Clinical Trials List
Protocol NumberMK3475-045
NCT Number(ClinicalTrials.gov Identfier)NCT02256436
2014-10-01 - 2020-12-01
Phase III
Terminated5
ICD-10C67.9
Malignant neoplasm of bladder, unspecified
A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) versus Paclitaxel, Docetaxel or Vinflunine in Subjects with Recurrent or Progressive Metastatic Urothelial Cancer
-
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
- Wen-Chi Chen Division of Urology
- 何子龍 Division of Radiology
- Chao-Hsiang Chang Division of Urology
- Su-Peng Yeh Division of Hematology & Oncology
- Chi-Ping Huang Division of Urology
- Chi-Rei Yang Division of Urology
- Chin-Chung Yeh Division of Urology
- Ching-Chan Lin Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Wen-Pin Su Division of Hematology & Oncology
- Wei-Pang Chung Division of Hematology & Oncology
- Shang-Yin Wu Division of Hematology & Oncology
- Yu-Min Yeh Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Yen-Hwa Chang Division of Urology
- 沈書慧 Division of Radiology
- Jin-Hwang Liu Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 羅浩倫 Division of Urology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Yeong-Shiau Pu Division of Urology
- Yu-Chieh Tsai Division of Hematology & Oncology
- - - Division of Urology
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Recurrent or Progressive Metastatic Urothelial Cancer
Objectives
Primary Objective(s) & Hypothesis(es)
(1) Objective: To evaluate the overall survival (OS) of subjects with
metastatic or locally advanced/unresectable urothelial cancer that has
recurred or progressed following platinum-based chemotherapy
(recurrent/progressive metastatic urothelial cancer), when treated with
pembrolizumab (MK-3475) compared to paclitaxel, docetaxel or
vinflunine.
Hypothesis: Pembrolizumab (MK-3475) prolongs OS in subjects with
recurrent/progressive metastatic urothelial cancer compared to paclitaxel,
docetaxel or vinflunine.
(2) Objective: To evaluate progression-free survival (PFS) per RECIST
1.1 by independent radiologists’ review of subjects with
recurrent/progressive metastatic urothelial cancer treated with
pembrolizumab (MK-3475)compared to paclitaxel, docetaxel or
vinflunine.
Hypotheses: Pembrolizumab (MK-3475) prolongs PFS by RECIST 1.1
(as assessed by blinded central radiology review) in subjects with
recurrent/progressive metastatic urothelial cancer compared to paclitaxel,
docetaxel or vinflunine.
Test Drug
Pembrolizumab (MK-3475)
Active Ingredient
Humanized anti-PD-1 mAb
Dosage Form
Injection
Dosage
100 mg/ 4 mL/ vial
Endpoints
Primary Outcome Measures :
1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - All Participants [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was assessed by blinded independent central review (BICR) in all participants up through the primary analysis database cut-off date of 07-Sep-2016.
2. Overall Survival (OS) - All Participants [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
OS was defined as the time from randomization to death due to any cause. The OS was assessed in all participants up through the primary analysis database cut-off date of 07-Sep-2016.
3. PFS Per RECIST 1.1 - Participants With Programmed Cell Death-Ligand (PD-L1) Positive Tumors [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 was assessed by BICR in all participants who had PD-L1 positive tumors (combined positive score [CPS] ≥1%) up through the primary analysis database cut-off date of 07-Sep-2016.
4. OS - Participants With PD-L1 Positive Tumors [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
OS was defined as the time from randomization to death due to any cause. For the purposes of this study, participants with PD-L1 CPS ≥1% were considered to have a PD-L1 positive tumor status. OS was assessed in all participants who had PD-L1 positive tumors (CPS ≥1%) up through the primary analysis database cut-off date of 07-Sep-2016.
5. PFS Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 was assessed by BICR in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the primary analysis database cut-off date of 07-Sep-2016.
6. OS - Participants With Strongly PD-L1 Positive Tumors [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
OS was defined as the time from randomization to death due to any cause. For the purposes of this study, participants with a PD-L1 CPS ≥10% were considered to have a strongly PD-L1 positive tumor status. The OS was assessed in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the primary analysis database cut-off date of 07-Sep-2016.
1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - All Participants [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was assessed by blinded independent central review (BICR) in all participants up through the primary analysis database cut-off date of 07-Sep-2016.
2. Overall Survival (OS) - All Participants [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
OS was defined as the time from randomization to death due to any cause. The OS was assessed in all participants up through the primary analysis database cut-off date of 07-Sep-2016.
3. PFS Per RECIST 1.1 - Participants With Programmed Cell Death-Ligand (PD-L1) Positive Tumors [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 was assessed by BICR in all participants who had PD-L1 positive tumors (combined positive score [CPS] ≥1%) up through the primary analysis database cut-off date of 07-Sep-2016.
4. OS - Participants With PD-L1 Positive Tumors [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
OS was defined as the time from randomization to death due to any cause. For the purposes of this study, participants with PD-L1 CPS ≥1% were considered to have a PD-L1 positive tumor status. OS was assessed in all participants who had PD-L1 positive tumors (CPS ≥1%) up through the primary analysis database cut-off date of 07-Sep-2016.
5. PFS Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 was assessed by BICR in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the primary analysis database cut-off date of 07-Sep-2016.
6. OS - Participants With Strongly PD-L1 Positive Tumors [ Time Frame: Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months) ]
OS was defined as the time from randomization to death due to any cause. For the purposes of this study, participants with a PD-L1 CPS ≥10% were considered to have a strongly PD-L1 positive tumor status. The OS was assessed in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the primary analysis database cut-off date of 07-Sep-2016.
Inclution Criteria
Inclusion criteria:
• Histologically- or cytologically-confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra, that is transitional cell or mixed transitional/non-transitional (predominantly transitional) cell type
• Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen (e.g cisplatin, carboplatin) for metastatic or inoperable locally advanced disease; or adjuvant platinum-based therapy following cystectomy for localized muscle-invasive urothelial cancer with recurrence/progression <=12 months following completion of therapy; or neoadjuvant platinum-containing therapy prior to cystectomy for localized muscle-invasive urothelial cancer with recurrence <=12 months following completion of therapy
• No more than 2 prior lines of systemic chemotherapy for metastatic urothelial cancer
• Able to provide tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Measureable disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Adequate organ function
• Female participants of childbearing potential have a negative urine or serum pregnancy test; or are surgically sterile, or willing to use 2 acceptable methods of birth control, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine
• Male participants must be willing to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine
• Histologically- or cytologically-confirmed diagnosis of urothelial cancer of the renal pelvis, ureter, bladder, or urethra, that is transitional cell or mixed transitional/non-transitional (predominantly transitional) cell type
• Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen (e.g cisplatin, carboplatin) for metastatic or inoperable locally advanced disease; or adjuvant platinum-based therapy following cystectomy for localized muscle-invasive urothelial cancer with recurrence/progression <=12 months following completion of therapy; or neoadjuvant platinum-containing therapy prior to cystectomy for localized muscle-invasive urothelial cancer with recurrence <=12 months following completion of therapy
• No more than 2 prior lines of systemic chemotherapy for metastatic urothelial cancer
• Able to provide tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Measureable disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Adequate organ function
• Female participants of childbearing potential have a negative urine or serum pregnancy test; or are surgically sterile, or willing to use 2 acceptable methods of birth control, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine
• Male participants must be willing to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of pembrolizumab or 180 days after the last dose of paclitaxel, docetaxel, or vinflunine
Exclusion Criteria
Exclusion criteria:
• Urothelial cancer that is suitable for local therapy administered with curative intent
• Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of trial medication
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
• Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from adverse events due to agents administered more than 4 weeks earlier
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of study Day 1 or not recovered from adverse events due to a previously administered agent
• Prior therapy with all choices of active comparator
• Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cancer; or prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer that is Stage T2N0M0 or lower, Gleason score<= 6, or prostatic-specific antigen (PSA) undetectable
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents
• Active cardiac disease
• Evidence of interstitial lung disease or active non-infectious pneumonitis
• Active infection requiring systemic therapy
• History of severe hypersensitivity reaction to paclitaxel, docetaxel, or to other drugs formulated with polysorbate 80 or polyoxyethylated castor oil, or to vinflunine or other vinca alkaloids
• Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the cytochrome 3A4 (CYP3A4) enzymes
• Pregnant, 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 paclitaxel, docetaxel, or vinflunine
• Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 agent, or with an agent directed to another co-inhibitory T-cell receptor
• Human immunodeficiency virus (HIV)
• Active hepatitis B or hepatitis C
• Received a live virus vaccine within 30 days of planned start of trial treatment
• Urothelial cancer that is suitable for local therapy administered with curative intent
• Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of trial medication
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
• Anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from adverse events due to agents administered more than 4 weeks earlier
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of study Day 1 or not recovered from adverse events due to a previously administered agent
• Prior therapy with all choices of active comparator
• Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cancer; or prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer that is Stage T2N0M0 or lower, Gleason score<= 6, or prostatic-specific antigen (PSA) undetectable
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents
• Active cardiac disease
• Evidence of interstitial lung disease or active non-infectious pneumonitis
• Active infection requiring systemic therapy
• History of severe hypersensitivity reaction to paclitaxel, docetaxel, or to other drugs formulated with polysorbate 80 or polyoxyethylated castor oil, or to vinflunine or other vinca alkaloids
• Requires ongoing therapy with a medication that is a strong inhibitor or inducer of the cytochrome 3A4 (CYP3A4) enzymes
• Pregnant, 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 paclitaxel, docetaxel, or vinflunine
• Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PD-Ligand 1 agent, or with an agent directed to another co-inhibitory T-cell receptor
• Human immunodeficiency virus (HIV)
• Active hepatitis B or hepatitis C
• Received a live virus vaccine within 30 days of planned start of trial treatment
The Estimated Number of Participants
-
Taiwan
30 participants
-
Global
470 participants
