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)

Phase 3Active Not RecruitingNCT05173987

Merck Sharp & Dohme LLC280 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

280

Conditions

Endometrial Neoplasms

Interventions

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

The main inclusion and exclusion criteria include but are not limited to the following: Inclusion Criteria: * Has a histologically confirmed diagnosis of inoperable, Stage III or IV or recurrent Endometrial Carcinoma (EC) or carcinosarcoma (mixed Mullerian tumor) that is centrally confirmed as dMMR. * Has radiographically evaluable disease, either measurable or non-measurable per RECIST 1.1, as assessed by the investigator. Note: primary Stage IVB that has undergone surgical resection is allowed regardless of presence of measurable or evaluable disease. * Has received no prior systemic therapy for EC except for the following: 1. May have received 1 prior line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy in the setting of curative-intent resection if the recurrence occurred ≥6 months after the last dose of chemotherapy. 2. 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. 3. 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. * If Hepatitis B surface antigen (HBsAg) positive, has received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and has undetectable HBV viral load prior to randomization. * If has a history of Hepatitis C virus (HCV) infection, 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 any advanced or metastatic EC. (Note: Prior chemotherapy administered as adjuvant therapy, neoadjuvant therapy, and/or concurrently with radiation is permitted. * 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.

Locations (195)

HonorHealth-USOR HonorHealth ( Site 8000)

Phoenix, Arizona, United States

Moores Cancer Center ( Site 0037)

La Jolla, California, United States

Kaiser Permanente Riverside Medical Center ( Site 0045)

Riverside, California, United States

Yale-New Haven Hospital-Smilow Cancer Hospital at Yale-New Haven ( Site 0013)

New Haven, Connecticut, United States

Mount Sinai Cancer Center ( Site 0018)

Miami Beach, Florida, United States

Outcomes

Primary Outcomes

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)

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.

Time frame: Up to approximately 45 months

Overall Survival

OS is defined as the time from randomization to death due to any cause. The OS will be reported for all participants.

Time frame: Up to approximately 59 months

Secondary Outcomes

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)

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.

Time frame: Up to approximately 45 months

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)

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.

Time frame: Up to approximately 45 months

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)

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.

Time frame: Up to approximately 45 months

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 45 months

Progression-Free Survival 2 (PFS2) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator

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.

Time frame: Up to approximately 45 months

Number of Participants Who Experience at Least One Adverse Event (AE)

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.

Time frame: Up to approximately 27 months

Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)

Time frame: Up to approximately 24 months

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

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.

Time frame: Baseline and up to approximately 25 months

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

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.

Time frame: Baseline and up to approximately 25 months