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

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ClinicalTrials.gov Identifier: NCT02256436
Recruitment Status : Active, not recruiting
First Posted : October 3, 2014
Results First Posted : August 31, 2017
Last Update Posted : December 20, 2017
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

September 29, 2014
October 3, 2014
June 12, 2017
August 31, 2017
December 20, 2017
October 22, 2014
September 7, 2016   (Final data collection date for primary outcome measure)
  • 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.
  • Overall survival (OS) [ Time Frame: Up to 27 months ]
  • Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) [ Time Frame: Up to 27 months ]
Complete list of historical versions of study NCT02256436 on ClinicalTrials.gov Archive Site
  • 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.
  • Objective response rate (ORR) per RECIST 1.1 [ Time Frame: Up to 27 months ]
  • PFS per modified RECIST 1.1 [ Time Frame: Up to 27 months ]
  • ORR per modified RECIST 1.1 [ Time Frame: Up to 27 months ]
Not Provided
Not Provided
 
A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045)
A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel or Vinflunine in Subjects With Recurrent or Progressive Metastatic Urothelial Cancer

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.

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.
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Urothelial Cancer
  • Biological: pembrolizumab
    IV infusion
    Other Names:
    • MK-3475
    • KEYTRUDA®
  • Drug: paclitaxel
    IV infusion
  • Drug: vinflunine
    IV infusion
  • Drug: docetaxel
    IV infusion
  • Experimental: Pembrolizumab
    Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W)
    Intervention: Biological: pembrolizumab
  • 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
    Interventions:
    • Drug: paclitaxel
    • Drug: vinflunine
    • Drug: docetaxel

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
542
470
March 15, 2019
September 7, 2016   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
Australia,   Austria,   Belgium,   Canada,   Chile,   Denmark,   France,   Germany,   Hungary,   Ireland,   Israel,   Italy,   Japan,   Korea, Republic of,   Netherlands,   New Zealand,   Norway,   Peru,   Poland,   Portugal,   Puerto Rico,   Romania,   Singapore,   Spain,   Sweden,   Taiwan,   Turkey,   United Kingdom,   United States
 
NCT02256436
3475-045
2014-002009-40 ( EudraCT Number )
152903 ( Registry Identifier: JAPIC-CTI )
MK-3475-045 ( Other Identifier: Merck Protocol Number )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Merck Sharp & Dohme Corp.
Merck Sharp & Dohme Corp.
Not Provided
Study Director: Medical Director Merck Sharpe & Dohme Corp.
Merck Sharp & Dohme Corp.
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP