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Pembrolizumab Plus Epacadostat vs Pembrolizumab Plus Placebo in Metastatic Non-Small Cell Lung Cancer (KEYNOTE-654-05/ECHO-305-05)

Sponsor
Incyte Corporation (Industry)
Overall Status
Completed
CT.gov ID
NCT03322540
Collaborator
Merck Sharp & Dohme LLC (Industry)
154
Enrollment
101
Locations
2
Arms
34.8
Actual Duration (Months)
1.5
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus epacadostat compared to pembrolizumab plus placebo as first-line treatment in participants with metastatic non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death ligand 1 (PD-L1).

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
154 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
With the implementation of Amendment 05 the study is no longer blinded.
Primary Purpose:
Treatment
Official Title:
A Phase 2, Randomized, Double-Blind Study of Pembrolizumab (MK-3475) Plus Epacadostat (INCB024360) Versus Pembrolizumab Plus Placebo as First-Line Treatment in Patients With Metastatic Non-Small Cell Lung Cancer Expressing High Levels of PD-L1
Actual Study Start Date :
Dec 15, 2017
Actual Primary Completion Date :
Jan 10, 2019
Actual Study Completion Date :
Nov 9, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Pembrolizumab + Epacadostat

Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05.

Drug: Pembrolizumab
Pembrolizumab administered intravenously every 3 weeks.
Other Names:
  • MK-3475

    • Drug: Epacadostat
    Epacadostat administered orally twice daily.
    Other Names:
  • INCB024360

    		•
    Active Comparator: Pembrolizumab + Placebo

    Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.

    Drug: Pembrolizumab
    Pembrolizumab administered intravenously every 3 weeks.
    Other Names:
  • MK-3475

    • Drug: Placebo
    Matching placebo administered orally twice daily.

    Outcome Measures

    Primary Outcome Measures

    1. Objective Response Rate (ORR) of Pembrolizumab Plus Epacadostat Versus Pembrolizumab Plus Placebo [Up to approximately 6 months]

      ORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 based on blinded independent central review (BICR).

    Secondary Outcome Measures

    1. Progression-free Survival (PFS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo [Up to approximately 36 months]

      PFS is defined as the time from randomization to the first documented progressive disease per RECIST v1.1 based on BICR or death due to any cause, whichever occurs first.

    2. Overall Survival (OS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo [Up to approximately 36 months]

      OS is defined as the time from randomization to death due to any cause.

    3. Duration of Response (DOR) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo [Up to approximately 36 months]

      DOR is defined as the time from the earliest date of qualifying response until earliest date of disease progression per RECIST v1.1 or death from any cause, whichever comes first.

    4. Number of Participants With Adverse Events (AEs) [Up to 37 months]

      AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.

    5. Number of Participants Who Discontinued Study Drug Due to AEs [Up to 37 months]

      AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Histologically or cytologically confirmed diagnosis of stage IV NSCLC without epidermal growth factor receptor (EGFR)-sensitizing mutation, ROS1 and/or anaplastic lymphoma kinase (ALK) translocation.

    • Measurable disease based on RECIST 1.1.

    • Tumor tissue that demonstrates programmed cell death ligand 1 (PD-L1) expression in ≥ 50% of tumor cells (tumor proportion score [TPS] ≥ 50%) as assessed by immunohistochemistry at a central laboratory.

    • Life expectancy of at least 3 months.

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

    • Adequate organ function per protocol-defined criteria.

    Exclusion Criteria:

    • Known untreated central nervous system metastases and/or carcinomatous meningitis.

    • History of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.

    • Symptomatic ascites or pleural effusion.

    • Known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.

    • Active autoimmune disease that has required systemic treatment in past 2 years.

    • Has had an allogeneic tissue/solid organ transplant.

    • Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by the local health authority.

    • Has known history of or is positive for active Hepatitis B (HBsAg reactive) or has active Hepatitis C (HCV RNA). Note: Testing must be performed to determine eligibility.

    • History or presence of an abnormal electrocardiogram (ECG) that, in the Investigator's opinion, is clinically meaningful.

