We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02256436
First Posted: October 3, 2014
Last Update Posted: October 9, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
  Purpose

Participants with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy will be randomly assigned to receive pembrolizumab or Investigator's choice of paclitaxel, docetaxel, or vinflunine. The primary study hypotheses are that pembrolizumab will prolong Overall Survival (OS) and Progression-free Survival (PFS) compared to paclitaxel, docetaxel, or vinflunine.

Effective with Amendment 15, eligible participants who were allocated to the Active Comparator arm and experienced disease progression will be provided with the opportunity to crossover to receive pembrolizumab 200 mg one time every three weeks (Q3W) for up to two years of treatment in the Crossover Phase of the study.


Condition Intervention Phase
Urothelial Cancer Biological: pembrolizumab Drug: paclitaxel Drug: vinflunine Drug: docetaxel Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel or Vinflunine in Subjects With Recurrent or Progressive Metastatic Urothelial Cancer

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Overall Survival (OS) - All Participants [ Time Frame: Through database cutoff 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 database cutoff date of 07-Sep-2016.

  • Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - All Participants [ Time Frame: Through database cutoff 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 radiologist review in all participants up through the database cutoff date of 07-Sep-2016.

  • OS - Participants With Strongly PD-L1 Positive Tumors [ Time Frame: Through database cutoff 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 programmed cell death-ligand 1 (PD-L1) combined proportion score (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 database cutoff date of 07-Sep-2016.

  • PFS Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors [ Time Frame: Through database cutoff 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 blinded independent radiologist review in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the database cutoff date of 07-Sep-2016.

  • OS - Participants With PD-L1 Positive Tumors [ Time Frame: Through database cutoff 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 database cutoff date of 07-Sep-2016.

  • PFS Per RECIST 1.1 - Participants With PD-L1 Positive Tumors [ Time Frame: Through database cutoff 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 blinded independent radiologist review in all participants who had PD-L1 positive tumors (CPS ≥1%) up through the database cutoff date of 07-Sep-2016.


Secondary Outcome Measures:
  • Objective Response Rate (ORR) Per RECIST 1.1 - All Participants [ Time Frame: Through database cutoff date of 07-Sep-2016 (Up to approximately 20 months) ]
    ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by blinded independent radiologist review in all participants up through the database cutoff date of 07-Sep-2016.

  • ORR Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors [ Time Frame: Through database cutoff date of 07-Sep-2016 (Up to approximately 20 months) ]
    ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by blinded independent radiologist review in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the database cutoff date of 07-Sep-2016.

  • ORR Per RECIST 1.1 - Participants With PD-L1 Positive Tumors [ Time Frame: Through database cutoff date of 07-Sep-2016 (Up to approximately 20 months) ]
    ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by blinded independent radiologist review in participants with PD-L1 positive tumors (CPS ≥1%) up through the database cutoff date of 07-Sep-2016.

  • PFS Per Modified RECIST - All Participants [ Time Frame: Through database cutoff 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 modified (immune-related [ir]) RECIST, progressive disease (irPD) was defined as: increase in tumor burden ≥25% relative to minimum recorded tumor burden confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented. PFS per modified RECIST was assessed by blinded independent radiologist review in all randomized participants up through the database cutoff date of 07-Sep-2016.

  • ORR Per Modified RECIST - All Participants [ Time Frame: Through database cutoff date of 07-Sep-2016 (Up to approximately 20 months) ]
    ORR per modified RECIST was defined as the percentage of participants in the analysis population who had a Complete Response (irCR: complete disappearance of all lesions [and no new lesions] confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a Partial Response (irPR: decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per modified RECIST was assessed by blinded independent radiologist review in all participants up through the database cutoff date of 07-Sep-2016.

  • Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 23 months ]
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Participants were monitored for the occurrence nonserious AEs for up to 30 days after last dose of study treatment and for serious AEs for up to 90 days after last dose of study treatment. The number of participants who experienced an AE was assessed.

  • Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 20 months ]
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who discontinued study treatment due to an AE was assessed.

  • Response Duration Per RECIST 1.1 - All Participants [ Time Frame: Through database cutoff date of 07-Sep-2016 (Up to approximately 20 months) ]
    For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, response duration was defined as the time from first documented evidence of CR or PR until disease progression or death. Response duration for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Response duration was assessed in all participants based on independent radiologist review and was analyzed using the Kaplan-Meier method.

  • Response Duration Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors [ Time Frame: Through database cutoff date of 07-Sep-2016 (Up to approximately 20 months) ]
    For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, response duration was defined as the time from first documented evidence of CR or PR until disease progression or death. Response duration for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Response duration was assessed in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) based on independent radiologist review and was analyzed using the Kaplan-Meier method.

  • Response Duration Per RECIST 1.1 - Participants With PD-L1 Positive Tumors [ Time Frame: Through database cutoff date of 07-Sep-2016 (Up to approximately 20 months) ]
    For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, response duration was defined as the time from first documented evidence of CR or PR until disease progression or death. Response duration for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Response duration was assessed in all participants who had PD-L1 positive tumors (CPS ≥1%) based on independent radiologist review and was analyzed using the Kaplan-Meier method.


Enrollment: 542
Actual Study Start Date: October 22, 2014
Estimated Study Completion Date: March 15, 2019
Primary Completion Date: September 7, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pembrolizumab
Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W)
Biological: pembrolizumab
IV infusion
Other Names:
  • MK-3475
  • KEYTRUDA®
Active Comparator: Active Comparator
Participants receive paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 Q3W
Drug: paclitaxel
IV infusion
Drug: vinflunine
IV infusion
Drug: docetaxel
IV infusion

Detailed Description:
For the purposes of this study, participants with a programmed cell death-ligand 1 (PD-L1) combined proportion score (CPS) ≥10% were considered to have a strongly PD-L1 positive tumor status and participants with PD-L1 CPS ≥1% were considered to have a PD-L1 positive tumor status.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02256436


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharpe & Dohme Corp.
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT02256436     History of Changes
Other Study ID Numbers: 3475-045
2014-002009-40 ( EudraCT Number )
152903 ( Registry Identifier: JAPIC-CTI )
First Submitted: September 29, 2014
First Posted: October 3, 2014
Results First Submitted: June 12, 2017
Results First Posted: August 31, 2017
Last Update Posted: October 9, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Merck Sharp & Dohme Corp.:
P-D1
PD-1
PD1
P-DL1
PD-L1
PDL-1
PDL1
Bladder cancer

Additional relevant MeSH terms:
Paclitaxel
Vinblastine
Docetaxel
Pembrolizumab
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action