Study of Pembrolizumab (MK-3475) in Combination With Adjuvant Chemotherapy With or Without Radiotherapy in Participants With Newly Diagnosed Endometrial Cancer After Surgery With Curative Intent (MK-3475-B21 / KEYNOTE-B21 / ENGOT-en11 / GOG-3053)

Study Overview
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Brief Summary
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The purpose of this study is to compare pembrolizumab + adjuvant chemotherapy with placebo + adjuvant chemotherapy, with or without radiotherapy, with respect to disease-free survival (DFS) as assessed radiographically by the investigator or by histopathologic confirmation of suspected disease recurrence, and with respect to overall survival (OS). The primary hypotheses are that pembrolizumab + adjuvant chemotherapy is superior to placebo + adjuvant chemotherapy, with or without radiotherapy, with respect to DFS as assessed radiographically by the investigator or by histopathologic confirmation of suspected disease recurrence, and with respect to OS.

Official Title
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A Phase 3, Randomized, Double-Blind Study of Pembrolizumab Versus Placebo in Combination With Adjuvant Chemotherapy With or Without Radiotherapy for the Treatment of Newly Diagnosed High-Risk Endometrial Cancer After Surgery With Curative Intent (KEYNOTE-B21 / ENGOT-en11 / GOG-3053)

Conditions
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Endometrial Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Placebo for pembrolizumab
* Drug: Docetaxel
* Drug: Cisplatin
* Radiation: External Beam Radiotherapy (EBRT)
* Drug: Cisplatin (as radiosensitizer)
* Radiation: Brachytherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically confirmed new diagnosis of Endometrial Carcinoma or Carcinosarcoma (Mixed Mullerian Tumor) and: Has undergone curative intent surgery that included hysterectomy and bilateral salpingo-oophorectomy; and Is at high risk for recurrence following treatment with curative intent surgery, ie: Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) 2009 surgical stage I/II with myometrial invasion of non-endometrioid histology; FIGO 2009 surgical stage I/II with myometrial invasion of any histology with known aberrant p53 expression or p53 mutation; or FIGO (2009) surgical stage III or IVA of any histology. Is disease-free with no evidence of loco-regional disease or distant metastasis post operatively and on imaging. Has not received any radiation or systemic therapy, including immunotherapy, hormonal therapy, or hyperthermic intraperitoneal chemotherapy (HIPEC), in any setting including the neoadjuvant setting for endometrial cancer (EC). Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before randomization. Submission of a tumor tissue sample from current diagnosis of Endometrial Carcinoma or Carcinosarcoma for prospective determination of histology and mismatch repair (MMR) status by central vendor is required for all participants. Has adequate organ function within 7 days of randomization. Exclusion Criteria: Has recurrent endometrial carcinoma or carcinosarcoma. Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas are also not allowed. Has FIGO (2009) Surgical Stage I/II EC of endometrioid histology without a known aberrant p53 expression or p53 mutation. Is known to have a deoxyribonucleic acid (DNA) polymerase epsilon catalytic subunit A (POLE) mutation. Has FIGO Stage IVB disease of any histology even if there is no evidence of disease after surgery. Has residual tumor whether measurable or non-measurable after surgery. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years. Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers. Has received prior therapy with an anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137). Has received a live vaccine within 30 days before the first dose of study intervention. Note: killed vaccines are allowed. Has a known intolerance to study intervention (or any of the excipients). Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Has any contraindication to the use of carboplatin or paclitaxel. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, 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 HIV infection. Has a known history of Hepatitis B or known active Hepatitis C virus infection. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. Has had an allogenic tissue/solid organ transplant. Has not recovered adequately from surgery and/or any complications from the surgery. Is breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Chemotherapy<br>Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for 6 cycles followed by pembrolizumab 400 mg IV on Day 1 of each 6-week cycle (Q6W) for an additional 6 cycles. During the Q3W dosing period of pembrolizumab, participants receive concurrent standard of care (SoC) chemotherapy for 4 or 6 cycles. Participants optionally receive radiotherapy starting within 6 weeks of completion of SoC chemotherapy. The SoC chemotherapy regimen includes carboplatin AUC 5 or 6 IV Q3W plus paclitaxel 175 mg/m^2 IV Q3W. In the event of severe hypersensitivity to, or an AE requiring discontinuation of, carboplatin or paclitaxel, cisplatin or docetaxel may be substituted after investigator consults with sponsor. The SoC radiotherapy regimen may include, at the discretion of the investigator, external beam radiotherapy (EBRT) ≥4500 cGY with variable dose frequency, with or without cisplatin 50 mg/m^2 IV on days 1 and 29 of EBRT, and/or brachytherapy radiation. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;Drug: Carboplatin<br>* IV infusion<br>Drug: Paclitaxel<br>* IV infusion<br>Drug: Docetaxel<br>* IV infusion docetaxel 75 mg/m^2 Q3W or 25 mg/m2 QW may be given in place of paclitaxel following sponsor consultation if a participant experiences severe hypersensitivity to paclitaxel or an adverse event requiring discontinuation of paclitaxel.<br>Drug: Cisplatin<br>* Cisplatin 75 mg/m^2 IV infusion Q3W may be given in place of carboplatin following sponsor consultation if a participant experiences severe hypersensitivity to carboplatin or an adverse event requiring discontinuation of carboplatin.<br>* Other names: Platinol®-AQ;Radiation: External Beam Radiotherapy (EBRT)<br>* ≥4500 cGY given according to local practice, at the discretion of the investigator<br>Drug: Cisplatin (as radiosensitizer)<br>* If a participant receives external beam radiotherapy (EBRT), then cisplatin 50 mg/m^2 IV infusion may be administered as a radiosensitizer at the discretion of the investigator, on days 1 and 29<br>* Other names: Platinol®-AQ;Radiation: Brachytherapy<br>* Given according to local practice, at the discretion of the investigator<br>* Other names: Internal radiation therapy;|
| Placebo Comparator: Placebo + Chemotherapy<br>Participants receive placebo to pembrolizumab intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for 6 cycles followed by placebo IV on Day 1 of each 6-week cycle (Q6W) for an additional 6 cycles. During the Q3W dosing period of placebo, participants receive concurrent standard of care (SoC) chemotherapy for 4 or 6 cycles. Participants optionally receive radiotherapy starting within 6 weeks of completion of SoC chemotherapy. The SoC chemotherapy regimen includes carboplatin AUC 5 or 6 IV Q3W plus paclitaxel 175 mg/m^2 IV Q3W. In the event of severe hypersensitivity to, or an AE requiring discontinuation of, carboplatin or paclitaxel, cisplatin or docetaxel may be substituted after investigator consults with sponsor. The SoC radiotherapy regimen may include, at the discretion of the investigator, external beam radiotherapy (EBRT) ≥4500 cGY with variable dose frequency, with or without cisplatin 50 mg/m^2 IV on days 1 and 29 of EBRT, and/or brachytherapy radiation. | Drug: Carboplatin<br>* IV infusion<br>Drug: Paclitaxel<br>* IV infusion<br>Drug: Placebo for pembrolizumab<br>* IV infusion<br>Drug: Docetaxel<br>* IV infusion docetaxel 75 mg/m^2 Q3W or 25 mg/m2 QW may be given in place of paclitaxel following sponsor consultation if a participant experiences severe hypersensitivity to paclitaxel or an adverse event requiring discontinuation of paclitaxel.<br>Drug: Cisplatin<br>* Cisplatin 75 mg/m^2 IV infusion Q3W may be given in place of carboplatin following sponsor consultation if a participant experiences severe hypersensitivity to carboplatin or an adverse event requiring discontinuation of carboplatin.<br>* Other names: Platinol®-AQ;Radiation: External Beam Radiotherapy (EBRT)<br>* ≥4500 cGY given according to local practice, at the discretion of the investigator<br>Drug: Cisplatin (as radiosensitizer)<br>* If a participant receives external beam radiotherapy (EBRT), then cisplatin 50 mg/m^2 IV infusion may be administered as a radiosensitizer at the discretion of the investigator, on days 1 and 29<br>* Other names: Platinol®-AQ;Radiation: Brachytherapy<br>* Given according to local practice, at the discretion of the investigator<br>* Other names: Internal radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence | DFS is defined as the time from randomization to the first documented local recurrence, distant