Clinical trial NCT02335424: Study of Pembrolizumab (MK-3475) in Participants With Advanced Urothelial Cancer (MK-3475-052/KEYNOTE-052)
Official title: A Phase II Clinical Trial of Pembrolizumab (MK-3475) in Subjects With Advanced/Unresectable or Metastatic Urothelial Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Urothelial Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1)
Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
bladder cancer
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-01-09
Enrollment: 374
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a study using pembrolizumab (MK-3475, KEYTRUDA®) for first-line treatment of participants with advanced/unresectable (inoperable) or metastatic urothelial cancer who are ineligible for cisplatin-based therapy. The primary study objective is to determine the objective response rate (ORR) in all participants and by programmed cell death ligand 1 (PD-L1) status.

With Amendment 4, once a participant has achieved the study objective or the study has ended, the participant will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment.

Detailed description: Participants receiving pembrolizumab who attain a complete response (CR) may consider stopping trial treatment if they meet criteria for holding therapy. Participants who stop trial treatment after receiving 24 months of trial treatment for reasons other than progressive disease (PD) or intolerability, or participants who attain a CR and stop trial treatment may be eligible for up to one year of retreatment upon experiencing PD.

Eligibility criteria: Inclusion Criteria:

* Histologically- or cytologically-confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell and mixed transitional/non-transitional cell histologies)
* Ineligible for cisplatin therapy
* No prior systemic chemotherapy for metastatic disease (adjuvant or neoadjuvant platinum-based chemotherapy with recurrence \>12 months since completion of therapy is allowed)
* Available tissue from a newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
* Measurable 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; 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 study treatment
* 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 study treatment

Exclusion Criteria:

* Disease that is suitable for local therapy administered with curative intent
* Currently participating or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study treatment
* Prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to study Day 1 or who has 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 prior to study Day 1 or not recovered from AEs due to a previously administered agent
* Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cancer
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active autoimmune disease that has required systemic treatment in past 2 years
* Evidence of interstitial lung disease or active non-infectious pneumonitis
* Active infection requiring systemic therapy
* 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 study treatment
* Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor
* Known human immunodeficiency virus (HIV)
* Known active Hepatitis B or C
* Received a live virus vaccine within 30 days of planned start of study treatment

Primary outcomes:
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
timeFrame: Up to approximately 80.5 months
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Up to approximately 80.5 months
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Up to approximately 80.5 months
Secondary outcomes:
measure: Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
timeFrame: Up to approximately 80.5 months
measure: Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Up to approximately 80.5 months
measure: Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Up to approximately 80.5 months
measure: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in All Participants
timeFrame: Up to approximately 80.5 months
measure: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Up to approximately 80.5 months
measure: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Up to approximately 80.5 months
measure: Overall Survival (OS) in All Participants
timeFrame: Up to approximately 80.5 months
measure: Overall Survival (OS) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Up to approximately 80.5 months
measure: Overall Survival (OS) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Up to approximately 80.5 months
measure: Progression Free Survival Rate (PFS Rate) at Month 6 in All Participants
timeFrame: Month 6
measure: Progression Free Survival Rate (PFS Rate) at Month 6 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Month 6
measure: Progression Free Survival Rate (PFS Rate) at Month 6 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Month 6
measure: Progression Free Survival Rate (PFS Rate) at Month 12 in All Participants
timeFrame: Month 12
measure: Progression Free Survival Rate (PFS Rate) at Month 12 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Month 12
measure: Progression Free Survival Rate (PFS Rate) at Month 12 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Month 12
measure: Overall Survival Rate (OS Rate) at Month 6 in All Participants
timeFrame: Month 6
measure: Overall Survival Rate (OS Rate) at Month 6 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Month 6
measure: Overall Survival Rate (OS Rate) at Month 6 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Month 6
measure: Overall Survival Rate (OS Rate) at Month 12 in All Participants
timeFrame: Month 12
measure: Overall Survival Rate (OS Rate) at Month 12 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Month 12
measure: Overall Survival Rate (OS Rate) at Month 12 in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Month 12
measure: Programmed Cell Death Ligand 1 (PD-L1) Expression Status
timeFrame: Day 1
measure: Number of Participants Who Experienced At Least One Adverse Event (AE)
timeFrame: Up to approximately 80.5 months
measure: Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 26 months
Other outcomes:
measure: Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (Modified RECIST) in All Participants
timeFrame: Up to approximately 80.5 months
measure: Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (Modified RECIST) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1%
timeFrame: Up to approximately 80.5 months
measure: Objective Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors (Modified RECIST) in Participants With a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥10%
timeFrame: Up to approximately 80.5 months
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. doi: 10.1016/S1470-2045(17)30616-2. Epub 2017 Sep 26.
citation: Vuky J, Balar AV, Castellano D, O'Donnell PH, Grivas P, Bellmunt J, Powles T, Bajorin D, Hahn NM, Savage MJ, Fang X, Godwin JL, Frenkl TL, Homet Moreno B, de Wit R, Plimack ER. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2020 Aug 10;38(23):2658-2666. doi: 10.1200/JCO.19.01213. Epub 2020 Jun 17.
citation: Bellmunt J, de Wit R, Fradet Y, Climent MA, Petrylak DP, Lee JL, Fong L, Necchi A, Sternberg CN, O'Donnell PH, Powles T, Plimack ER, Bajorin DF, Balar AV, Castellano D, Choueiri TK, Culine S, Gerritsen W, Gurney H, Quinn DI, Vuky J, Vogelzang NJ, Cristescu R, Lunceford J, Saadatpour A, Loboda A, Ma J, Rajasagi M, Godwin JL, Homet Moreno B, Grivas P. Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials. Clin Cancer Res. 2022 May 13;28(10):2050-2060. doi: 10.1158/1078-0432.CCR-21-3089.
citation: van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.