    • Use of protocol-defined prior/concomitant therapy.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pacific Cancer Medical Center, Inc. Anaheim California United States 92801
    2 Innovative Clinical Research Institute Whittier California United States 90603
    3 Florida Cancer Specialists (South Region) Fort Myers Florida United States 33916
    4 Florida Cancer Specialists (North Region) Saint Petersburg Florida United States 33705
    5 Southeastern Regional Medical Center, Inc. Newnan Georgia United States 30265
    6 Anne Arundel Health System Research Institute Annapolis Maryland United States 21401
    7 Weinberg Cancer Institute at Franklin Square Baltimore Maryland United States 21237
    8 Maryland Oncology Hematology, P.A. Rockville Maryland United States 20850
    9 UMass Memorial Medical Center Worcester Massachusetts United States 01655
    10 Minnesota Oncology Hematology, PA Coon Rapids Minnesota United States 55433
    11 Nebraska Cancer Specialists Omaha Nebraska United States 68130
    12 Allegheny General Hospital Pittsburgh Pennsylvania United States 15224
    13 Tennessee Oncology, PLLC/The Sarah Cannon Research Institute Chattanooga Tennessee United States 37404
    14 Tennessee Oncology, PLLC/The Sarah Cannon Research Institute Nashville Tennessee United States 37203
    15 Texas Oncology-South Austin Austin Texas United States 78745
    16 Austin Health-Austin Hospital Heidelberg Victoria Australia 3084
    17 St John of God Murdoch Medical Clinic Murdoch Western Australia Australia 6150
    18 Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
    19 Moncton Hospital - Horizon Health Network Moncton New Brunswick Canada E1C 6Z8
    20 William Osler Health System Brampton Ontario Canada L6R 3J7
    21 Cancer Centre of Southeastern Ontario at Kingston General Hospital Kingston Ontario Canada K7L 2V7
    22 Sault Area Hospital Sault Ste Marie Ontario Canada P6B 0A8
    23 Rigshospitalet Copenhagen Denmark 2100
    24 Regionshospitalet Herning Herning Denmark 7400
    25 Odense Universitetshospital Odense Denmark 5000
    26 SA Tartu Ulikooli Kliinikum Tartu Estonia 51014
    27 Galway University Hospital Galway Connacht Ireland H91 YR71
    28 St Vincents University Hospital Dublin Ireland Dublin 4
    29 Soroka Medical Center Beer Sheva Israel 8457108
    30 Rambam Medical Center Haifa Israel 31096
    31 Meir Medical Center Kfar Saba Israel 4428164
    32 Rabin Medical Center Petah Tikva Israel 4941492
    33 Chaim Sheba Medical Center Ramat Gan Israel 52621
    34 IRCCS A.O.U. San Martino - IST Genova Italy 16132
    35 Policlinico Universitario Agostino Gemelli Roma Italy 00168
    36 National Hospital Organization Nagoya Medical Center Nagoya Aichi Japan 460-0001
    37 National Hospital Organization Shikoku Cancer Center Matsuyama Ehime Japan 791-0280
    38 Kurume University Hospital Kurume Fukuoka Japan 830-0011
    39 Kanazawa University Hospital Kanazawa Ishikawa Japan 920-8641
    40 Kanagawa Cancer Center Yokohama Kanagawa Japan 241-8515
    41 Sendai Kousei Hospital Sendai Miyagi Japan 980-0873
    42 Kansai Medical University Hospital Hirakata Osaka Japan 573-1191
    43 Kindai University Hospital Osakasayama Osaka Japan 589-8511
    44 Shizuoka Cancer Center Nagaizumi-chō Shizuoka Prefecture Japan 411-8777
    45 National Hospital Organization Kyushu Cancer Center Fukuoka Japan 811-1395
    46 Kyushu University Hospital Fukuoka Japan 812-8582
    47 Niigata Cancer Center Hospital Niigata Japan 951-8566
    48 Okayama University Hospital Okayama Japan 700-8558
    49 National Cancer Center Hospital Tokyo Japan 104-0045
    50 Nippon Medical School Hospital Tokyo Japan 113-8603
    51 The Cancer Institute Hospital of JFCR Tokyo Japan 135-8550