metastasis, secondary systemic malignancy, or death due to any cause, whichever occurs first. The DFS as assessed radiographically by investigator or by histopathologic confirmation of suspected disease recurrence, will be presented. | Up to approximately 42 months | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 54 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-Free Survival (DFS) as Assessed Radiographically by Blinded Independent Central Review (BICR) or by Histopathologic Confirmation of Suspected Disease Recurrence | DFS is defined as the time from randomization to the first documented local recurrence, distant metastasis, secondary systemic malignancy, or death due to any cause, whichever occurs first. The DFS as assessed radiographically by BICR or by histopathologic confirmation of suspected disease recurrence, will be presented. | Up to approximately 42 months | 
| Disease-Free Survival (DFS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Combined Positivity Score (CPS)-Determined Programmed Cell Death 1 Ligand 1 (PD-L1) Status | DFS is defined as the time from randomization to the first documented local recurrence, distant metastasis, secondary systemic malignancy, or death due to any cause, whichever occurs first. The DFS as assessed radiographically by investigator or by histopathologic confirmation of suspected disease recurrence by CPS-determined PD-L1 status will be presented. | Up to approximately 42 months | 
| Overall Survival (OS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Combined Positivity Score (CPS)-Determined Programmed Cell Death 1 Ligand 1 (PD-L1) Status | OS is defined as the time from randomization to death due to any cause. The OS as assessed radiographically by investigator or by histopathologic confirmation of suspected disease recurrence by CPS-determined PD-L1 status will be presented. | Up to approximately 54 months | 
| Disease-Free Survival (DFS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Tumor Mutation Burden (TMB) Status | DFS is defined as the time from randomization to the first documented local recurrence, distant metastasis, secondary systemic malignancy, or death due to any cause, whichever occurs first. The DFS as assessed radiographically by investigator or by histopathologic confirmation of suspected disease recurrence by tumor mutation burden (TMB) status, will be presented. | Up to approximately 42 months | 
| Overall Survival (OS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Tumor Mutation Burden (TMB) Status | OS is defined as the time from randomization to death due to any cause. The OS as assessed radiographically by investigator or by histopathologic confirmation of suspected disease recurrence by tumor mutation burden (TMB) status will be presented. | Up to approximately 54 months | 
| Number of Participants Who Experience One or More Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be presented. | Up to approximately 54 months | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 52 weeks | 
| Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (QoL) Score | The EORTC QLQ-C30 is a questionnaire that rates the overall quality of life in cancer participants. Participant responses to questions 29 (How would you rate your overall health during the past week?) and 30 (How would you rate your overall quality of life during the past week?) are scored on a 7-point scale (1= Very poor to 7=Excellent). A higher score indicates a better overall health/quality of life status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined scores will be presented. | Baseline and up to approximately 54 months | 
| Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Physical Function Score | The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=not at all to 4=very much). A higher score indicates a better quality of life. The change from baseline in physical function (EORTC QLQ-C30 Items 1-5) score will be presented. | Baseline and up to approximately 54 months | 
| Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Symptom Specific Scale for Endometrial Cancer (EORTC QLQ-EN24) Score | The EORTC-QLQ-EN24 is a 24-item questionnaire developed to be used in conjunction with the EORTC-QLQ-C30 to assess the quality of life of endometrial cancer patients. Participant responses are scored on a 4-point scale (1=not at all to 4=very much). A higher score indicates a better quality of life. The change from baseline in EORTC QLQ-E24 score will be presented. | Baseline and up to approximately 54 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2 )