1 3/20 (15%) 3 4/382 (1%) 4 10/444 (2.3%) 11
Myalgia 0/4 (0%) 0 4/20 (20%) 4 3/18 (16.7%) 3 5/20 (25%) 7 22/382 (5.8%) 25 34/444 (7.7%) 39
Neck pain 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 12/382 (3.1%) 12 14/444 (3.2%) 14
Osteoporosis 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Pain in extremity 3/4 (75%) 4 3/20 (15%) 4 0/18 (0%) 0 5/20 (25%) 7 40/382 (10.5%) 45 51/444 (11.5%) 60
Trismus 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Seborrhoeic keratosis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 3/444 (0.7%) 3
Nervous system disorders
Amnesia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Ataxia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Balance disorder 0/4 (0%) 0 0/20 (0%) 0 2/18 (11.1%) 2 0/20 (0%) 0 1/382 (0.3%) 1 3/444 (0.7%) 3
Cerebral cyst 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Disturbance in attention 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Dizziness 0/4 (0%) 0 5/20 (25%) 9 2/18 (11.1%) 2 3/20 (15%) 4 40/382 (10.5%) 49 50/444 (11.3%) 64
Dizziness postural 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 2 2/382 (0.5%) 2 3/444 (0.7%) 4
Dysgeusia 0/4 (0%) 0 0/20 (0%) 0 2/18 (11.1%) 2 0/20 (0%) 0 8/382 (2.1%) 8 10/444 (2.3%) 10
Headache 2/4 (50%) 4 6/20 (30%) 13 1/18 (5.6%) 1 4/20 (20%) 5 58/382 (15.2%) 77 71/444 (16%) 100
Hyperaesthesia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Hypoaesthesia 0/4 (0%) 0 2/20 (10%) 2 1/18 (5.6%) 1 2/20 (10%) 3 12/382 (3.1%) 13 17/444 (3.8%) 19
Memory impairment 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 7/382 (1.8%) 8 8/444 (1.8%) 9
Migraine 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 3/382 (0.8%) 3 4/444 (0.9%) 4
Neuropathy peripheral 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 0/20 (0%) 0 14/382 (3.7%) 14 16/444 (3.6%) 16
Paraesthesia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 9/382 (2.4%) 10 11/444 (2.5%) 12
Peripheral sensory neuropathy 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 3/20 (15%) 4 5/382 (1.3%) 5 8/444 (1.8%) 9
Post herpetic neuralgia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Restless legs syndrome 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Seizure 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Slow speech 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Taste disorder 1/4 (25%) 1 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 10/382 (2.6%) 10 12/444 (2.7%) 12
VIth nerve paralysis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Psychiatric disorders
Anxiety 1/4 (25%) 1 2/20 (10%) 2 2/18 (11.1%) 3 3/20 (15%) 3 23/382 (6%) 24 31/444 (7%) 33
Confusional state 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 8/382 (2.1%) 8 9/444 (2%) 9
Depression 2/4 (50%) 2 2/20 (10%) 2 0/18 (0%) 0 2/20 (10%) 2 18/382 (4.7%) 20 24/444 (5.4%) 26
Insomnia 2/4 (50%) 2 6/20 (30%) 6 1/18 (5.6%) 1 2/20 (10%) 2 44/382 (11.5%) 48 55/444 (12.4%) 59
Mental status changes 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Renal and urinary disorders
Acute kidney injury 0/4 (0%) 0 1/20 (5%) 2 0/18 (0%) 0 0/20 (0%) 0 6/382 (1.6%) 7 7/444 (1.6%) 9
Chromaturia 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Dysuria 0/4 (0%) 0 2/20 (10%) 2 1/18 (5.6%) 1 0/20 (0%) 0 5/382 (1.3%) 5 8/444 (1.8%) 8
Haematuria 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 6/382 (1.6%) 8 7/444 (1.6%) 9
Micturition urgency 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 6/382 (1.6%) 7 7/444 (1.6%) 8
Nocturia 0/4 (0%) 0 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 4 6/444 (1.4%) 6
Pollakiuria 0/4 (0%) 0 2/20 (10%) 2 1/18 (5.6%) 1 0/20 (0%) 0 14/382 (3.7%) 16 17/444 (3.8%) 19
Ureteric obstruction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Urinary retention 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 4/382 (1%) 4 6/444 (1.4%) 6
Reproductive system and breast disorders
Balanoposthitis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Erectile dysfunction 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 3/444 (0.7%) 3
Nipple pain 0/4 (0%) 0 1/20 (5%) 2 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 2
Pelvic pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 4/382 (1%) 4 5/444 (1.1%) 5
Vulvovaginal pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Respiratory, thoracic and mediastinal disorders
Aspiration 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Asthma 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Cough 3/4 (75%) 4 7/20 (35%) 9 3/18 (16.7%) 3 9/20 (45%) 9 100/382 (26.2%) 114 122/444 (27.5%) 139
Dry throat 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Dysphonia 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 10/382 (2.6%) 11 12/444 (2.7%) 13
Dyspnoea 2/4 (50%) 3 2/20 (10%) 2 6/18 (33.3%) 7 5/20 (25%) 7 69/382 (18.1%) 77 84/444 (18.9%) 96
Dyspnoea exertional 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 20/382 (5.2%) 23 22/444 (5%) 25
Epistaxis 1/4 (25%) 1 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 12/382 (3.1%) 13 15/444 (3.4%) 16
Haemoptysis 0/4 (0%) 0 0/20 (0%) 0 2/18 (11.1%) 2 0/20 (0%) 0 11/382 (2.9%) 12 13/444 (2.9%) 14
Nasal congestion 0/4 (0%) 0 2/20 (10%) 2 2/18 (11.1%) 2 1/20 (5%) 1 20/382 (5.2%) 22 25/444 (5.6%) 27
Oropharyngeal pain 1/4 (25%) 1 1/20 (5%) 2 0/18 (0%) 0 3/20 (15%) 4 19/382 (5%) 21 24/444 (5.4%) 28
Paranasal sinus discomfort 0/4 (0%) 0 1/20 (5%) 2 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 3
Paranasal sinus hypersecretion 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Pharyngeal paraesthesia 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1
Pleuritic pain 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 3/444 (0.7%) 3
Pneumonitis 0/4 (0%) 0 1/20 (5%) 2 0/18 (0%) 0 0/20 (0%) 0 5/382 (1.3%) 5 6/444 (1.4%) 7
Productive cough 0/4 (0%) 0 3/20 (15%) 5 2/18 (11.1%) 2 1/20 (5%) 1 25/382 (6.5%) 28 31/444 (7%) 36
Pulmonary embolism 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 5/382 (1.3%) 5 6/444 (1.4%) 6
Respiratory tract congestion 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 4/382 (1%) 4 5/444 (1.1%) 5
Rhinitis allergic 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 1/20 (5%) 1 3/382 (0.8%) 3 6/444 (1.4%) 6
Rhinorrhoea 1/4 (25%) 1 2/20 (10%) 3 0/18 (0%) 0 0/20 (0%) 0 8/382 (2.1%) 8 11/444 (2.5%) 12
Sinus congestion 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 2/20 (10%) 2 10/382 (2.6%) 10 13/444 (2.9%) 13
Sinus pain 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Sneezing 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Throat irritation 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Upper-airway cough syndrome 0/4 (0%) 0 1/20 (5%) 1 1/18 (5.6%) 1 2/20 (10%) 2 10/382 (2.6%) 10 14/444 (3.2%) 14
Wheezing 1/4 (25%) 1 0/20 (0%) 0 1/18 (5.6%) 1 1/20 (5%) 1 16/382 (4.2%) 18 19/444 (4.3%) 21
Skin and subcutaneous tissue disorders
Actinic keratosis 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Alopecia 1/4 (25%) 1 1/20 (5%) 1 0/18 (0%) 0 1/20 (5%) 1 6/382 (1.6%) 6 9/444 (2%) 9