    52 Wakayama Medical University Hospital Wakayama Japan 641-8509
    53 Chungbuk National University Hospital Cheongju si Chungcheongbuk Do Korea, Republic of 28644
    54 Seoul National University Bundang Hospital Seongnam-si Gyeonggi-do Korea, Republic of 13620
    55 Gacheon University Gil Medical Center Incheon Korea, Republic of 21565
    56 Hospital Tengku Ampuan Afzan Kuantan Pahang Malaysia 25100
    57 Institut Kanser Negara - National Cancer Institute Putrajaya Wilayah Persekutuan Malaysia 62250
    58 University Malaya Medical Centre Kuala Lumpur Malaysia 59100
    59 Pantai Hospital Kuala Lumpur Kuala Lumpur Malaysia
    60 Sarawak General Hospital Kuching Malaysia
    61 Swietokrzyskie Centrum Onkologii SPZOZ Kielce Swietokrzyskie Poland 25-734
    62 Centrum Onkologii im. Prof. Franciszka Lukaszczyka Bydgoszcz Poland 85-796
    63 Centrum Onkologii. Instytut im. Marii Sklodowskiej-Curie Gliwice Poland 44-101
    64 Swietokrzyskie Centrum Onkologii SPZOZ Kielce Poland 25-734
    65 Przychodnia Lekarska Komed Konin Poland 62-500
    66 Samodzielny Publiczny Zespol Gruzlicy i Chorob Pluc Olsztyn Poland 10-357
    67 Wojewodzki Szpital im. Zofii z Zamoyskich Tarnowskiej w Tarnobrzegu Tarnobrzeg Poland 39-400
    68 Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie Warszawa Poland 02-781
    69 Belgorod Regional Oncology Dispensary Belgorod Russian Federation 308010
    70 Central Clinical Hospital with polyclinic Moscow Russian Federation 121359
    71 Moscow Research Oncology Institute named after P.A. Hertsen Moscow Russian Federation 125284
    72 SBHI Leningrad Regional Clinical Hospital Saint Petersburg Russian Federation 194291
    73 SBHI Samara Regional Clinical Oncology Dispensary Samara Russian Federation 443031
    74 Republican Clinical Oncology Dispensary of Republic of Bashkortostan Ufa Russian Federation 450054
    75 Hospital Alvaro Cunqueiro Vigo Pontevedra Spain 36312
    76 Hospital General de Alicante Alicante Spain 03010
    77 Hospital del Mar Barcelona Spain 8003
    78 Hospital Clinico San Carlos Madrid Spain 28040
    79 Hospital Universitario 12 de Octubre Madrid Spain 28041
    80 Hospital Universitario Virgen Macarena Sevilla Spain 41009
    81 Hospital Clinico de Valencia Valencia Spain 46010
    82 Oncological Institute of Southern Switzerland Bellinzona Switzerland 6500
    83 Inselspital Universitatsspital Bern Bern Switzerland 3010
    84 Hopitaux Universitaires de Geneve HUG. Geneva Switzerland 1211
    85 Kantonsspital Winterthur Winterthur Switzerland 8401
    86 Universitaetsspital Zuerich Zuerich Switzerland 8091
    87 Basken Uni. Adana Dr.Turgut Noyan Uygulama ve Arastirma Merkezi Adana Turkey 01120
    88 Ankara University Medical Faculty Ankara Turkey 06100
    89 Akdeniz Universitesi Tip Fakultesi Antalya Turkey 07059
    90 Erciyes Universitesi Tip Fakultesi Kayseri Turkey 38039
    91 Necmettin Erbakan Universitesi Meram Tip Fakultesi Hastanesi Konya Turkey 42080
    92 MI Kryviy Rih Center of Dnipropetrovsk Regional Council Kryvyi Rih Dnipropetrovsk Region Ukraine 50048
    93 Dnipropetrovsk City Multidiscipline Clinical Hosp.4 of DRC Dnipropetrovsk Ukraine 49102
    94 Grigoriev Institute for medical Radiology NAMS of Ukraine Kharkiv Ukraine 61024
    95 PP PPC Acinus Medical and Diagnostic Centre Kirovohrad Ukraine 25001
    96 Kyiv City Clinical Oncological Center Kyiv Ukraine 03115
    97 Dobryi Prognoz Kyiv Ukraine 03126
    98 Volyn Regional Oncological Dispensary Lutsk Ukraine 43018
    99 MI Odessa Regional Oncological Centre Odesa Ukraine 65055
    100 Zaporizhzhya Regional Clinical Oncology Center Zaporizhzhya Ukraine 69040
    101 Leeds Teaching Hospital NHS Trust. St. James University Hospital Leeds United Kingdom LS9 7TF

    Sponsors and Collaborators

    • Incyte Corporation
    • Merck Sharp & Dohme LLC

    Investigators

    • Study Director: Lance Leopold, MD, Incyte Corporation

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Incyte Corporation
    ClinicalTrials.gov Identifier:
    NCT03322540
    Other Study ID Numbers:
    • KEYNOTE-654-05/ECHO-305-05
    First Posted:
    Oct 26, 2017
    Last Update Posted:
    Jan 24, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Incyte Corporation
    non-small cell lung cancer
    programmed cell death 1 (PD-1) inhibitor
    indoleamine 2
    3-dioxygenase 1 (IDO1) inhibitor
    Additional relevant MeSH terms:
    Lung Neoplasms
    Carcinoma, Non-Small-Cell Lung
    Pembrolizumab

    Study Results

    Participant Flow

    Recruitment Details A total of 154 participants were randomized in 1:1 to either combination (Pembrolizumab+Epacadostat) and control (Pembrolizumab+Placebo) groups. As of Amendment 05, study design was changed to unblinded, open-label, and single-arm (epacadostat and placebo were removed).
    Pre-assignment Detail Phase 3 design of the study has been amended soon after it had started to a prospectively randomized phase 2 study. At the time of amendment existing participants were given a choice to move/participate in the new phase 2 study, and some participants who chose to discontinue the study at phase 3 were assigned to "study terminated by sponsor" as the reason for not completing the study in disposition table. The results posted are combined in the prospectively redesigned phase 2 trial.
    Arm/Group Title Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.
    Period Title: Overall Study
    STARTED 77 77
    Number of Subjects Received Treatment (Actual Treatment) (ASaT) 75 77
    COMPLETED 46 40
    NOT COMPLETED 31 37

    Baseline Characteristics

    Arm/Group Title Pembrolizumab + Epacadostat Pembrolizumab + Placebo Total
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05. Total of all reporting groups
    Overall Participants 77 77 154
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    63.7
    (9.5)
    66.9
    (10.1)
    65.3
    (9.9)
    Sex: Female, Male (Count of Participants)
    Female
    24
    31.2%
    18
    23.4%
    42
    27.3%
    Male
    53
    68.8%
    59
    76.6%
    112
    72.7%
    Race/Ethnicity, Customized (Count of Participants)
    Asian
    25
    32.5%
    23
    29.9%
    48
    31.2%
    White
    52
    67.5%
    54
    70.1%
    106
    68.8%
    Race/Ethnicity, Customized (Count of Participants)
    Hispanic Or Latino
    7
    9.1%
    4
    5.2%
    11
    7.1%
    Not Hispanic Or Latino
    66
    85.7%
    73
    94.8%
    139
    90.3%
    Not Reported
    3
    3.9%
    0
    0%
    3
    1.9%
    Unknown
    1
    1.3%
    0
    0%
    1
    0.6%

    Outcome Measures

    1. Primary Outcome
    Title Objective Response Rate (ORR) of Pembrolizumab Plus Epacadostat Versus Pembrolizumab Plus Placebo
    Description ORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 based on blinded independent central review (BICR).
    Time Frame Up to approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    ITT population consisted of all randomized participants.
    Arm/Group Title Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.
    Measure Participants 77 77
    Number (95% Confidence Interval) [percentage of participants]
    32.5
    42.2%
    39.0
    50.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Pembrolizumab + Epacadostat, Pembrolizumab + Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8000
    Comments
    Method Stratified Miettinen and Nurminen method
    Comments One-sided p-value for testing. H0: difference in % = 0 versus H1: difference in % > 0.
    Method of Estimation Estimation Parameter Difference in Percentages
    Estimated Value -6.5
    Confidence Interval (2-Sided) 95%
    -21.5 to 8.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments Point estimate was assessed based on Miettinen & Nurminen method stratified by predominant tumor histology (squamous vs non-squamous).
    2. Secondary Outcome
    Title Progression-free Survival (PFS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo
    Description PFS is defined as the time from randomization to the first documented progressive disease per RECIST v1.1 based on BICR or death due to any cause, whichever occurs first.
    Time Frame Up to approximately 36 months

    Outcome Measure Data

    Analysis Population Description
    ITT population consisted of all randomized participants.
    Arm/Group Title Pembrolizumab + Epacadostat Pembrolizumab + Placebo
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.
    Measure Participants 77 77
    Median (95% Confidence Interval) [months]
    6.7
    6.2
    3. Secondary Outcome
    Title Overall Survival (OS) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo
    Description OS is defined as the time from randomization to death due to any cause.
    Time Frame Up to approximately 36 months

    Outcome Measure Data

    Analysis Population Description
    ITT population consisted of all randomized participants.
    Arm/Group Title Pembrolizumab + Epacodostat Pembrolizumab + Placebo
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.
    Measure Participants 77 77
    Median (95% Confidence Interval) [Months]
    NA
    NA
    4. Secondary Outcome
    Title Duration of Response (DOR) of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo
    Description DOR is defined as the time from the earliest date of qualifying response until earliest date of disease progression per RECIST v1.1 or death from any cause, whichever comes first.
    Time Frame Up to approximately 36 months

    Outcome Measure Data

    Analysis Population Description
    DOR included all responders in ITT population. Response duration was calculated from product-limit (Kaplan-Meier) method for censored data.
    Arm/Group Title Pembrolizumab + Epacodostat Pembrolizumab + Placebo
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.
    Measure Participants 77 77
    Median (Full Range) [Months]
    6.2
    NA
    5. Secondary Outcome
    Title Number of Participants With Adverse Events (AEs)
    Description AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
    Time Frame Up to 37 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pembrolizumab + Epacodostat Pembrolizumab + Placebo
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.
    Measure Participants 75 77
    Number [Participants]
    72
    93.5%
    72
    93.5%
    6. Secondary Outcome
    Title Number of Participants Who Discontinued Study Drug Due to AEs
    Description AE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment.
    Time Frame Up to 37 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pembrolizumab + Epacodostat Pembrolizumab + Placebo
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.
    Measure Participants 75 77
    Number [Participants]
    15
    19.5%
    12
    15.6%

    Adverse Events

    Time Frame Up to 37 months
    Adverse Event Reporting Description The all participants as treated (APaT) population will be used for the analysis of safety data in this study. The APaT population consists of all randomized participants who received at least one dose of study treatment.
    Arm/Group Title Pembrolizumab + Epacadostat Pembrolizumab + Placebo Total
    Arm/Group Description Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05. Total
    All Cause Mortality
    Pembrolizumab + Epacadostat Pembrolizumab + Placebo Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 23/75 (30.7%) 29/77 (37.7%) 52/152 (34.2%)
    Serious Adverse Events
    Pembrolizumab + Epacadostat Pembrolizumab + Placebo Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 36/75 (48%) 35/77 (45.5%) 71/152 (46.7%)
    Blood and lymphatic system disorders
    Anaemia 2/75 (2.7%) 2 0/77 (0%) 0 2/152 (1.3%) 2
    Cardiac disorders
    Atrial fibrillation 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Autoimmune myocarditis 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Cardiac arrest 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Pericardial effusion 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Endocrine disorders
    Hypothyroidism 1/75 (1.3%) 1 1/77 (1.3%) 1 2/152 (1.3%) 2
    Gastrointestinal disorders
    Colitis 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Colitis ischaemic 1/75 (1.3%) 2 0/77 (0%) 0 1/152 (0.7%) 2
    Constipation 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Ileus 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Intestinal perforation 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Pancreatitis 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Pseudodiverticular disease 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Small intestinal haemorrhage 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    General disorders
    Asthenia 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Death 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    General physical health deterioration 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Multiple organ dysfunction syndrome 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Hepatobiliary disorders
    Cholangitis 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Cholangitis sclerosing 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Hepatitis 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Infections and infestations
    Cytomegalovirus viraemia 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Gastroenteritis 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Lower respiratory tract infection 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Peritonitis 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Pneumonia 6/75 (8%) 6 7/77 (9.1%) 7 13/152 (8.6%) 13
    Pyelonephritis 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Septic shock 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Urinary tract infection 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Viral infection 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Injury, poisoning and procedural complications
    Fibula fracture 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Infusion related reaction 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Rib fracture 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Tibia fracture 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Metabolism and nutrition disorders
    Decreased appetite 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Diabetes mellitus 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Hypercalcaemia 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Hyperkalaemia 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Hypokalaemia 0/75 (0%) 0 2/77 (2.6%) 2 2/152 (1.3%) 2
    Musculoskeletal and connective tissue disorders
    Back pain 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Muscular weakness 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Pathological fracture 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    High-grade B-cell lymphoma 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Malignant neoplasm progression 6/75 (8%) 6 8/77 (10.4%) 8 14/152 (9.2%) 14
    Tumour pseudoprogression 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Nervous system disorders
    Cerebral ischaemia 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Epilepsy 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Ischaemic stroke 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Polyneuropathy 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Spinal cord compression 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Psychiatric disorders
    Fear of death 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Renal and urinary disorders
    Acute kidney injury 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Reproductive system and breast disorders
