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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03635567




Registration number
NCT03635567
Ethics application status
Date submitted
15/08/2018
Date registered
17/08/2018
Date last updated
14/01/2020

Titles & IDs
Public title
Efficacy and Safety Study of First-line Treatment With Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Women With Persistent, Recurrent, or Metastatic Cervical Cancer (MK-3475-826/KEYNOTE-826)
Scientific title
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Chemotherapy Plus Placebo for the First-Line Treatment of Persistent, Recurrent, or Metastatic Cervical Cancer (KEYNOTE-826)
Secondary ID [1] 0 0
2018-001440-53
Secondary ID [2] 0 0
3475-826
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cervical Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Womb (Uterine or endometrial cancer)
Cancer 0 0 0 0
Cervical (cervix)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Pembrolizumab
Treatment: Drugs - Paclitaxel
Treatment: Drugs - Cisplatin
Treatment: Drugs - Carboplatin
Other interventions - Bevacizumab
Treatment: Drugs - Placebo to pembrolizumab

Experimental: Pembrolizumab+Chemotherapy - On Day 1 of each 21-day cycle, participants receive an intravenous (IV) infusion of pembrolizumab 200 mg PLUS Investigator choice of chemotherapy (paclitaxel 175 mg/m^2 PLUS cisplatin 50 mg/m^2 WITH or WITHOUT bevacizumab 15 mg/kg OR paclitaxel 175 mg/m^2 PLUS carboplatin Area Under the Curve (AUC) 5, WITH or WITHOUT bevacizumab 15 mg/kg). All treatments are administered until disease progression or toxicity, for up to 35 cycles (up to approximately 2 years).

Placebo Comparator: Placebo+Chemotherapy - On Day 1 of each 21-day cycle, participants receive an IV infusion of placebo (Normal Saline or Dextrose solution) PLUS Investigator choice of chemotherapy (paclitaxel 175 mg/m^2 PLUS cisplatin 50 mg/m^2 WITH or WITHOUT bevacizumab 15 mg/kg OR paclitaxel 175 mg/m^2 PLUS carboplatin AUC 5, WITH or WITHOUT bevacizumab 15 mg/kg). All treatments are administered until disease progression or toxicity, for up to 35 cycles (up to approximately 2 years).


Other interventions: Pembrolizumab
IV infusion

Treatment: Drugs: Paclitaxel
IV infusion

Treatment: Drugs: Cisplatin
IV infusion

Treatment: Drugs: Carboplatin
IV infusion

Other interventions: Bevacizumab
IV infusion

Treatment: Drugs: Placebo to pembrolizumab
IV infusion

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) - PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as = 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of =5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 as assessed by BICR will be presented.
Timepoint [1] 0 0
Up to approximately 2 years
Primary outcome [2] 0 0
Overall Survival (OS) - OS is defined as the time from randomization to death due to any cause. The OS will be presented.
Timepoint [2] 0 0
Up to approximately 2 years
Secondary outcome [1] 0 0
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR - ORR is defined as the percentage of the participants in the analysis population who have 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, taking as reference the baseline sum diameters). The ORR per RECIST 1.1 as assessed by BICR will be presented.
Timepoint [1] 0 0
Up to approximately 2 years
Secondary outcome [2] 0 0
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR - For participants who demonstrate CR or PR, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. The DOR per RECIST 1.1 as assessed by BICR will be presented.
Timepoint [2] 0 0
Up to approximately 2 years
Secondary outcome [3] 0 0
Month 12 PFS Rate Per RECIST 1.1 as Assessed by BICR - PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as = 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of =5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS Rate per RECIST 1.1 as assessed by BICR at Month 12 will be presented
Timepoint [3] 0 0
Month 12
Secondary outcome [4] 0 0
Number of Participants Who Experience an Adverse Event (AE) - An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experience an AE will be presented.
Timepoint [4] 0 0
From randomization through 30 days after last dose of study treatment (Up to approximately 25 months)
Secondary outcome [5] 0 0
Number of Participants Who Experience a Serious AE (SAE) - An SAE is defined as any untoward medical occurrence that, at any dose: a.) Results in death; b.) Is life-threatening; c.) Requires inpatient hospitalization or prolongation of existing hospitalization; d.) Results in persistent or significant disability/incapacity; e.) Is a congenital anomaly/birth defect; f.) Other important medical events; h.) Is a new cancer (that is not a condition of the study) or i.) Is associated with an overdose. The number of participants who experience an SAE will be presented.
Timepoint [5] 0 0
From randomization through 90 days after last dose of study treatment (Up to approximately 27 months)
Secondary outcome [6] 0 0
Number of Participants Who Experience an Immune-related AE (irAE) - AEs associated with pembrolizumab exposure may be a result of an immune response. These irAEs may occur shortly after the first dose or several months after the last dose of pembrolizumab treatment and may affect more than one body system simultaneously. For this study irAEs include, but are not limited to: -Pneumonitis;
Diarrhea/Colitis;
Aspartate transaminase (AST)/Alanine transaminase (ALT) elevation or Increased bilirubin;
Type 1 diabetes mellitus or Hyperglycemia;
Hypophysitis;
Hyperthyroidism;
Hypothyroidism;
Nephritis and Renal dysfunction; and
Myocarditis. The number of participants who experience an irAE will be presented.
Timepoint [6] 0 0
From randomization through 90 days after last dose of study treatment for serious irAEs (Up to approximately 27 months); From randomization through 30 days after last dose of study treatment for nonserious irAEs (Up to approximately 25 months)
Secondary outcome [7] 0 0
Number of Participants Who Discontinue Study Treatment Due to an AE - The number of participants who discontinue study treatment due to an AE will be presented.
Timepoint [7] 0 0
Up to approximately 2 years
Secondary outcome [8] 0 0
Number of Participants with a 10-point Change from Baseline in Quality of Life (QoL) Based on the European Organisation for the Research & Treatment of Cancer (EORTC) QoL Questionnaire-30 (QLQ-C30) Global Score - The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the QoL of cancer patients. It incorporates 5 functional scales (physical, role, cognitive, emotional & social), 3 symptom scales (fatigue, pain, & nausea & vomiting), a global health status/QoL scale, & single items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation & diarrhoea) & perceived financial impact of the disease. All of the scales & single-item measures range in score from 0 to 100. A 10-point change in the EORTC QLQ-C30 score is perceived to be clinically meaningful. Participant post-baseline EORTC QLQ-C30 scores will be classified as "improvement", "stable", or "deterioration" according to a 10-point or greater change for EORTC QLQ-C30 global score. The number of participants with "improved", "stable", or "deteriorated" symptoms/scales will be presented.
Timepoint [8] 0 0
Baseline (Cycle 1 Day 1: Predose) and up to 30 days after last dose of study treatment (Up to approximately 25 months)

Eligibility
Key inclusion criteria
- Has persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous
carcinoma, or adenocarcinoma of the cervix which has not been treated with systemic
chemotherapy and is not amenable to curative treatment (such as with surgery and/or
radiation)

- Not pregnant or breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP), b.) A WOCBP must agree to use
effective contraception during the treatment period and for at least 120 days after
the last dose of pembrolizumab/placebo and 210 days after the last dose of
chemotherapy/bevacizumab

- Has measurable disease per RECIST 1.1 as assessed by the local site
investigator/radiology

- Has provided archival tumor tissue sample or newly obtained core or excisional biopsy
of a tumor lesion not previously irradiated for prospective determination of
Programmed Cell Death-Ligand 1 (PD-L1) status prior to randomization

- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within
14 days prior to randomization

- Has adequate organ function
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Participants with known brain metastases may participate provided that the
brain metastases have been previously treated (except with chemotherapy) and are
radiographically stable.

- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer,
or carcinoma in situ (e.g. breast cancer) that have undergone potentially curative
therapy are not excluded.

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in doses exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to randomization

- Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment and is allowed

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis

- Has an active infection requiring systemic therapy

- Has a known history of human immunodeficiency virus (HIV) infection

- Has a known history of Hepatitis B or known active Hepatitis C virus infection

- Has a known history of active tuberculosis (TB; Bacillus tuberculosis)

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.
cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137)

- Has received prior systemic chemotherapy for treatment of cervical cancer.

- Has not recovered adequately from toxicity and/or complications from major surgery
prior to randomization

- Has received prior radiotherapy within 2 weeks prior to randomization. Participants
must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis.

- Has received a live vaccine within 30 days prior to randomization

- Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients.

- Has a contraindication or hypersensitivity to any component of cisplatin, carboplatin,
paclitaxel, or bevacizumab

- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to randomization

- Is pregnant or breastfeeding or expecting to conceive within the projected duration of
the study, starting with the screening visit through 120 days following last dose of
pembrolizumab/placebo and 210 days following last dose of chemotherapy/bevacizumab

- Has had an allogeneic tissue/solid organ transplant

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA
Recruitment hospital [1] 0 0
Royal North Shore Hospital ( Site 1514) - St Leonards
Recruitment hospital [2] 0 0
Mater Misericordiae Ltd Mater Cancer Care Centre ( Site 1521) - South Brisbane
Recruitment hospital [3] 0 0
Flinders Medical Centre ( Site 1513) - Bedford Park
Recruitment hospital [4] 0 0
St John of God Subiaco Hospital ( Site 1512) - Subiaco
Recruitment hospital [5] 0 0
Monash Health-Monash Medical Centre ( Site 1519) - Clayton
Recruitment postcode(s) [1] 0 0
2065 - St Leonards
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
5042 - Bedford Park
Recruitment postcode(s) [4] 0 0
6008 - Subiaco
Recruitment postcode(s) [5] 0 0
3168 - Clayton
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alaska
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Connecticut
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Georgia
Country [7] 0 0
United States of America
State/province [7] 0 0
Michigan
Country [8] 0 0
United States of America
State/province [8] 0 0
Missouri
Country [9] 0 0
United States of America
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New Jersey
Country [10] 0 0
United States of America
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New York
Country [11] 0 0
United States of America
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Ohio
Country [12] 0 0
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Oklahoma
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United States of America
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South Carolina
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United States of America
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Tennessee
Country [15] 0 0
United States of America
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Texas
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United States of America
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Washington
Country [17] 0 0
Argentina
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Buenos Aires
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Argentina
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La Rioja
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Argentina
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Tucuman
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Canada
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Alberta
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Canada
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British Columbia
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Canada
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Manitoba
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Canada
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Nova Scotia
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Ontario
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Quebec
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Chile
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Valparaiso
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Chile
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Santiago
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Chile
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Temuco
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Colombia
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Cesar
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Colombia
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Cundinamarca
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Colombia
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Valle
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Colombia
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Barranquilla
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Colombia
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Monteria
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Colombia
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Pasto
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France
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Clermont Ferrand
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France
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Marseille
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France
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Paris
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France
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Rennes
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France
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Saint-Cloud
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Germany
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Dresden
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Germany
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Duesseldorf
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Germany
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Essen
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Germany
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Hamburg
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Germany
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Hannover
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Germany
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Kiel
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Germany
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Muenchen
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Germany
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Oldenburg
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Germany
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Regensburg
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Israel
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Beer-Sheva
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Israel
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Haifa
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Israel
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Jerusalem
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Israel
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Petah Tikva
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Israel
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Ramat Gan
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Israel
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Tel Aviv
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Italy
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Aviano
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Italy
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Bolgna
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Italy
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Milano
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Italy
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Napoli
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Italy
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Roma
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Japan
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Chiba
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Japan
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Ehime
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Japan
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Fukuoka
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Japan
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Hokkaido
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Japan
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Hyogo
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Japan
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Iwate
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Japan
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Okinawa
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Japan
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Saitama
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Japan
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Shizuoka
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Japan
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Tokyo
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Korea, Republic of
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Daegu
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Korea, Republic of
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Seoul
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Mexico
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Yucatan
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Mexico
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Chihuahua
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Mexico
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Ciudad de Mexico
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Mexico
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Mexico
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Mexico
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San Pedro Garza Garcia
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Mexico
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Veracruz
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Peru
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La Libertad
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Peru
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Arequipa
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Peru
State/province [80] 0 0
Lima
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Russian Federation
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Kazan
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Russian Federation
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Moscow
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Russian Federation
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Novosibirsk
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Russian Federation
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Saint Petersburg
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Russian Federation
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Saransk
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Russian Federation
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St. Petersburg
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Russian Federation
State/province [87] 0 0
Tomsk
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Russian Federation
State/province [88] 0 0
Ufa
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Spain
State/province [89] 0 0
Guipuzcoa
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Spain
State/province [90] 0 0
Madrid
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Spain
State/province [91] 0 0
Badalona
Country [92] 0 0
Spain
State/province [92] 0 0
Sevilla
Country [93] 0 0
Taiwan
State/province [93] 0 0
Kaohsiung
Country [94] 0 0
Taiwan
State/province [94] 0 0
Taichung
Country [95] 0 0
Taiwan
State/province [95] 0 0
Taipei
Country [96] 0 0
Taiwan
State/province [96] 0 0
Taoyuan
Country [97] 0 0
Turkey
State/province [97] 0 0
Adana
Country [98] 0 0
Turkey
State/province [98] 0 0
Ankara
Country [99] 0 0
Turkey
State/province [99] 0 0
Antalya
Country [100] 0 0
Turkey
State/province [100] 0 0
Istanbul
Country [101] 0 0
Turkey
State/province [101] 0 0
Izmir
Country [102] 0 0
Turkey
State/province [102] 0 0
Konya
Country [103] 0 0
Ukraine
State/province [103] 0 0
Dnipropetrovsk
Country [104] 0 0
Ukraine
State/province [104] 0 0
Ivano-Frankivsk
Country [105] 0 0
Ukraine
State/province [105] 0 0
Kharkiv
Country [106] 0 0
Ukraine
State/province [106] 0 0
Kyiv
Country [107] 0 0
Ukraine
State/province [107] 0 0
Odesa
Country [108] 0 0
Ukraine
State/province [108] 0 0
Zaporizhzhya

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475)
plus one of four platinum-based chemotherapy regimens compared to the efficacy and safety of
placebo plus one of four platinum-based chemotherapy regimens in the treatment of adult women
with persistent, recurrent, or metastatic cervical cancer. Possible chemotherapy regimens
include: paclitaxel plus cisplatin with or without bevacizumab and paclitaxel plus
carboplatin with or without bevacizumab.

The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy is
superior to placebo plus chemotherapy with respect to: 1) Progression-free Survival (PFS) per
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent
central review (BICR), or, 2) Overall Survival (OS).
Trial website
https://clinicaltrials.gov/show/NCT03635567
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications