History of Changes for Study: NCT03635567

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)

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Study Record Versions

Version	Submitted Date	Changes
1	August 15, 2018	None (earliest Version on record)
2	August 28, 2018	Oversight and Study Status
3	September 14, 2018	Study Status
4	October 24, 2018	Recruitment Status, Study Status and Contacts/Locations
5	November 11, 2018	Study Status
6	November 14, 2018	Study Status and Contacts/Locations
7	November 22, 2018	Contacts/Locations and Study Status
8	November 29, 2018	Contacts/Locations and Study Status
9	December 6, 2018	Study Status, IPDSharing and Contacts/Locations
10	December 13, 2018	Contacts/Locations and Study Status
11	December 21, 2018	Contacts/Locations and Study Status
12	December 27, 2018	Contacts/Locations and Study Status
13	January 4, 2019	Study Status and Contacts/Locations
14	January 18, 2019	Contacts/Locations and Study Status
15	January 25, 2019	Contacts/Locations and Study Status
16	January 31, 2019	Contacts/Locations and Study Status
17	February 8, 2019	Contacts/Locations and Study Status
18	February 14, 2019	Contacts/Locations and Study Status
19	February 22, 2019	Contacts/Locations and Study Status
20	March 1, 2019	Contacts/Locations and Study Status
21	March 8, 2019	Contacts/Locations and Study Status
22	March 14, 2019	Contacts/Locations and Study Status
23	March 22, 2019	Contacts/Locations and Study Status
24	March 26, 2019	Contacts/Locations and Study Status
25	April 5, 2019	Contacts/Locations and Study Status
26	April 11, 2019	Contacts/Locations and Study Status
27	April 17, 2019	Contacts/Locations and Study Status
28	April 26, 2019	Contacts/Locations and Study Status
29	May 3, 2019	Contacts/Locations and Study Status
30	May 9, 2019	Contacts/Locations and Study Status
31	May 17, 2019	Contacts/Locations and Study Status
32	May 30, 2019	Contacts/Locations and Study Status
33	June 7, 2019	Study Status
34	June 13, 2019	Contacts/Locations and Study Status
35	July 8, 2019	Study Status, Study Identification and Eligibility
36	July 25, 2019	Contacts/Locations and Study Status
37	August 8, 2019	Contacts/Locations and Study Status
38	August 21, 2019	Contacts/Locations, Study Status and Study Identification
39	August 29, 2019	Contacts/Locations and Study Status
40	September 4, 2019	Study Status and Contacts/Locations
41	September 13, 2019	Contacts/Locations and Study Status
42	October 16, 2019	Contacts/Locations and Study Status
43	December 12, 2019	Contacts/Locations and Study Status
44	January 10, 2020	Recruitment Status, Study Status, Contacts/Locations and References
45	November 11, 2020	Outcome Measures, Study Status, Conditions and Study Description
46	June 16, 2022	Study Status
47	September 2, 2022	Study Status
48	October 19, 2022	Study Status and Study Design
49	September 20, 2023	Outcome Measures, Study Status, References, Document Section, Results, Eligibility and Arms and Interventions
50	October 28, 2023	Outcome Measures and Study Status
51	January 12, 2024	Study Status and References

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	3475-826
Brief 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)
Official 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 IDs:	2018-001440-53 [EudraCT Number] MK-3475-826 [Merck Protocol Number]

Study Status


Record Verification:	August 2018
Overall Status:	Not yet recruiting
Study Start:	September 26, 2018
Primary Completion:	November 23, 2022 [Anticipated]
Study Completion:	November 23, 2022 [Anticipated]

First Submitted:	August 15, 2018
First Submitted that Met QC Criteria:	August 15, 2018
First Posted:	August 17, 2018 [Actual]

Last Update Submitted that Met QC Criteria:	August 15, 2018
Last Update Posted:	August 17, 2018 [Actual]

Sponsor/Collaborators


Sponsor:	Merck Sharp & Dohme LLC
Responsible Party:	Sponsor
Collaborators:

Oversight


U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Data Monitoring:	Yes

Study Description

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).

Detailed Description:

Conditions


Conditions:	Cervical Cancer
Keywords:	Programmed Cell Death 1 PD1 PD-1 Programmed Cell Death Ligand 1 PDL1 PD-L1

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 3
Interventional Study Model:	Parallel Assignment
Number of Arms:	2
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Allocation:	Randomized
Enrollment:	600 [Anticipated]

Arms and Interventions

Arms

Assigned Interventions

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).

Biological: Pembrolizumab

IV infusion

Other Names:

MK-3475
KEYTRUDA®

Drug: Paclitaxel

IV infusion

Other Names:

TAXOL®

Drug: Cisplatin

IV infusion

Other Names:

PLATINOL®

Drug: Carboplatin

IV infusion

Other Names:

PARAPLATIN®

Biological: Bevacizumab

IV infusion

Other Names:

AVASTIN®

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).

Drug: Paclitaxel

IV infusion

Other Names:

TAXOL®

Drug: Cisplatin

IV infusion

Other Names:

PLATINOL®

Drug: Carboplatin

IV infusion

Other Names:

PARAPLATIN®

Biological: Bevacizumab

IV infusion

Other Names:

AVASTIN®

Drug: Placebo to pembrolizumab

IV infusion

Other Names:

Normal Saline or Dextrose solution

Outcome Measures


Primary Outcome Measures:
1.	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.
2.	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.
Secondary Outcome Measures:
1.	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.
2.	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.
3.	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
4.	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.
5.	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.
6.	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.
7.	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.
8.	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.

Eligibility


Minimum Age:	18 Years
Maximum Age:
Sex:	Female
Gender Based:
Accepts Healthy Volunteers:	No
Criteria:	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 or 210 days after the last dose of chemotherapy 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 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 Has had an allogeneic tissue/solid organ transplant

Contacts/Locations


Study Officials:	Medical Director Study Director Merck Sharp & Dohme LLC
Locations:

IPDSharing


Plan to Share IPD:

References


Links:
Available IPD/Information: