Clinical Trials List
Protocol NumberMK3475-698
NCT Number(ClinicalTrials.gov Identfier)NCT03374488
2018-01-15 - 2019-08-21
Phase III
Terminated5
ICD-10C66.2
Malignant neoplasm of left ureter
ICD-9188.9
Malignant neoplasm of bladder, part unspecified
A Phase 3 Randomized, Double-Blind Clinical Study of Pembrolizumab + Epacadostat vs Pembrolizumab + Placebo as a Treatment for Recurrent or Progressive Metastatic Urothelial Carcinoma in Patients Who Have Failed a First-Line Platinum-containing Chemotherapy Regimen for Advanced/Metastatic Disease (KEYNOTE-698/ECHO-303)
-
Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
-
Sponsor
Merck Sharp & Dohme Corp.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Sin-Syue Li Division of Hematology & Oncology
- Wu-Chou Su Division of Hematology & Oncology
- Jui-Hung Tsai Division of Hematology & Oncology
- Ya-Ting Hsu Division of Hematology & Oncology
- Shang-Yin Wu Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Co-Principal Investigator
- Yeong-Shiau Pu Division of Urology
- JHE-CYUAN GUO Division of Hematology & Oncology
- Ying-Chun Shen Division of Hematology & Oncology
- CHUNG-HSIN CHEN Division of Urology
- Yu-Chieh Tsai Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chi-Rei Yang Division of Urology
- Che-Hung Lin Division of Hematology & Oncology
- Chao-Hsiang Chang Division of Urology
- Wei-Ching Lin Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Yi-Hsiu Huang Division of Urology
- Tzeon-jye Chiou Division of Hematology & Oncology
- 潘競成 Division of General Surgery
- Yen-Hwa Chang Division of Urology
- Mu-Hsin Chang Division of Hematology & Oncology
- Tzu-Ping Lin Division of Urology
- Chueh-Chuan Yen Division of Hematology & Oncology
- Hsiao-Jen Chung Division of Urology
- Jin-Hwang Liu Division of Hematology & Oncology
- 沈書慧 Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Tai-Jan Chiu Division of Hematology & Oncology
- 陳彥仰 Division of Hematology & Oncology
- 陳彥豪 Division of Hematology & Oncology
- 劉建廷 Division of Hematology & Oncology
- Shau-Hsuan Li Division of Hematology & Oncology
- 吳佳哲 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Urothelial Cancer
Objectives
The purpose of this study was to evaluate the efficacy and safety of pembrolizumab + epacadostat vs pembrolizumab + placebo as a treatment for recurrent or progressive metastatic urothelial carcinoma in patients who have failed a first-line platinum-containing chemotherapy regimen for advanced/metastatic disease.
Test Drug
Pembrolizumab ; Epacadostat
Active Ingredient
Epacadostat
Pembrolizumab
Pembrolizumab
Dosage Form
injection
tablet
tablet
Dosage
100
100 、25
100 、25
Endpoints
Primary Outcome Measures :
Objective Response Rate (ORR) With Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo [ Time Frame: up to 9 weeks +14 days ]
ORR was defined as the percentage of participants who had a complete response (CR), disappearance of all target lesions or partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions per RECIST v1.1 by investigator determination.
Secondary Outcome Measures :
Safety and Tolerability of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo as Measured by Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to 8 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.
Safety and Tolerability of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo as Measured by Number of Participants Discontinuing Study Treatment Due to AE [ Time Frame: Up to 8 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.
Objective Response Rate (ORR) With Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo [ Time Frame: up to 9 weeks +14 days ]
ORR was defined as the percentage of participants who had a complete response (CR), disappearance of all target lesions or partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions per RECIST v1.1 by investigator determination.
Secondary Outcome Measures :
Safety and Tolerability of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo as Measured by Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to 8 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.
Safety and Tolerability of Pembrolizumab + Epacadostat Versus Pembrolizumab + Placebo as Measured by Number of Participants Discontinuing Study Treatment Due to AE [ Time Frame: Up to 8 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.
Inclution Criteria
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have histologically-confirmed diagnosis of UC of the renal pelvis, ureter, bladder, or
urethra, that is transitional cell, or mixed transitional/non-transitional (predominantly
transitional) cell type.
2. Have progression or recurrence of UC following one prior platinum containing
chemotherapy regimen for metastatic or unresectable locally advanced disease. No
additional lines of systemic treatment are allowed.
• Note: A participant who receives a neoadjuvant or adjuvant platinum-containing
regimen following cystectomy for localized muscle-invasive UC is acceptable
(without further systemic treatment), if recurrence/progression occurs ≤12 months
following completion of therapy.
3. Have the presence of at least one measurable lesion by computed tomography (CT) or
Magnetic Resonance Imaging (MRI) per RECIST 1.1 as determined by the investigator/
local radiology assessment.
a. If participants have only 1 measurable lesion per RECIST 1.1, any biopsy specimen
should be obtained from the non-target lesion or archival tissue.
b. If participants have only 1 measurable lesion per RECIST 1.1, this lesion should not
have been in the field of prior irradiation unless there is documented progression of
the lesion(s).
4. Have provided an archival tumor tissue sample or newly obtained core or excisional
biopsy of a tumor lesion not previously irradiated for PD-L1 analysis. A newly
obtained biopsy is strongly preferred but not required if archival tissue is adequate for
analysis. If submitting unstained cut slides, freshly cut slides should be submitted to the
central laboratory within 14 days from when the slides are cut. Refer to Section 9.8.1 in
the protocol for an explanation. PD-L1 status (CPS ≥10 or CPS <10) must be
determined by the central laboratory prior to randomization. Participants will be
excluded if PD-L1 status cannot be determined.
5. Have resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to
Grade 1 or less (except alopecia). Participants with ≤Grade 2 neuropathy are an exception
and may enroll.
Demographics
6. Be ≥18 years of age on day of signing informed consent.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 14 days
prior to randomization.
Male participants:
8. A male participant must agree to use a contraception as detailed in Appendix 2 of this
protocol during the treatment period and for at least 120 days after the last dose of study
treatment and refrain from donating sperm during this period.
Female participants:
• A female participant is eligible to participate if she is not pregnant (see Appendix 2), not
breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 2
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during the
treatment period and for at least 120 days (corresponding to time needed to eliminate any
study treatments (MK-3475 and epacadostat) after the last dose of study treatment.
Informed Consent
9. The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
Laboratory Values
10. Have adequate organ function as defined in the following table (Table 1). Specimens
must be collected within 14 days prior to randomization.
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have histologically-confirmed diagnosis of UC of the renal pelvis, ureter, bladder, or
urethra, that is transitional cell, or mixed transitional/non-transitional (predominantly
transitional) cell type.
2. Have progression or recurrence of UC following one prior platinum containing
chemotherapy regimen for metastatic or unresectable locally advanced disease. No
additional lines of systemic treatment are allowed.
• Note: A participant who receives a neoadjuvant or adjuvant platinum-containing
regimen following cystectomy for localized muscle-invasive UC is acceptable
(without further systemic treatment), if recurrence/progression occurs ≤12 months
following completion of therapy.
3. Have the presence of at least one measurable lesion by computed tomography (CT) or
Magnetic Resonance Imaging (MRI) per RECIST 1.1 as determined by the investigator/
local radiology assessment.
a. If participants have only 1 measurable lesion per RECIST 1.1, any biopsy specimen
should be obtained from the non-target lesion or archival tissue.
b. If participants have only 1 measurable lesion per RECIST 1.1, this lesion should not
have been in the field of prior irradiation unless there is documented progression of
the lesion(s).
4. Have provided an archival tumor tissue sample or newly obtained core or excisional
biopsy of a tumor lesion not previously irradiated for PD-L1 analysis. A newly
obtained biopsy is strongly preferred but not required if archival tissue is adequate for
analysis. If submitting unstained cut slides, freshly cut slides should be submitted to the
central laboratory within 14 days from when the slides are cut. Refer to Section 9.8.1 in
the protocol for an explanation. PD-L1 status (CPS ≥10 or CPS <10) must be
determined by the central laboratory prior to randomization. Participants will be
excluded if PD-L1 status cannot be determined.
5. Have resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to
Grade 1 or less (except alopecia). Participants with ≤Grade 2 neuropathy are an exception
and may enroll.
Demographics
6. Be ≥18 years of age on day of signing informed consent.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 14 days
prior to randomization.
Male participants:
8. A male participant must agree to use a contraception as detailed in Appendix 2 of this
protocol during the treatment period and for at least 120 days after the last dose of study
treatment and refrain from donating sperm during this period.
