Clinical trial NCT02853305: Study of Pembrolizumab With or Without Platinum-based Combination Chemotherapy Versus Chemotherapy Alone in Urothelial Carcinoma (MK-3475-361/KEYNOTE-361)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Urothelial Carcinoma Associated 1 RNA, Human
Keywords: Programmed Cell Death-1 (PD1, PD-1)
Programmed Death-Ligand 1 (PDL1, PD-L1)
Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2016-08-02
Enrollment: 1010
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the efficacy and safety of pembrolizumab (pembro, 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 all participants, and that pembrolizumab alone is superior to chemotherapy alone with respect to OS in all participants and in participants with programmed cell death ligand 1 (PD-L1) positive tumors (Combined Positive Score \[CPS\] ≥10%).

Detailed description: As specified by the protocol, the study hypotheses will be evaluated by comparing the pembro combo arm or pembro arm separately to the chemo arm.

Eligibility 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.

Primary outcomes:
measure: Pembro Combo vs Chemo: Progression-free Survival (PFS) Using Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
timeFrame: Up to approximately 42 months
measure: Pembro Combo vs Chemo: Overall Survival (OS)
timeFrame: Up to approximately 42 months
measure: Pembro vs Chemo: OS in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10%
timeFrame: Up to approximately 42 months
measure: Pembro vs Chemo: OS
timeFrame: Up to approximately 42 months
Secondary outcomes:
measure: Pembro vs Chemo: PFS Using RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 42 months
measure: Number of Participants Who Experience an Adverse Event (AE)
timeFrame: Up to approximately 55 months
measure: Number of Participants Who Discontinue Study Drug Due to an AE
timeFrame: Up to approximately 52 months
measure: Pembro Combo vs Chemo: Objective Response Rate (ORR) Using RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 42 months
measure: Pembro Combo vs Chemo: Duration of Response (DOR) Using RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 42 months
measure: Pembro Combo vs Chemo: Disease Control Rate (DCR) Using RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 42 months
measure: Pembro vs Chemo: ORR Using RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 42 months
measure: Pembro vs Chemo: DOR Using RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 42 months
measure: Pembro vs Chemo: DCR Using RECIST 1.1 as Assessed by BICR
timeFrame: Up to approximately 42 months
measure: PFS Using RECIST 1.1 as Assessed by BICR at 6 Months
timeFrame: 6 months
measure: PFS Using RECIST 1.1 as Assessed by BICR at 12 Months
timeFrame: 12 months
measure: PFS Using RECIST 1.1 as Assessed by BICR at 18 Months
timeFrame: 18 months
measure: Pembro Combo vs Chemo: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
timeFrame: Baseline, Week 18
measure: Pembro Combo vs Chemo: Time to Deterioration (TTD) in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score
timeFrame: Baseline up to approximately 25 months
measure: Pembro vs Chemo: Change From Baseline To Week 18 in the EORTC QLQ-C30 GHS/QoL Combined Score
timeFrame: Baseline, Week 18
measure: Pembro vs Chemo: TTD in the EORTC-QLQ-C30 GHS/QoL (Items 29 and 30) Combined Score
timeFrame: Baseline up to approximately 25 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Powles T, Csoszi T, Ozguroglu M, Matsubara N, Geczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Flechon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. doi: 10.1016/S1470-2045(21)00152-2. Epub 2021 May 26.