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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)

NCT04634877

Description:

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.

Related Conditions:
  • Endometrial Carcinoma
  • Malignant Mixed Mesodermal (Mullerian) Tumor
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-B21
  • SECONDARY ID: KEYNOTE-B21
  • SECONDARY ID: ENGOT-en11
  • SECONDARY ID: GOG-3053
  • SECONDARY ID: 2020-003424-17
  • NCT ID: NCT04634877

Conditions

  • Endometrial Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®, MK-3475Pembrolizumab + Chemotherapy
CarboplatinPembrolizumab + Chemotherapy
PaclitaxelPembrolizumab + Chemotherapy
Placebo for pembrolizumabPlacebo + Chemotherapy
DocetaxelPembrolizumab + Chemotherapy
CisplatinPlatinol®, Platinol®-AQPembrolizumab + Chemotherapy
Cisplatin (as radiosensitizer)Platinol®, Platinol®-AQPembrolizumab + Chemotherapy

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + ChemotherapyExperimentalParticipants 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.
  • Pembrolizumab
  • Carboplatin
  • Paclitaxel
  • Docetaxel
  • Cisplatin
  • Cisplatin (as radiosensitizer)
Placebo + ChemotherapyPlacebo ComparatorParticipants receive placebo 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.
  • Carboplatin
  • Paclitaxel
  • Placebo for pembrolizumab
  • Docetaxel
  • Cisplatin
  • Cisplatin (as radiosensitizer)

Eligibility Criteria

        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 or
             hormonal therapy, 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease-Free Survival (DFS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence
Time Frame:Up to approximately 42 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Disease-Free Survival (DFS) as Assessed Radiographically by Blinded Independent Central Review (BICR) or by Histopathologic Confirmation of Suspected Disease Recurrence
Time Frame:Up to approximately 42 months
Safety Issue:
Description: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.
Measure: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
Time Frame:Up to approximately 42 months
Safety Issue:
Description: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.
Measure: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
Time Frame:Up to approximately 54 months
Safety Issue:
Description: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.
Measure:Disease-Free Survival (DFS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Tumor Mutation Burden (TMB) Status
Time Frame:Up to approximately 42 months
Safety Issue:
Description: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.
Measure:Overall Survival (OS) as Assessed Radiographically by Investigator or by Histopathologic Confirmation of Suspected Disease Recurrence by Tumor Mutation Burden (TMB) Status
Time Frame:Up to approximately 54 months
Safety Issue:
Description: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.
Measure:Number of Participants Who Experience One or More Adverse Events (AEs)
Time Frame:Up to approximately 54 months
Safety Issue:
Description: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.
Measure:Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
Time Frame:Up to approximately 52 weeks
Safety Issue:
Description: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.
Measure: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
Time Frame:Baseline and up to approximately 54 months
Safety Issue:
Description: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.
Measure:Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Physical Function Score
Time Frame:Baseline and up to approximately 54 months
Safety Issue:
Description: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.
Measure: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
Time Frame:Baseline and up to approximately 54 months
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death-1 (PD1, PD-1)
  • Programmed Death-Ligand 1 (PDL1, PD-L1)
  • Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2 )

Last Updated

November 18, 2020