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Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15)

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ClinicalTrials.gov Identifier: NCT05173987
Recruitment Status : Recruiting
First Posted : December 30, 2021
Last Update Posted : September 27, 2022
Sponsor:
Collaborators:
European Network of Gynaecological Oncological Trial Groups (ENGOT)
Gynecologic Oncology Group
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Brief Summary:

The purpose of this study is to assess the safety and efficacy of treatment with pembrolizumab (MK-3475) compared to a combination of carboplatin and paclitaxel in women with mismatch repair deficient (dMMR) advanced or recurrent endometrial carcinoma who have not previously been treated with prior systemic chemotherapy.

The primary study hypotheses are that pembrolizumab is superior to the combination of carboplatin and paclitaxel with respect to 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) and Overall Survival (OS).


Condition or disease Intervention/treatment Phase
Endometrial Neoplasms Biological: pembrolizumab Drug: carboplatin Drug: paclitaxel Drug: docetaxel Drug: cisplatin Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 350 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3 Randomized, Open-label, Active-comparator Controlled Clinical Study of Pembrolizumab Versus Platinum Doublet Chemotherapy in Participants With Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma in the First-line Setting (KEYNOTE-C93/GOG-3064/ENGOT-en15)
Actual Study Start Date : February 3, 2022
Estimated Primary Completion Date : July 17, 2026
Estimated Study Completion Date : July 17, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab
Participants receive pembrolizumab 400 mg via IV infusion on Day 1 of each 6-week cycle (Q6W) for up to 18 cycles (up to approximately 2 years).
Biological: pembrolizumab
Intravenous (IV) infusion
Other Names:
  • KEYTRUDA®
  • MK-3475

Active Comparator: Carboplatin+paclitaxel
Participants receive a combination of paclitaxel 175 mg/m^2 on Day 1 of each 3-week cycle (Q3W) and carboplatin AUC 5 or 6 on Day 1 Q3W for 6 cycles (up to approximately 4 months). Participants who experience a severe hypersensitivity reaction to paclitaxel or an adverse event (AE) requiring discontinuation of paclitaxel may receive docetaxel 75 mg/m^2 in place of paclitaxel on Day 1 Q3W after Sponsor consultation. Participants who experience a severe hypersensitivity reaction to carboplatin or an AE requiring discontinuation of carboplatin may receive cisplatin 75 mg/m^2 in place of carboplatin on Day 1 Q3W after Sponsor consultation.
Drug: carboplatin
IV infusion
Other Name: PARAPLATIN®

Drug: paclitaxel
IV infusion
Other Name: TAXOL®

Drug: docetaxel
IV infusion
Other Name: TAXOTERE®

Drug: cisplatin
IV infusion
Other Name: PLATINOL-AQ®




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 30 months ]
    PFS is defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 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. 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 lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by BICR will be reported for participants.

  2. Overall Survival [ Time Frame: Up to approximately 49 months ]
    OS is defined as the time from randomization to death due to any cause. The OS will be reported for all participants.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) 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 30 months ]
    ORR is defined as the percentage of participants who have a best response of confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by BICR will be presented.

  2. Disease Control Rate (DCR) 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 30 months ]
    DCR is defined, per RECIST 1.1, as the percentage of participants who have achieved Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or demonstrated Stable Disease (SD) for at least 24 weeks. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD.) The DCR as assessed by BICR will be presented.

  3. Duration of Response (DOR) 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 30 months ]
    DOR is defined as the time from first documented evidence of CR or PR until the first documented date of disease progression (PD) or death due to any cause, whichever occurs first, for participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.

  4. 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 30 months ]
    PFS is defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 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. 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 lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS per RECIST 1.1 as assessed by investigator will be reported for participants.

  5. Progression-Free Survival 2 (PFS2) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator [ Time Frame: Up to approximately 30 months ]
    PFS2 is defined as the time from randomization to subsequent disease progression (PD) per RECIST 1.1 after initiation of a new anticancer therapy, 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. 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 lesions and the unequivocal progression of non-target lesions is also considered PD. The PFS2 per RECIST 1.1 as assessed by investigator will be reported for participants.

  6. Number of Participants Who Experience at Least One Adverse Event (AE) [ Time Frame: Up to approximately 27 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experience an AE will be reported.

  7. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 24 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinue study treatment due to an AE will be reported.

  8. Change From Baseline in European Organization for Research And Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) (Item 29) And Quality of Life (QoL) (Item 30) Combined Score [ Time Frame: Baseline and up to approximately 25 months ]
    The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "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). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score will be presented.

  9. Change From Baseline in European Organization for Research And Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Combined Score [ Time Frame: Baseline and up to approximately 25 months ]
    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). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) score will be presented. A higher score indicates a better quality of life.

  10. Time to Deterioration (TTD) in European Organization for Research And Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (GHS) (Item 29) And Quality of Life (QoL) (Item 30) Combined Score [ Time Frame: Up to approximately 25 months ]
    TTD is defined as the time from baseline to the first onset of a ≥10-point deterioration (decrease) from baseline in EORTC QLQ-C30 GHS (Item 29) and QoL (Item 30) combined score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline, in combined GHS (Item 29 and QoL (Item 30) score will be presented. A longer TTD indicates a better outcome.

  11. Time to Deterioration (TTD) in European Organization for Research And Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Combined Score [ Time Frame: Up to approximately 25 months ]
    TTD is defined as the time from baseline to the first onset of a ≥10-point deterioration (decrease) from baseline in EORTC QLQ-C30 physical functioning (Items 1-5) combined score. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The TTD, as assessed based on a ≥10-point negative change (decrease) from baseline, in combined GHS (Item 29 and QoL (Item 30) score will be presented. A longer TTD indicates a better outcome.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

  • Has a histologically confirmed diagnosis of Stage III or IV or recurrent Endometrial Carcinoma (EC) or carcinosarcoma (mixed Mullerian tumor) that is centrally confirmed as dMMR
  • Has received no prior systemic therapy for advanced EC except for the following:

    1. May have received prior radiation with or without radiosensitizing chemotherapy if >2 weeks before the start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
    2. May have received prior hormonal therapy for treatment of EC, provided that it was discontinued ≥1 week prior to randomization
  • Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before randomization.
  • Is not pregnant or breastfeeding and agrees to not donate eggs and use a highly effective contraceptive method for 120 days after the last dose of pembrolizumab or 180 days after the last dose of chemotherapy if a woman of childbearing potential (WOCBP)
  • Has a negative highly sensitive pregnancy test (urine or serum) within 24 hours for urine or 72 hours for serum before the first dose of study intervention if a WOCBP
  • Provides an archival tumor tissue sample or newly obtained (core, incisional, or excisional) biopsy of a tumor lesion not previously irradiated for verification of dMMR status and histology.
  • Is Hepatitis B surface antigen (HBsAg) positive but has received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and has undetectable HBV viral load prior to randomization.
  • Has a history of Hepatitis C virus (HCV) infection but has undetectable HCV viral load at screening

Exclusion Criteria:

  • Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas and neuroendocrine tumors are not allowed
  • Has EC of any histology that is proficient mismatch repair (pMMR)
  • Is a candidate for curative-intent surgery or curative-intent radiotherapy
  • 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 coinhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], Tumor necrosis factor receptor superfamily, member 4 [OX 40], tumor necrosis factor receptor superfamily member 9 [CD137])
  • Has received prior systemic anticancer therapy including investigational agents for EC. This includes any chemotherapy given for EC other than as a radiosensitizer
  • Has had a major operation and has not recovered adequately from the procedure and/or any complications from the operation before starting study intervention
  • Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed
  • Is currently participating in or has participated in a study of an investigational agent for EC, has participated in a study of an investigational agent for non-EC within 4 weeks before the first dose of study intervention, or has used an investigational device within 4 weeks before the first dose of study intervention
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
  • Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) that have undergone potentially curative therapy are not excluded
  • Has known active CNS metastases and/or carcinomatous meningitis
  • Has a known intolerance to any study intervention and/or any of its excipients
  • Has an active autoimmune disease that has required systemic treatment in past 2 years
  • Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
  • Has an active infection, requiring systemic therapy
  • Has a known history of human immunodeficiency virus (HIV) infection
  • Has had an allogenic tissue/solid organ transplant

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05173987


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
Show Show 125 study locations
Sponsors and Collaborators
Merck Sharp & Dohme LLC
European Network of Gynaecological Oncological Trial Groups (ENGOT)
Gynecologic Oncology Group
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
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Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT05173987    
Other Study ID Numbers: 3475-C93
MK-3475-C93 ( Other Identifier: Merck )
KEYNOTE-C93 ( Other Identifier: Merck )
GOG-3064 ( Other Identifier: Gynecologic Oncology Group )
ENGOT-en15 ( Other Identifier: European Network of Gynaecological Oncological Trial Groups (ENGOT) )
jRCT2011210065 ( Registry Identifier: jRCT )
2021-003185-12 ( EudraCT Number )
First Posted: December 30, 2021    Key Record Dates
Last Update Posted: September 27, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme LLC:
Programmed Cell Death-1 (PD1, PD-1)
Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1)
Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Additional relevant MeSH terms:
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Endometrial Neoplasms
Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Paclitaxel
Docetaxel
Cisplatin
Carboplatin
Pembrolizumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological