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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03635567
Recruitment Status : Active, not recruiting
First Posted : August 17, 2018
Last Update Posted : November 13, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE August 15, 2018
First Posted Date  ICMJE August 17, 2018
Last Update Posted Date November 13, 2020
Actual Study Start Date  ICMJE October 25, 2018
Estimated Primary Completion Date November 23, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 11, 2020)
  • Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator [ Time Frame: Up to approximately 2 years ]
    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 Investigator will be presented.
  • Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
    OS is defined as the time from randomization to death due to any cause. The OS will be presented.
Original Primary Outcome Measures  ICMJE
 (submitted: August 15, 2018)
  • 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) [ Time Frame: Up to approximately 2 years ]
    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.
  • Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
    OS is defined as the time from randomization to death due to any cause. The OS will be presented.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 11, 2020)
  • Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by Investigator [ Time Frame: Up to approximately 2 years ]
    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 Investigator will be presented.
  • Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator [ Time Frame: Up to approximately 2 years ]
    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 Investigator will be presented.
  • Month 12 PFS Rate Per RECIST 1.1 as Assessed by Investigator [ Time Frame: Month 12 ]
    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. PFS Rate was defined as the percentage of participants that are PFS event-free at Month 12. The PFS Rate per RECIST 1.1 as assessed by Investigator at Month 12 will be presented.
  • PFS per RECIST 1.1 as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 2 years ]
    PFS is defined as the time from randomization to the first documented 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.
  • Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: From randomization through 30 days after last dose of study treatment (Up to approximately 25 months) ]
    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.
  • Number of Participants Who Experience a Serious AE (SAE) [ Time Frame: From randomization through 90 days after last dose of study treatment (Up to approximately 27 months) ]
    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.
  • Number of Participants Who Experience an Immune-related AE (irAE) [ Time Frame: 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) ]
    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.
  • Number of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: Up to approximately 2 years ]
    The number of participants who discontinue study treatment due to an AE will be presented.
  • 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 [ Time Frame: Baseline (Cycle 1 Day 1: Predose) and up to 30 days after last dose of study treatment (Up to approximately 25 months) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 15, 2018)
  • Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 2 years ]
    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.
  • Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 2 years ]
    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.
  • Month 12 PFS Rate Per RECIST 1.1 as Assessed by BICR [ Time Frame: Month 12 ]
    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
  • Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: From randomization through 30 days after last dose of study treatment (Up to approximately 25 months) ]
    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.
  • Number of Participants Who Experience a Serious AE (SAE) [ Time Frame: From randomization through 90 days after last dose of study treatment (Up to approximately 27 months) ]
    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.
  • Number of Participants Who Experience an Immune-related AE (irAE) [ Time Frame: 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) ]
    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.
  • Number of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: Up to approximately 2 years ]
    The number of participants who discontinue study treatment due to an AE will be presented.
  • 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 [ Time Frame: Baseline (Cycle 1 Day 1: Predose) and up to 30 days after last dose of study treatment (Up to approximately 25 months) ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE 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)
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 the Investigator, or, 2) Overall Survival (OS).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Cervical Cancer
Intervention  ICMJE
  • Biological: Pembrolizumab
    IV infusion
    Other Names:
    • MK-3475
    • KEYTRUDA®
  • Drug: Paclitaxel
    IV infusion
    Other Name: TAXOL®
  • Drug: Cisplatin
    IV infusion
    Other Name: PLATINOL®
  • Drug: Carboplatin
    IV infusion
    Other Name: PARAPLATIN®
  • Biological: Bevacizumab
    IV infusion
    Other Name: AVASTIN®
  • Drug: Placebo to pembrolizumab
    IV infusion
    Other Name: Normal Saline or Dextrose solution
Study Arms  ICMJE
  • 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).
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Paclitaxel
    • Drug: Cisplatin
    • Drug: Carboplatin
    • Biological: Bevacizumab
  • 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).
    Interventions:
    • Drug: Paclitaxel
    • Drug: Cisplatin
    • Drug: Carboplatin
    • Biological: Bevacizumab
    • Drug: Placebo to pembrolizumab
Publications * Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. doi: 10.1056/NEJMoa2112435. Epub 2021 Sep 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: August 15, 2018)
600
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 23, 2022
Estimated Primary Completion Date November 23, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Canada,   Chile,   Colombia,   France,   Germany,   Israel,   Italy,   Japan,   Korea, Republic of,   Mexico,   Peru,   Russian Federation,   Spain,   Taiwan,   Turkey,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03635567
Other Study ID Numbers  ICMJE 3475-826
2018-001440-53 ( EudraCT Number )
MK-3475-826 ( Other Identifier: Merck )
KEYNOTE-826 ( Other Identifier: Merck )
184183 ( Registry Identifier: JAPAC-CTI )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP