Phase 3 Randomized Study of Pembrolizumab Versus Platinum-Based Chemotherapy in Mismatch Repair Deficient Advanced or Recurrent Endometrial Carcinoma
- Trial ID
- 2023-506361-56-00
- Protocol
- MK-3475-C93
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 clinical study is to compare **pembrolizumab** to chemotherapy in terms of progression-free survival (PFS) as assessed by blinded independent central review (BICR) and overall survival (OS) in participants with mismatch repair deficient (dMMR) advanced or recurrent **endometrial cancer**. This comparison is clinically relevant as it aims to determine the efficacy of pembrolizumab, a potential first-line treatment option, against the standard chemotherapy regimen, potentially improving patient outcomes in this specific cancer subtype.
Secondary objectives include:
- Comparing pembrolizumab to chemotherapy with respect to objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) per RECIST 1.1 by BICR in participants with measurable disease at study entry.
- Evaluating PFS and PFS2 per RECIST 1.1 as assessed by the investigator.
- Assessing the safety and tolerability of pembrolizumab compared to chemotherapy.
- Comparing changes from baseline in the EORTC QLQ-C30 global health status/quality of life (GHS/QoL) score.
Participants
The clinical trial involves a total of **255 participants** diagnosed with **endometrial cancer**, specifically inoperable Stage III or IV, or recurrent endometrial carcinoma or carcinosarcoma. The study population is exclusively female, with an age range that includes adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of the disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial does not include male subjects and involves a vulnerable population. Participants may have received prior systemic therapy under certain conditions, and lifestyle factors such as pregnancy status and contraceptive use are considered. The trial requires participants to provide a tumor tissue sample for verification of dMMR status and histology. Additionally, participants with a history of Hepatitis B or C must have an undetectable viral load to be eligible for the study.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, open-label, active-comparator controlled study designed to evaluate the efficacy and safety of **pembrolizumab** compared to platinum doublet chemotherapy in participants with mismatch repair deficient (dMMR) advanced or recurrent **endometrial carcinoma**. The trial aims to assess progression-free survival (PFS) and overall survival (OS) as primary endpoints, with secondary endpoints including objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) among others. The study is expected to run from April 2022 to April 2026, with a maximum treatment period of 24 months for pembrolizumab and 18 months for chemotherapy.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis, radiographically evaluable disease, and ECOG performance status. Following randomization, participants will receive either pembrolizumab or chemotherapy, administered intravenously. Study visits will include regular follow-up assessments to monitor treatment response and adverse events, with evaluations conducted per RECIST 1.1 criteria by a blinded independent central review. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participant involvement is expected to last up to 24 months, depending on the treatment arm. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on clinical judgment. The trial is designed to ensure rigorous assessment of the investigational and comparator treatments, contributing valuable data to the understanding of therapeutic options for advanced or recurrent endometrial carcinoma.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Carboplatin** is utilized in the study as a **concentrate for solution for infusion**. It is administered intravenously with a maximum daily dose of 6 units and a total dose not exceeding 108 units over a treatment period of up to 18 weeks. The active substance, carboplatin, is of chemical origin and is not formulated for pediatric use.
**Paclitaxel** is another experimental medication used in this trial. It is also provided as a **concentrate for solution for infusion** and administered intravenously. The dosing regimen allows for a maximum daily dose of 175 mg/m², with a total dose limit of 1050 mg/m² over the same 18-week period. Paclitaxel is a chemical compound and is not intended for pediatric patients.
**Docetaxel** is included as a comparator treatment in the study. It is administered in the form of a **concentrate for solution for infusion** via intravenous route. The maximum daily dose is set at 75 mg/m², with a cumulative dose cap of 450 mg/m² over 18 weeks. Like the other chemotherapeutic agents, docetaxel is chemically derived and not suitable for pediatric use.
**Cisplatin** is another comparator treatment, provided as a **concentrate for solution for infusion** and administered intravenously. The dosing schedule permits a maximum daily dose of 75 mg/m², with a total dose not exceeding 450 mg/m² over the 18-week treatment period. Cisplatin is a chemical substance and is not formulated for pediatric patients.
**Pembrolizumab**, marketed as **Keytruda**, is the primary experimental medication in this trial. It is a **biological** agent provided as a **solution for infusion** and administered via intravenous infusion. The maximum daily dose is 400 mg, with a total dose limit of 10800 mg over a 24-week period. Pembrolizumab is a protein-based therapeutic and is not intended for pediatric use. The administration of pembrolizumab is monitored to ensure compliance with the dosing schedule.
Efficacy
The efficacy of the clinical trial will be assessed using the primary endpoints of **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. PFS will be evaluated according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and assessed by Blinded Independent Central Review (BICR). OS will also be a key measure of efficacy. Secondary endpoints include Objective Response Rate (ORR), Disease Control Rate (DCR), and Duration of Response (DOR), all assessed per RECIST 1.1 by BICR. Additional secondary endpoints involve PFS as assessed by the investigator, Progression-Free Survival 2 (PFS2), and the number of participants experiencing adverse events or discontinuing treatment due to adverse events. Patient-reported outcomes will be measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess changes in Global Health Status and Quality of Life scores.
Inclusion and Exclusion Criteria
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: a. 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. b. 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. c. c. 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 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Apr 2022 | 4 |
 Czechia | Not Recruiting | 01 Apr 2022 | 20 |
 Denmark | Not Recruiting | 01 Apr 2022 | 10 |
 Finland | Not Recruiting | 01 Apr 2022 | 6 |
 Germany | Not Recruiting | 01 Apr 2022 | 6 |
 Hungary | Not Recruiting | 01 Apr 2022 | 3 |
 Ireland | Not Recruiting | 01 Apr 2022 | 6 |
 Italy | Not Recruiting | 01 Apr 2022 | 34 |
 The Netherlands | Not Recruiting | 01 Apr 2022 | — |
 Norway | Not Recruiting | 01 Apr 2022 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 400 | 24 | PRD4323105 |
PACLITAXEL | Comparator | — | INTRAVENOUS | 175 | 18 | SUB09583MIG |
CISPLATIN | Comparator | — | INTRAVENOUS | 75 | 18 | SUB07483MIG |
CARBOPLATIN | Comparator | — | INTRAVENOUS | 6 | 18 | SUB06614MIG |
DOCETAXEL | Comparator | — | INTRAVENOUS | 75 | 18 | SUB12492MIG |