    Priapism 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis 2/75 (2.7%) 2 0/77 (0%) 0 2/152 (1.3%) 2
    Chronic obstructive pulmonary disease 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Dyspnoea 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Haemoptysis 1/75 (1.3%) 1 1/77 (1.3%) 1 2/152 (1.3%) 2
    Pleural effusion 1/75 (1.3%) 2 1/77 (1.3%) 1 2/152 (1.3%) 3
    Pneumonitis 4/75 (5.3%) 4 2/77 (2.6%) 2 6/152 (3.9%) 6
    Pulmonary embolism 1/75 (1.3%) 1 0/77 (0%) 0 1/152 (0.7%) 1
    Respiratory failure 1/75 (1.3%) 1 1/77 (1.3%) 1 2/152 (1.3%) 2
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative generalised 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Vascular disorders
    Hypotension 0/75 (0%) 0 2/77 (2.6%) 2 2/152 (1.3%) 2
    Hypovolaemic shock 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Peripheral ischaemia 0/75 (0%) 0 1/77 (1.3%) 1 1/152 (0.7%) 1
    Other (Not Including Serious) Adverse Events
    Pembrolizumab + Epacadostat Pembrolizumab + Placebo Total
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 69/75 (92%) 67/77 (87%) 136/152 (89.5%)
    Blood and lymphatic system disorders
    Anaemia 7/75 (9.3%) 8 10/77 (13%) 12 17/152 (11.2%) 20
    Endocrine disorders
    Hyperthyroidism 8/75 (10.7%) 8 6/77 (7.8%) 6 14/152 (9.2%) 14
    Hypothyroidism 10/75 (13.3%) 11 6/77 (7.8%) 6 16/152 (10.5%) 17
    Gastrointestinal disorders
    Constipation 20/75 (26.7%) 23 18/77 (23.4%) 21 38/152 (25%) 44
    Diarrhoea 16/75 (21.3%) 30 17/77 (22.1%) 25 33/152 (21.7%) 55
    Nausea 14/75 (18.7%) 16 8/77 (10.4%) 8 22/152 (14.5%) 24
    Vomiting 7/75 (9.3%) 8 6/77 (7.8%) 6 13/152 (8.6%) 14
    General disorders
    Asthenia 8/75 (10.7%) 9 6/77 (7.8%) 8 14/152 (9.2%) 17
    Chest pain 5/75 (6.7%) 5 6/77 (7.8%) 7 11/152 (7.2%) 12
    Chills 4/75 (5.3%) 5 1/77 (1.3%) 2 5/152 (3.3%) 7
    Fatigue 9/75 (12%) 11 16/77 (20.8%) 21 25/152 (16.4%) 32
    Oedema peripheral 4/75 (5.3%) 6 5/77 (6.5%) 5 9/152 (5.9%) 11
    Pyrexia 7/75 (9.3%) 8 8/77 (10.4%) 8 15/152 (9.9%) 16
    Infections and infestations
    Nasopharyngitis 2/75 (2.7%) 2 8/77 (10.4%) 10 10/152 (6.6%) 12
    Oral candidiasis 2/75 (2.7%) 3 4/77 (5.2%) 6 6/152 (3.9%) 9
    Pneumonia 4/75 (5.3%) 4 3/77 (3.9%) 3 7/152 (4.6%) 7
    Respiratory tract infection 5/75 (6.7%) 5 1/77 (1.3%) 2 6/152 (3.9%) 7
    Upper respiratory tract infection 6/75 (8%) 6 8/77 (10.4%) 8 14/152 (9.2%) 14
    Urinary tract infection 4/75 (5.3%) 4 6/77 (7.8%) 10 10/152 (6.6%) 14
    Investigations
    Alanine aminotransferase increased 5/75 (6.7%) 5 5/77 (6.5%) 8 10/152 (6.6%) 13
    Amylase increased 8/75 (10.7%) 9 4/77 (5.2%) 8 12/152 (7.9%) 17
    Aspartate aminotransferase increased 4/75 (5.3%) 4 4/77 (5.2%) 7 8/152 (5.3%) 11
    Blood creatinine increased 4/75 (5.3%) 4 7/77 (9.1%) 8 11/152 (7.2%) 12
    Lipase increased 9/75 (12%) 9 4/77 (5.2%) 5 13/152 (8.6%) 14
    Lymphocyte count decreased 1/75 (1.3%) 1 4/77 (5.2%) 7 5/152 (3.3%) 8
    Weight decreased 7/75 (9.3%) 7 8/77 (10.4%) 8 15/152 (9.9%) 15
    Metabolism and nutrition disorders
    Decreased appetite 17/75 (22.7%) 18 10/77 (13%) 12 27/152 (17.8%) 30
    Hyperglycaemia 6/75 (8%) 7 2/77 (2.6%) 2 8/152 (5.3%) 9
    Hyperkalaemia 2/75 (2.7%) 5 7/77 (9.1%) 11 9/152 (5.9%) 16
    Hypokalaemia 4/75 (5.3%) 6 5/77 (6.5%) 7 9/152 (5.9%) 13
    Hyponatraemia 6/75 (8%) 8 1/77 (1.3%) 1 7/152 (4.6%) 9
    Musculoskeletal and connective tissue disorders
    Arthralgia 17/75 (22.7%) 22 10/77 (13%) 12 27/152 (17.8%) 34
    Back pain 10/75 (13.3%) 13 8/77 (10.4%) 11 18/152 (11.8%) 24
    Myalgia 2/75 (2.7%) 2 7/77 (9.1%) 9 9/152 (5.9%) 11
    Pain in extremity 5/75 (6.7%) 6 4/77 (5.2%) 4 9/152 (5.9%) 10
    Nervous system disorders
    Dizziness 5/75 (6.7%) 5 6/77 (7.8%) 6 11/152 (7.2%) 11
    Dysgeusia 4/75 (5.3%) 4 1/77 (1.3%) 1 5/152 (3.3%) 5
    Headache 13/75 (17.3%) 15 4/77 (5.2%) 4 17/152 (11.2%) 19
    Psychiatric disorders
    Insomnia 6/75 (8%) 7 4/77 (5.2%) 5 10/152 (6.6%) 12
    Respiratory, thoracic and mediastinal disorders
    Cough 7/75 (9.3%) 9 8/77 (10.4%) 8 15/152 (9.9%) 17
    Dyspnoea 10/75 (13.3%) 13 10/77 (13%) 13 20/152 (13.2%) 26
    Haemoptysis 6/75 (8%) 6 7/77 (9.1%) 7 13/152 (8.6%) 13
    Productive cough 4/75 (5.3%) 4 2/77 (2.6%) 2 6/152 (3.9%) 6
    Skin and subcutaneous tissue disorders
    Dry skin 5/75 (6.7%) 5 4/77 (5.2%) 4 9/152 (5.9%) 9
    Pruritus 16/75 (21.3%) 21 16/77 (20.8%) 22 32/152 (21.1%) 43
    Rash 15/75 (20%) 22 11/77 (14.3%) 16 26/152 (17.1%) 38
    Rash maculo-papular 4/75 (5.3%) 5 7/77 (9.1%) 8 11/152 (7.2%) 13
    Vascular disorders
    Hypotension 2/75 (2.7%) 2 4/77 (5.2%) 4 6/152 (3.9%) 6

    Limitations/Caveats

    [Not Specified]

    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:
    NCT03322540
    Other Study ID Numbers:
    • KEYNOTE-654-05/ECHO-305-05
    First Posted:
    Oct 26, 2017
    Last Update Posted:
    Jan 24, 2022
    Last Verified:
    Jan 1, 2022