Clinical Trials List
Protocol NumberMK3475-361
NCT Number(ClinicalTrials.gov Identfier)NCT02853305
Completed
2016-09-01 - 2020-12-31
Phase III
Terminated5
ICD-10C67
Malignant neoplasm of bladder
A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab with or without Platinum-Based Combination Chemotherapy versus Chemotherapy in Subjects with Advanced or Metastatic Urothelial Carcinoma
-
Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
-
Sponsor
Merck Sharp & Dohme Corp.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2026/02/01
Investigators and Locations
Co-Principal Investigator
- Yen-Hwa Chang Division of Urology
- Jin-Hwang Liu Division of Hematology & Oncology
- 沈書慧 Division of Radiology
- Hsiao-Jen Chung Division of Urology
- Tzeon-jye Chiou Division of Hematology & Oncology
- 潘競成 Division of General Surgery
- Tzu-chun Wei Division of Urology
- Mu-Hsin Chang Division of Radiation Therapy
- Chueh-Chuan Yen Division of Radiation Therapy
- Tzu-Ping Lin Division of Urology
The Actual Total Number of Participants Enrolled
10 Terminated
Audit
None
Co-Principal Investigator
- Wu-Chou Su Division of Hematology & Oncology
- Sin-Syue Li Division of Hematology & Oncology
- Yu-Min Yeh Division of Hematology & Oncology
- Wei-Pang Chung 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
- Tai-Jan Chiu 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
- 陳彥仰 Division of Hematology & Oncology
- 陳彥豪 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Linkou Chang Gung Medical Foundation
Taiwan National PI
林永昌
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
CRO
Co-Principal Investigator
- CHUNG-HSIN CHEN Division of Urology
- YU-CHUAN LU Division of Urology
- Yu-Chieh Tsai Division of Hematology & Oncology
- - - Division of Urology
- Chia-Chi Lin Division of Hematology & Oncology
- Yeong-Shiau Pu Division of Urology
- JHE-CYUAN GUO Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Condition/Disease
Advanced or Metastatic Urothelial Carcinoma
Objectives
Primary Objective(s) & Hypothesis(es)
Objectives: To compare PFS using RECIST 1.1 as assessed by BICR and OS
in PD-L1 positive subjects and all subjects between the following treatment
comparisons:
(a) Pembrolizumab + chemotherapy versus chemotherapy
(b) Pembrolizumab versus chemotherapy
Test Drug
Pembrolizumab (MK-3475)/Keytruda
Active Ingredient
Humanized anti-PD-1 mAb
Dosage Form
Injection
Dosage
100 mg/ 4 mL
Endpoints
Primary
1. Progression-free Survival (PFS) per RECIST 1.1 as assessed by BICR for
PD-L1 positive and all subjects, respectively.
2. Overall survival (OS) for PD-L1 positive and all subjects, respectively.
Secondary
The secondary efficacy endpoints of this trial are to evaluate DOR, and ORR
per RECIST 1.1 assessed by BICR.
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and
tolerability of pembrolizumab in subjects with recurrent/progressive urothelial
cancer. The primary safety analysis will be based on subjects who experienced
toxicities as defined by CTCAE Version 4.0 criteria. Safety will be assessed by
quantifying the toxicities and grades experienced by subjects who have received
pembrolizumab, including SAEs and ECIs. The attribution to drug, time-of-onset,
duration of the event, its resolution, and any concomitant medications
administered will be recorded. Adverse events will be analyzed including but not
limited to all AEs, SAEs, fatal AEs, and laboratory changes. The mandatory
Safety Follow-up Visit will be conducted approximately 30 days after the last dose
of trial treatment or before the initiation of a new anti-neoplastic treatment,
whichever comes first. All AEs that occur prior to the Safety Follow-up Visit
should be recorded. Subjects with an AE of Grade >1 will be followed until the
resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic
therapy, whichever occurs first. Serious adverse events will be collected for 90
days after the trial treatment or 30 days after the end of treatment, if the subject
initiates new anti-cancer therapy, whichever is earlier.
1. Progression-free Survival (PFS) per RECIST 1.1 as assessed by BICR for
PD-L1 positive and all subjects, respectively.
2. Overall survival (OS) for PD-L1 positive and all subjects, respectively.
Secondary
The secondary efficacy endpoints of this trial are to evaluate DOR, and ORR
per RECIST 1.1 assessed by BICR.
