A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045)
- Conditions
- Urothelial Cancer
- Interventions
- Registration Number
- NCT02256436
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
Participants with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy will be randomly assigned to receive Investigator's choice of paclitaxel, docetaxel, or vinflunine (Control), or pembrolizumab. The primary study hypotheses are that pembrolizumab will prolong Overall Survival (OS) and Progression-free Survival (PFS) compared to paclitaxel, docetaxel, or vinflunine.
- Detailed Description
For the purposes of this study, participants with a programmed cell death-ligand 1 (PD-L1) combined positive 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.
Effective with Amendment 15, eligible participants who are allocated to the Control arm (Investigator's Choice) and experience disease progression will be provided with the opportunity to switch over to receive pembrolizumab 200 mg one time every three weeks (Q3W) for up to two years of treatment.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 542
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control paclitaxel Participants receive paclitaxel 175 mg/m\^2 intravenously (IV) or docetaxel 75 mg/m\^2 IV or vinflunine 320 mg/m\^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experience disease progression may be able to switch over to receive pembrolizumab 200 mg Q3W for up to 35 treatment administrations (up to approximately 2 years). Control vinflunine Participants receive paclitaxel 175 mg/m\^2 intravenously (IV) or docetaxel 75 mg/m\^2 IV or vinflunine 320 mg/m\^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experience disease progression may be able to switch over to receive pembrolizumab 200 mg Q3W for up to 35 treatment administrations (up to approximately 2 years). Control docetaxel Participants receive paclitaxel 175 mg/m\^2 intravenously (IV) or docetaxel 75 mg/m\^2 IV or vinflunine 320 mg/m\^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experience disease progression may be able to switch over to receive pembrolizumab 200 mg Q3W for up to 35 treatment administrations (up to approximately 2 years). Pembrolizumab pembrolizumab Participants receive pembrolizumab 200 mg IV on Day 1 Q3W. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab 200 mg for up to 17 cycles (up to approximately 1 additional year).
- Primary Outcome Measures
Name Time Method OS - Participants With PD-L1 Positive Tumors 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.
PFS Per RECIST 1.1 - Participants With Programmed Cell Death-Ligand (PD-L1) Positive Tumors 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.
PFS Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors 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.
OS - Participants With Strongly PD-L1 Positive Tumors 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.
Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - All Participants 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.
Overall Survival (OS) - All Participants 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.
- Secondary Outcome Measures
Name Time Method Number of Participants Who Discontinued Study Treatment Due to an AE Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this 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 discontinued study treatment due to an AE was reported for each arm.
Number of Participants Who Experienced an Adverse Event (AE) Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this 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 reported for each arm.
ORR Per RECIST 1.1 - All Participants Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by BICR in all participants up through the final analysis database cut-off date of 26-Oct-2017.
PFS Per mRECIST - All Participants Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 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 mRECIST, PD was defined as at least 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. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in all randomized participants up through the final analysis database cut-off date of 26-Oct-2017.
ORR Per mRECIST - Participants With Strongly PD-L1 Positive Tumors Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017.
Objective Response Rate (ORR) Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 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 BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017.
ORR Per RECIST 1.1 - Participants With PD-L1 Positive Tumors Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017.
PFS Per Modified RECIST (mRECIST) - Participants With Strongly PD-L1 Positive Tumors Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 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 mRECIST, PD was defined was defined as at least 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. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017.
PFS Per mRECIST - Participants With PD-L1 Positive Tumors Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 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 mRECIST, PD was defined was defined as at least 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. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017.
ORR Per mRECIST - Participants With PD-L1 Positive Tumors Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017.
ORR Per mRECIST - All Participants Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in all participants up through the final analysis database cut-off date of 26-Oct-2017.
Duration of Response (DOR) Per RECIST 1.1 - Participants With Strongly PD-L1 Positive Tumors Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR was to be censored at the date of the last tumor assessment for participants who had progressed or died after 2 or more missed visits, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response. DOR was assessed in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) based on BICR and was analyzed using the Kaplan-Meier method.
DOR Per RECIST 1.1 - Participants With PD-L1 Positive Tumors Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR was to be censored at the date of the last tumor assessment for participants who had progressed or died after 2 or more missed visits, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response. DOR was assessed in all participants who had PD-L1 positive tumors (CPS ≥1%) based on BICR and was analyzed using the Kaplan-Meier method.
DOR Per RECIST 1.1 - All Participants Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months) For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR was to be censored at the date of the last tumor assessment for participants who had progressed or died after 2 or more missed visits, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response. DOR was assessed in all participants based on BICR and was analyzed using the Kaplan-Meier method.