Alopecia areata 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Blister 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 2/382 (0.5%) 2 3/444 (0.7%) 3
Dermatitis acneiform 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Diffuse alopecia 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Dry skin 1/4 (25%) 1 0/20 (0%) 0 2/18 (11.1%) 2 1/20 (5%) 1 16/382 (4.2%) 18 20/444 (4.5%) 22
Ecchymosis 1/4 (25%) 1 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 2/444 (0.5%) 2
Eczema 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Erythema 1/4 (25%) 3 1/20 (5%) 1 1/18 (5.6%) 3 2/20 (10%) 2 8/382 (2.1%) 9 13/444 (2.9%) 18
Erythema multiforme 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Hair colour changes 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Hyperhidrosis 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 2/20 (10%) 2 10/382 (2.6%) 11 12/444 (2.7%) 13
Nail bed disorder 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Pain of skin 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Palmar-plantar erythrodysaesthesia syndrome 0/4 (0%) 0 1/20 (5%) 1 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Pruritus 3/4 (75%) 4 6/20 (30%) 12 2/18 (11.1%) 2 9/20 (45%) 12 78/382 (20.4%) 96 98/444 (22.1%) 126
Rash 2/4 (50%) 3 6/20 (30%) 10 1/18 (5.6%) 1 6/20 (30%) 13 86/382 (22.5%) 108 101/444 (22.7%) 135
Rash erythematous 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 2 2/382 (0.5%) 2 3/444 (0.7%) 4
Rash follicular 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Rash maculo-papular 0/4 (0%) 0 3/20 (15%) 4 0/18 (0%) 0 4/20 (20%) 5 19/382 (5%) 23 26/444 (5.9%) 32
Rash papular 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Rash pruritic 1/4 (25%) 1 1/20 (5%) 1 0/18 (0%) 0 2/20 (10%) 11 11/382 (2.9%) 11 15/444 (3.4%) 24
Skin discolouration 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Skin disorder 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Skin exfoliation 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 1/382 (0.3%) 1 2/444 (0.5%) 2
Skin lesion 1/4 (25%) 1 2/20 (10%) 2 0/18 (0%) 0 1/20 (5%) 1 8/382 (2.1%) 10 12/444 (2.7%) 14
Skin ulcer 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Vitiligo 1/4 (25%) 1 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 4/382 (1%) 4 7/444 (1.6%) 7
Xeroderma 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 1/382 (0.3%) 1 2/444 (0.5%) 2
Vascular disorders
Deep vein thrombosis 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Hot flush 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 2/20 (10%) 2 7/382 (1.8%) 7 9/444 (2%) 9
Hypertension 0/4 (0%) 0 2/20 (10%) 2 0/18 (0%) 0 0/20 (0%) 0 9/382 (2.4%) 9 11/444 (2.5%) 11
Hypotension 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 11/382 (2.9%) 14 12/444 (2.7%) 15
Jugular vein thrombosis 1/4 (25%) 1 0/20 (0%) 0 0/18 (0%) 0 0/20 (0%) 0 0/382 (0%) 0 1/444 (0.2%) 1
Lymphoedema 0/4 (0%) 0 0/20 (0%) 0 1/18 (5.6%) 1 0/20 (0%) 0 2/382 (0.5%) 2 3/444 (0.7%) 3
Phlebitis superficial 0/4 (0%) 0 0/20 (0%) 0 0/18 (0%) 0 1/20 (5%) 1 0/382 (0%) 0 1/444 (0.2%) 1

Limitations/Caveats

Study enrollment was permanently discontinued on 17 May 2018 as a strategic decision.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Clinical Study Agreement

Results Point of Contact

Name/Title Study Director
Organization Incyte Corporation
Phone 1-855-463-3463
Email medinfo@incyte.com
Responsible Party:
Incyte Corporation
ClinicalTrials.gov Identifier:
NCT02178722
Other Study ID Numbers:
  • INCB 24360-202/ ECHO-202
First Posted:
Jul 1, 2014
Last Update Posted:
Feb 14, 2022
Last Verified:
Feb 1, 2022