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and
tolerability of pembrolizumab in subjects with recurrent/progressive urothelial
cancer. The primary safety analysis will be based on subjects who experienced
toxicities as defined by CTCAE Version 4.0 criteria. Safety will be assessed by
quantifying the toxicities and grades experienced by subjects who have received
pembrolizumab, including SAEs and ECIs. The attribution to drug, time-of-onset,
duration of the event, its resolution, and any concomitant medications
administered will be recorded. Adverse events will be analyzed including but not
limited to all AEs, SAEs, fatal AEs, and laboratory changes. The mandatory
Safety Follow-up Visit will be conducted approximately 30 days after the last dose
of trial treatment or before the initiation of a new anti-neoplastic treatment,
whichever comes first. All AEs that occur prior to the Safety Follow-up Visit
should be recorded. Subjects with an AE of Grade >1 will be followed until the
resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic
therapy, whichever occurs first. Serious adverse events will be collected for 90
days after the trial treatment or 30 days after the end of treatment, if the subject
initiates new anti-cancer therapy, whichever is earlier.
Inclution Criteria
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have a histologically or cytologically confirmed diagnosis of
advanced/unresectable (inoperable) or metastatic urothelial carcinoma of the
renal pelvis, ureter [upper urinary track], bladder, or urethra. Both transitional
cell and mixed transitional/nontransitional cell histologies are allowed, but
transitional cell carcinoma must be the predominant histology.
2. Have measurable disease based on RECIST 1.1 as determined by the local site
investigator/radiology assessment. Target lesions situated in a previously
irradiated area are considered measurable if progression has been
demonstrated in such lesions.
3. Voluntarily agree to participate by providing written informed consent/assent
for the trial. The subject may also provide consent for Future Biomedical
Research. However, the subject may participate in the main trial without
participating in Future Biomedical Research.
4. Be ≥18 years of age on the day of signing informed consent.
5. Have received no prior systemic chemotherapy for advanced or metastatic
urothelial carcinoma, with the following exceptions:
a. Neoadjuvant platinum-based chemotherapy with recurrence >12 months
from completion of therapy is permitted.
b. Adjuvant platinum-based chemotherapy following radical cystectomy with
recurrence >12 months from completion of therapy is permitted.
Note: Low-dose chemotherapy (e.g., low-dose cisplatin, cisplatin plus 5-FU,
mitomycin plus 5-FU, or cisplatin plus paclitaxel) given concurrently with
radiation to the primary tumor site is not considered systemic therapy. In the
clinical setting, chemotherapy is given with the sole purpose of sensitizing the
tumor to local radiation. It is not administered at doses with any systemic
efficacy. Surgery is not considered first-line therapy following diagnosis of
advanced/metastatic disease.
6. Have provided tissue for biomarker analysis from an archival tissue sample or
newly obtained core or excisional biopsy of a tumor lesion not previously
irradiated. A newly obtained biopsy is strongly preferred but not required if
archival tissue is adequate for analysis. Submit an evaluable sample for
analysis. If submitting unstained cut slides, freshly cut slides should be
submitted to the testing laboratory within 14 days from when the slides are cut.
Refer to Section 7.1.2.10 in protocol for an explanation. Adequacy of the
archived or freshly-obtained biopsy specimen must be confirmed by the
central laboratory during the screening period prior to enrollment.
7. Have an ECOG PS of 0, 1, or 2.
8. Demonstrate adequate organ function as defined in Table 3. (All screening
labs should be performed within 2 weeks prior to treatment initiation.)
9. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of trial
medication. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use an adequate
method of contraception as outlined in Protocol Section 5.7.2 –
Contraception, for the course of the trial through 120 days after the last dose of
pembrolizumab or 180 days after chemotherapy treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
11. Male subjects of childbearing potential must agree to use an adequate method
of contraception as outlined in Protocol Section 5.7.2 – Contraception,
starting with the first dose of trial therapy through 120 days after the last dose
of pembrolizumab or 180 days after chemotherapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
In order to be eligible for participation in this trial, the subject must:
1. Have a histologically or cytologically confirmed diagnosis of
advanced/unresectable (inoperable) or metastatic urothelial carcinoma of the
renal pelvis, ureter [upper urinary track], bladder, or urethra. Both transitional
cell and mixed transitional/nontransitional cell histologies are allowed, but
transitional cell carcinoma must be the predominant histology.
2. Have measurable disease based on RECIST 1.1 as determined by the local site
investigator/radiology assessment. Target lesions situated in a previously
irradiated area are considered measurable if progression has been
demonstrated in such lesions.
3. Voluntarily agree to participate by providing written informed consent/assent
for the trial. The subject may also provide consent for Future Biomedical
Research. However, the subject may participate in the main trial without
participating in Future Biomedical Research.
4. Be ≥18 years of age on the day of signing informed consent.
5. Have received no prior systemic chemotherapy for advanced or metastatic
urothelial carcinoma, with the following exceptions:
a. Neoadjuvant platinum-based chemotherapy with recurrence >12 months
from completion of therapy is permitted.
b. Adjuvant platinum-based chemotherapy following radical cystectomy with
recurrence >12 months from completion of therapy is permitted.
Note: Low-dose chemotherapy (e.g., low-dose cisplatin, cisplatin plus 5-FU,
mitomycin plus 5-FU, or cisplatin plus paclitaxel) given concurrently with
radiation to the primary tumor site is not considered systemic therapy. In the
clinical setting, chemotherapy is given with the sole purpose of sensitizing the
tumor to local radiation. It is not administered at doses with any systemic
efficacy. Surgery is not considered first-line therapy following diagnosis of
advanced/metastatic disease.
6. Have provided tissue for biomarker analysis from an archival tissue sample or
newly obtained core or excisional biopsy of a tumor lesion not previously
irradiated. A newly obtained biopsy is strongly preferred but not required if
archival tissue is adequate for analysis. Submit an evaluable sample for
analysis. If submitting unstained cut slides, freshly cut slides should be
submitted to the testing laboratory within 14 days from when the slides are cut.
Refer to Section 7.1.2.10 in protocol for an explanation. Adequacy of the
archived or freshly-obtained biopsy specimen must be confirmed by the
central laboratory during the screening period prior to enrollment.
7. Have an ECOG PS of 0, 1, or 2.
8. Demonstrate adequate organ function as defined in Table 3. (All screening
labs should be performed within 2 weeks prior to treatment initiation.)
9. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of trial
medication. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use an adequate
method of contraception as outlined in Protocol Section 5.7.2 –
Contraception, for the course of the trial through 120 days after the last dose of
pembrolizumab or 180 days after chemotherapy treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
11. Male subjects of childbearing potential must agree to use an adequate method
of contraception as outlined in Protocol Section 5.7.2 – Contraception,
starting with the first dose of trial therapy through 120 days after the last dose
of pembrolizumab or 180 days after chemotherapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
Exclusion Criteria
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has disease that is suitable for local therapy administered with curative intent.
An example of local therapy with curative intent is treatment with
chemotherapy and radiation for Stage 3 disease. A subject with non-urothelial
carcinoma of the urinary tract is also ineligible.
2. Is currently participating and receiving study therapy or has participated in a
study of an investigational agent and received study therapy or used an
investigation device within 4 weeks of the first dose of treatment
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to
randomization.
4. Has an active autoimmune disease that has required systemic treatment in the
past 2years (ie, with use of disease-modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insu
fficiency, etc.) is not considered a form of systemic treatment.
a. Brief (<7 days) use of systemic corticosteroids is allowed when use is
considered SOC.
b. Subjects with vitiligo, diabetes Type I, hypothyroidism, or resolved
childhood asthma/atopy would be an exception to this rule.
c. Subjects who require intermittent use of bronchodilators, inhaled steroids,
or local steroid injections would not be excluded from the trial.
d. Subjects with hypothyroidism stable on hormone replacement or Sjøgren’s
syndrome will not be excluded from the trial.
e. If a subject is on a stable dose of steroids for central nervous system (CNS)
metastases at screening, the subject will need to stop steroids 7 days prior
to first dose in order to qualify for the trial.
5. Has had a prior anti-cancer mAb for direct anti-neoplastic treatment within 4
weeks prior to the first dose of trial treatment (6 weeks for nitrosoureas or
mitomycin C) or who has not recovered (ie, ≤Grade 1 or at baseline) from AEs
due to mAbs administered more than 4 weeks earlier. Subjects previously
treated with a mAb will be eligible to participate after a 28-day washout
period.
6. Has not recovered (ie, AE ≤Grade 1 or at baseline) from AEs due to a
previously administered agent.
a. Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception
to this criterion and may qualify for the trial.
b. If subjects received major surgery they must have recovered adequately
from the toxicity and/or complications from the intervention prior to
starting trial therapy.
7. Has a known additional malignancy that is progressing or requires active
treatment.
a. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in
situ cervical cancer.
b. A history of prostate cancer that was identified incidentally following
cystoprostatectomy for bladder cancer is acceptable, provided that the
following criteria are met: Stage T2N0M0 or lower; Gleason score ≤6;
prostate-specific antigen (PSA) undetectable.
8. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
9. Has a known history of active tuberculosis (TB) (Bacillus tuberculosis).
10. Has an active infection requiring systemic therapy.
11. Has a history of severe hypersensitivity reaction (e.g., generalized
rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to
gemcitabine, carboplatin, or cisplatin or their analogs.
12. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject’s participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial. At the time of signing informed
consent is a known regular user (including "recreational use") of any illicit
drug(s) or had a recent history (within the last year) of drug or alcohol abuse.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within
the projected duration of the trial, starting with the screening visit through 120
days after the last dose of pembrolizumab or 180 days after the last dose of
chemotherapy treatment.
15. Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2
agent or with an agent directed to another co-inhibitory T-cell receptor (eg,
CTLA-4, OX-40, CD137).
16. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2
antibodies).
17. Has known active hepatitis B (eg, HBsAg reactive) or hepatitis C (eg, HCV
RNA [qualitative] is detected).
18. Has received a live virus vaccine within 30 days of planned start of trial
therapy.
19. Has known active CNS metastases and/or carcinomatous meningitis. Subjects
with previously treated brain metastases may participate provided they have
stable brain metastases (stability is normally defined as a period of 1 to 3
months in which there is no evidence of new or enlarging CNS metastases).
20. Has symptomatic ascites or pleural effusion; a subject who is clinically stable
following treatment for these conditions is eligible.
21. Has had a prior allogeneic stem cell or bone marrow transplant.
The subject must be excluded from participating in the trial if the subject:
1. Has disease that is suitable for local therapy administered with curative intent.
An example of local therapy with curative intent is treatment with
chemotherapy and radiation for Stage 3 disease. A subject with non-urothelial
carcinoma of the urinary tract is also ineligible.
2. Is currently participating and receiving study therapy or has participated in a
study of an investigational agent and received study therapy or used an
investigation device within 4 weeks of the first dose of treatment
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to
randomization.
4. Has an active autoimmune disease that has required systemic treatment in the
past 2years (ie, with use of disease-modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insu
fficiency, etc.) is not considered a form of systemic treatment.
a. Brief (<7 days) use of systemic corticosteroids is allowed when use is
considered SOC.
b. Subjects with vitiligo, diabetes Type I, hypothyroidism, or resolved
childhood asthma/atopy would be an exception to this rule.
c. Subjects who require intermittent use of bronchodilators, inhaled steroids,
or local steroid injections would not be excluded from the trial.
d. Subjects with hypothyroidism stable on hormone replacement or Sjøgren’s
syndrome will not be excluded from the trial.
e. If a subject is on a stable dose of steroids for central nervous system (CNS)
metastases at screening, the subject will need to stop steroids 7 days prior
to first dose in order to qualify for the trial.
5. Has had a prior anti-cancer mAb for direct anti-neoplastic treatment within 4
weeks prior to the first dose of trial treatment (6 weeks for nitrosoureas or
mitomycin C) or who has not recovered (ie, ≤Grade 1 or at baseline) from AEs
due to mAbs administered more than 4 weeks earlier. Subjects previously
treated with a mAb will be eligible to participate after a 28-day washout
period.
6. Has not recovered (ie, AE ≤Grade 1 or at baseline) from AEs due to a
previously administered agent.
a. Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception
to this criterion and may qualify for the trial.
b. If subjects received major surgery they must have recovered adequately
from the toxicity and/or complications from the intervention prior to
starting trial therapy.
7. Has a known additional malignancy that is progressing or requires active
treatment.
a. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in
situ cervical cancer.
b. A history of prostate cancer that was identified incidentally following
cystoprostatectomy for bladder cancer is acceptable, provided that the
following criteria are met: Stage T2N0M0 or lower; Gleason score ≤6;
prostate-specific antigen (PSA) undetectable.
8. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
9. Has a known history of active tuberculosis (TB) (Bacillus tuberculosis).
10. Has an active infection requiring systemic therapy.
11. Has a history of severe hypersensitivity reaction (e.g., generalized
rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to
gemcitabine, carboplatin, or cisplatin or their analogs.
12. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject’s participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial. At the time of signing informed
consent is a known regular user (including "recreational use") of any illicit
drug(s) or had a recent history (within the last year) of drug or alcohol abuse.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within
the projected duration of the trial, starting with the screening visit through 120
days after the last dose of pembrolizumab or 180 days after the last dose of
chemotherapy treatment.
15. Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2
agent or with an agent directed to another co-inhibitory T-cell receptor (eg,
CTLA-4, OX-40, CD137).
16. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2
antibodies).
17. Has known active hepatitis B (eg, HBsAg reactive) or hepatitis C (eg, HCV
RNA [qualitative] is detected).
18. Has received a live virus vaccine within 30 days of planned start of trial
therapy.
19. Has known active CNS metastases and/or carcinomatous meningitis. Subjects
with previously treated brain metastases may participate provided they have
stable brain metastases (stability is normally defined as a period of 1 to 3
months in which there is no evidence of new or enlarging CNS metastases).
20. Has symptomatic ascites or pleural effusion; a subject who is clinically stable
following treatment for these conditions is eligible.
21. Has had a prior allogeneic stem cell or bone marrow transplant.
The Estimated Number of Participants
-
Taiwan
40 participants
-
Global
990 participants