Female participants:
• A female participant is eligible to participate if she is not pregnant (see Appendix 2), not
breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 2
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during the
treatment period and for at least 120 days (corresponding to time needed to eliminate any
study treatments (MK-3475 and epacadostat) after the last dose of study treatment.
Informed Consent
9. The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
Laboratory Values
10. Have adequate organ function as defined in the following table (Table 1). Specimens
must be collected within 14 days prior to randomization.
Exclusion Criteria
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has urothelial carcinoma that is suitable for local therapy with curative intent.
2. Has presence of a gastrointestinal condition that in the opinion of the Investigator may
affect drug absorption.
3. Has clinically significant cardiac disease, including unstable angina, acute myocardial
infarction within 6 months from Day 1 of study drug administration, or New York Heart
Association Class III or IV congestive heart failure. Medically controlled arrhythmia
stable on medication is permitted.
4. Has a history or presence of an abnormal electrocardiogram (ECG) that, in the
investigator's opinion, is clinically meaningful. Screening corrected QT interval (QTc)
interval >480 msec is excluded (corrected by Fridericia formula or Bazett formula). In
the event that a single QTc is >480 milliseconds, the participant may enroll if the average
QTc for the 3 ECGs is <480 milliseconds.
5. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's participation
for the full duration of the study, or is not in the best interest of the participant to
participate, in the opinion of the treating investigator.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study treatment.
7. Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years.
• Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma
of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that
have undergone potentially curative therapy are not excluded. Participants with low-risk early stage prostate cancer defined as follows are not excluded; Stage T1c or
T2a with a Gleason score ≤ 6 and prostatic-specific antigen (PSA) < 10 ng/mL either
treated with definitive intent or untreated in active surveillance that has been stable
for the past year prior to study allocation.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Participants with previously treated brain metastases may participate
provided they are radiologically stable, ie, without evidence of progression for at least 4
weeks by repeat imaging, (note that repeat imaging should be performed during the study
screening), clinically stable and without requirement of steroid treatment for at least 14
days prior to first dose of study treatment.
9. Has severe hypersensitivity (≥Grade 3) to study treatment (pembrolizumab and
epacadostat) and/or any of its excipients.
10. Has an active autoimmune disease that has required systemic treatment in past 2 years
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic
treatment and is allowed.
11. 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.
• HBV DNA must be undetectable and HBsAg negative at screening visit.
• Hepatitis C Ab testing is allowed for screening purposes in countries where HCV
RNA is not part of SOC. In these cases, HCV antibody positive participants will
be excluded.
• Participants who have had definitive treatment for HCV are permitted if HCV
RNA undetectable at Screening Visit.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is
not required unless mandated by local health authority.
15. Has known psychiatric or substance abuse disorders that would interfere with
cooperating with the requirements of the study.
16. A WOCBP who has a positive urine pregnancy test within 72 hours before randomization
(see Appendix 2). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Note, in the event that 72 hours have elapsed between the screening pregnancy test
and the first dose of study treatment, another pregnancy test (urine or serum) must be
performed and must be negative in order for subject to start receiving study treatment.
Prior/Concomitant Therapy
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti PD-L2 agent, IDO1
inhibitor, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
(eg, CTLA-4, OX 40, CD137), or any other antibody or drug targeting T-cell
co-stimulatory pathways in the adjuvant or advanced/metastatic setting.
18. Has received prior systemic anti-cancer therapy including investigational agents within 4
weeks prior to randomization.
• Note: Participants must have recovered from all AEs due to previous therapies to
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
• Note: If participant received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting study
treatment.
19. Has received prior radiotherapy within 2 weeks of randomization. Participants must
have recovered from all radiation-related toxicities (to Grade ≤1), and not require
corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of
radiotherapy) to non-CNS disease.
20. Has received a live vaccine within 30 days prior to the first dose of study treatment.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines
and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and
are not allowed.
21. Has received therapy with a MAOI, melatonin supplement, or UGT1A9 inhibitor within
21 days prior to starting treatment, or anticipates requiring one of these prohibited
medications during the treatment phase. Examples of medications in these classes are
found in Section 7.7.2.
• Note: Propofol, if administered for an on-study biopsy procedure, may be permitted
per Section 7.7.2.
22. Has any history of SS after receiving serotonergic drugs.
Prior/Concurrent Clinical Study Experience
23. Is currently participating in or has participated in a study of an investigational agent or
has used an investigational device within 4 weeks prior to the first dose of study
treatment.
• Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
Other Exclusions
24. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days after
the last dose of study treatment.
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has urothelial carcinoma that is suitable for local therapy with curative intent.
2. Has presence of a gastrointestinal condition that in the opinion of the Investigator may
affect drug absorption.
3. Has clinically significant cardiac disease, including unstable angina, acute myocardial
infarction within 6 months from Day 1 of study drug administration, or New York Heart
Association Class III or IV congestive heart failure. Medically controlled arrhythmia
stable on medication is permitted.
4. Has a history or presence of an abnormal electrocardiogram (ECG) that, in the
investigator's opinion, is clinically meaningful. Screening corrected QT interval (QTc)
interval >480 msec is excluded (corrected by Fridericia formula or Bazett formula). In
the event that a single QTc is >480 milliseconds, the participant may enroll if the average
QTc for the 3 ECGs is <480 milliseconds.
5. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's participation
for the full duration of the study, or is not in the best interest of the participant to
participate, in the opinion of the treating investigator.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior the first dose of study treatment.
7. Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years.
• Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma
of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that
have undergone potentially curative therapy are not excluded. Participants with low-risk early stage prostate cancer defined as follows are not excluded; Stage T1c or
T2a with a Gleason score ≤ 6 and prostatic-specific antigen (PSA) < 10 ng/mL either
treated with definitive intent or untreated in active surveillance that has been stable
for the past year prior to study allocation.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Participants with previously treated brain metastases may participate
provided they are radiologically stable, ie, without evidence of progression for at least 4
weeks by repeat imaging, (note that repeat imaging should be performed during the study
screening), clinically stable and without requirement of steroid treatment for at least 14
days prior to first dose of study treatment.
9. Has severe hypersensitivity (≥Grade 3) to study treatment (pembrolizumab and
epacadostat) and/or any of its excipients.
10. Has an active autoimmune disease that has required systemic treatment in past 2 years
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic
treatment and is allowed.
11. 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.
• HBV DNA must be undetectable and HBsAg negative at screening visit.
• Hepatitis C Ab testing is allowed for screening purposes in countries where HCV
RNA is not part of SOC. In these cases, HCV antibody positive participants will
be excluded.
• Participants who have had definitive treatment for HCV are permitted if HCV
RNA undetectable at Screening Visit.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is
not required unless mandated by local health authority.
15. Has known psychiatric or substance abuse disorders that would interfere with
cooperating with the requirements of the study.
16. A WOCBP who has a positive urine pregnancy test within 72 hours before randomization
(see Appendix 2). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Note, in the event that 72 hours have elapsed between the screening pregnancy test
and the first dose of study treatment, another pregnancy test (urine or serum) must be
performed and must be negative in order for subject to start receiving study treatment.
Prior/Concomitant Therapy
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti PD-L2 agent, IDO1
inhibitor, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
(eg, CTLA-4, OX 40, CD137), or any other antibody or drug targeting T-cell
co-stimulatory pathways in the adjuvant or advanced/metastatic setting.
18. Has received prior systemic anti-cancer therapy including investigational agents within 4
weeks prior to randomization.
• Note: Participants must have recovered from all AEs due to previous therapies to
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
• Note: If participant received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting study
treatment.
19. Has received prior radiotherapy within 2 weeks of randomization. Participants must
have recovered from all radiation-related toxicities (to Grade ≤1), and not require
corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of
radiotherapy) to non-CNS disease.
20. Has received a live vaccine within 30 days prior to the first dose of study treatment.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines
and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and
are not allowed.
21. Has received therapy with a MAOI, melatonin supplement, or UGT1A9 inhibitor within
21 days prior to starting treatment, or anticipates requiring one of these prohibited
medications during the treatment phase. Examples of medications in these classes are
found in Section 7.7.2.
• Note: Propofol, if administered for an on-study biopsy procedure, may be permitted
per Section 7.7.2.
22. Has any history of SS after receiving serotonergic drugs.
Prior/Concurrent Clinical Study Experience
23. Is currently participating in or has participated in a study of an investigational agent or
has used an investigational device within 4 weeks prior to the first dose of study
treatment.
• Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
Other Exclusions
24. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days after
the last dose of study treatment.
The Estimated Number of Participants
-
Taiwan
4 participants
-
Global
85 participants
