Study of Pembrolizumab With or Without Platinum-based Combination Chemotherapy Versus Chemotherapy Alone in Urothelial Carcinoma (MK-3475-361/KEYNOTE-361)

• ClinicalTrials.gov Identifier: NCT02853305
• Recruitment Status: Active, not recruiting
• First Posted: August 2, 2016
• Last Update Posted: January 22, 2021
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

The purpose of this study is to determine the efficacy and safety of pembrolizumab (MK-3475) with or without chemotherapy versus chemotherapy alone in participants with advanced or metastatic urothelial carcinoma (bladder cancer).

The primary hypotheses are that pembrolizumab plus chemotherapy is superior to chemotherapy alone with respect to Progression-free Survival (PFS) and Overall Survival (OS) in participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score [CPS] ≥10%) and in all participants (includes those participants with PD-L1 positive tumors and those with PD-L1 negative tumors [CPS <10%]).

Condition or disease	Intervention/treatment	Phase
Urothelial Carcinoma Associated 1 RNA, Human	Biological: Pembrolizumab; Drug: Cisplatin; Drug: Carboplatin; Drug: Gemcitabine	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1010 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab With or Without Platinum-Based Combination Chemotherapy Versus Chemotherapy in Subjects With Advanced or Metastatic Urothelial Carcinoma
• Actual Study Start Date: September 15, 2016
• Actual Primary Completion Date: April 29, 2020
• Estimated Study Completion Date: May 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab; Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for a maximum of 35 doses.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®
Experimental: Pembrolizumab+Chemotherapy; Participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for a maximum of 35 doses PLUS EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle, OR carboplatin area under the curve 5 (AUC 5) (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Cisplatin; IV infusion; Drug: Carboplatin; IV infusion; Drug: Gemcitabine; IV infusion
Active Comparator: Chemotherapy; Participants receive EITHER cisplatin 70 mg/m^2 IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine IV infusion 1,000 mg/m^2 on Day 1 and Day 8 of each 3-week cycle OR carboplatin AUC 5 (or AUC 4.5 if required per local guidelines) IV on Day 1 (or Day 2 if required per local guidelines) of each 3-week cycle + gemcitabine 1,000 mg/m^2 IV on Day 1 and Day 8 of each 3-week cycle.	Drug: Cisplatin; IV infusion; Drug: Carboplatin; IV infusion; Drug: Gemcitabine; IV infusion

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 24 months ]
2. Overall Survival (OS) [ Time Frame: Up to approximately 24 months ]

Secondary Outcome Measures :

1. Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 27 months ]
2. Number of Participants Who Discontinue Study Drug Due to an AE [ Time Frame: Up to approximately 24 months ]
3. Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 24 months ]
4. Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 24 months ]
5. PFS Using RECIST 1.1 as Assessed by BICR at Milestone Timepoints [ Time Frame: At 6, 12, 18 and 24 months ]
6. Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 24 months ]
7. Change from Baseline in Health-related Quality of Life Score on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: Baseline and 24 months ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of advanced/unresectable (inoperable) or metastatic urothelial carcinoma of the renal pelvis, ureter [upper urinary tract], bladder, or urethra. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.
• Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment.

• Has received no prior systemic chemotherapy for advanced or metastatic urothelial carcinoma, with the following exceptions:

  • Neoadjuvant platinum-based chemotherapy with recurrence >12 months from completion of therapy is permitted.
  • Adjuvant platinum-based chemotherapy following radical cystectomy with recurrence >12 months from completion of therapy is permitted.
• Has provided tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated from a muscle invasive urothelial carcinoma or a metastatic biopsy, originally from the original tumor.
• Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
• Demonstrates adequate organ function.
• Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment.
• Male participants of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of pembrolizumab or 180 days after chemotherapy treatment.

Exclusion Criteria:

• Has disease that is suitable for local therapy administered with curative intent.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years.
• Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic treatment within 4 weeks prior to the first dose of study drug (6 weeks for nitrosoureas or mitomycin C) or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from adverse events (AEs) due to mAbs administered more than 4 weeks earlier.
• Has not recovered (i.e., AE ≤ Grade 1 or at Baseline) from AEs due to a previously administered agent.

• Has a known additional malignancy that is progressing or requires active treatment within the past 5 years.

  • Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  • A history of prostate cancer that was identified incidentally following cystoprostatectomy for bladder cancer is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤6; Prostate-specific Antigen (PSA) level undetectable.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Has a known history of active tuberculosis (TB).
• Has an active infection requiring systemic therapy.
• Has a history of severe hypersensitivity reaction (e.g. generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to pembrolizumab, gemcitabine, carboplatin, or cisplatin or their analogs and/or to any of their excipients.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is a known regular user (including "recreational use") of any illicit drug(s) or had a recent history (within the last year) of drug or alcohol abuse.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapy treatment.
• Has received prior therapy with an anti-PD-1, or anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137).
• Has a known history of human immunodeficiency virus (HIV).
• Has known active hepatitis B or hepatitis C.

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

Additional Information:

Merck Oncology Clinical Trials Information 

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT02853305
• Other Study ID Numbers: 3475-361; 2015-005731-41 ( EudraCT Number ); 163458 ( Registry Identifier: JAPIC-CTI ); MK-3475-361 ( Other Identifier: Merck Protocol Number )
• First Posted: August 2, 2016
• Last Update Posted: January 22, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:

PD1; PD-1; PDL1; PD-L1

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Transitional Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Gemcitabine; Cisplatin; Carboplatin; Pembrolizumab; Antineoplastic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents, Immunological