Phase 3 Randomized Study of Pembrolizumab and Lenvatinib Versus Chemotherapy in Advanced or Recurrent Endometrial Carcinoma
- Trial ID
- 2023-505614-17-00
- Protocol
- MK-7902-001
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3 study is to compare **progression-free survival** (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, for the combination of **pembrolizumab** (MK-3475) plus **lenvatinib** (MK-7902) versus chemotherapy in participants with advanced or recurrent **endometrial carcinoma**. Additionally, the study aims to compare **overall survival** (OS) for the combination of pembrolizumab plus lenvatinib versus chemotherapy. These objectives are clinically relevant as they assess the efficacy of the combination therapy in extending survival and delaying disease progression compared to standard chemotherapy.
Secondary objectives include: - Comparing the **objective response rate** (ORR) per RECIST 1.1 by BICR in mismatch repair proficient (pMMR) participants and in all-comer participants who have measurable disease at study entry. - Evaluating the impact of treatment on **Health-Related Quality-of-Life** (HRQoL) as assessed by using the global score of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ C30) in pMMR and in all-comer participants. - Comparing the **safety and tolerability** of pembrolizumab plus lenvatinib versus chemotherapy in all-comer participants.
Participants
The clinical trial involves a total of **768 participants** diagnosed with advanced or recurrent **endometrial carcinoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as having Stage III, Stage IV, or recurrent, histologically-confirmed endometrial carcinoma, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial also considers lifestyle factors, requiring participants to have adequately controlled blood pressure and adequate organ function. The study population includes vulnerable groups, and participants may have received prior treatments such as chemotherapy, radiation, or hormonal therapy, provided certain conditions are met. The trial does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy and safety of **pembrolizumab** in combination with **lenvatinib** compared to standard chemotherapy for the first-line treatment of advanced or recurrent **endometrial carcinoma**. The trial aims to assess progression-free survival and overall survival as primary endpoints, with secondary endpoints including objective response rate, changes in health-related quality of life, and the incidence of adverse events. The study is expected to run from April 2019 to April 2025, with participant involvement lasting up to 156 weeks, depending on the treatment arm and individual response.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as histologically-confirmed endometrial carcinoma and adequate organ function. Following randomization, participants will receive either the investigational combination therapy or chemotherapy. Study visits will include regular assessments to monitor disease progression, treatment response, and safety. Follow-up visits will occur at specified intervals to evaluate long-term outcomes and adverse events. The end-of-study visit will conclude the participant's involvement, with final assessments conducted to gather comprehensive data on the trial's endpoints.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial's design ensures that all participants receive appropriate care and monitoring throughout their involvement, with the primary objective of determining the comparative efficacy of the investigational therapy against standard chemotherapy in this patient population.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed as KEYTRUDA, which is a **concentrate for solution for infusion**. This biological product is administered via **intravenous infusion**. The dosage is set at a maximum of 200 mg per day, with a total maximum dose of 10,400 mg over a treatment period of up to 156 weeks. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02, and is produced by Merck Sharp & Dohme BV.
**Lenvatinib** is another experimental medication used in this trial, available in **capsule** form. It is administered **orally** with a maximum daily dose of 20 mg and a total maximum dose of 20,440 mg over a 156-week period. Lenvatinib is a chemical compound and is also produced by Merck & Co. Inc. It is identified by the sponsor product code MK-7902.
The trial also includes the use of **carboplatin**, a chemical compound administered as a **PHF00230MIG** form via **intravenous infusion**. The maximum daily dose is 6 units, with a total maximum dose of 84 units over a 42-week treatment period. Carboplatin is classified under the ATC code L01XA02.
**Paclitaxel** is utilized in the trial as a comparator treatment. It is administered in a **PHF00016MIG** form through **intravenous infusion**. The maximum daily dose is 175 mg/m², with a total maximum dose of 2,450 mg/m² over a 42-week period. Paclitaxel is a chemical compound, classified under the ATC code L01CD01, and is known by synonyms such as ONCOGEL and ABI-007.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of the combination of pembrolizumab and lenvatinib against standard chemotherapy treatments in patients with advanced or recurrent endometrial carcinoma.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. PFS will be evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), as assessed by a blinded independent central review (BICR). This assessment will be modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. OS will be compared for the combination of pembrolizumab plus lenvatinib versus chemotherapy.
Secondary endpoints will include the Objective Response Rate (ORR), which encompasses either confirmed complete response (CR) or partial response (PR) based on RECIST 1.1, as assessed by BICR in mismatch repair proficient (pMMR) participants and in all-comer participants with measurable disease at study entry. Additionally, changes from baseline in Health-Related Quality-of-Life (HRQoL) global scores will be measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ C30) in both pMMR and all-comer participants.
Further secondary endpoints will assess the safety profile, including the percentage of participants experiencing adverse events (AEs), serious adverse events (SAEs), immune-related adverse events (irAEs), and the percentage of participants discontinuing from study treatment due to AEs. These efficacy and safety parameters will be collected and analyzed throughout the trial duration, with specific timepoints and methods for data collection aligned with the trial protocol.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Has Stage III, Stage IV, or recurrent, histologically-confirmed endometrial carcinoma with disease that is either measurable or nonmeasurable but radiographically apparent, per RECIST 1.1 as assessed by BICR (note: may have received prior chemotherapy only if administered concurrently with radiation; may have received prior radiation without concurrent chemotherapy; may have received prior hormonal therapy for treatment of endometrial carcinoma, provided that it was discontinued ≥1 week prior to randomization; and may have received 1 prior line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy)
- Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion that was not previously irradiated, for determination of mismatch repair (MMR) status
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to the first dose of study intervention
- Is not pregnant or breastfeeding, and is either not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees to use contraception during the study and for ≥120 days after pembrolizumab, ≥30 days after lenvatinib, or ≥180 days after (chemotherapy) [if a WOCBP, a pregnancy test will be required within 24 hours of first dose of study drug]
- Has adequately controlled blood pressure within 7 days prior to randomization
- Has adequate organ function based on assessment within 7 days prior to the first dose of study intervention
Exclusion Criteria
- Has carcinosarcoma (malignant mixed Műllerian tumor), endometrial leiomyosarcoma or other high grade sarcomas, or endometrial stromal sarcomas
- Has a central nervous system (CNS) metastasis, unless local therapy (e.g., whole brain radiation therapy, surgery, or radiosurgery) has been completed and have discontinued use of corticosteroids for this indication for ≥4 weeks prior to starting study medication (major surgery within 3 weeks of the first dose of study drug will be exclusionary)
- Has a known additional malignancy (other than endometrial carcinoma) that is progressing or has required active treatment in the last 3 years
- Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
- Has a pre-existing Grade ≥3 gastrointestinal or nongastrointestinal fistula
- Has radiographic evidence of major blood vessel invasion/infiltration
- Has active hemoptysis (bright red blood at ≥0.5 teaspoon) within 3 weeks prior to the first dose of study intervention or tumor bleeding within 2 weeks prior to randomization
- Has clinically significant cardiovascular disease within 12 months from first dose of study intervention including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction or cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
- Has any infection requiring systemic treatment
- Has not recovered adequately from any toxicity and/or complications from major surgery prior to randomization
- Has a known history of human immunodeficiency virus (HIV) infection (HIV test is required at screening)
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV) [defined as HCV ribonucleic acid (RNA) is detected] (hepatitis B and C testing is required at screening only when mandated by local health authority)
- Has a history of (noninfectious) pneumonitis that required treatment with steroids, or has current pneumonitis
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
- Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
- 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 to randomization
- Has an active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
- Has received prior systemic chemotherapy in any setting for the treatment of endometrial carcinoma (note: prior chemotherapy administered concurrently with radiation is permitted)
- Has received prior radiotherapy within 4 weeks prior to randomization (participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis - a 2-week washout is permitted for palliative radiation to non-CNS disease and vaginal brachytherapy)
- Has received prior hormonal therapy for the treatment of endometrial carcinoma within 1 week of randomization
- Has received prior therapy with any treatment targeting vascular endothelial growth factor (VEGF)-directed angiogenesis, an anti-programmed cell death (PD)-1, anti-PD ligand (L)1, or anti-PD L2 agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137)
- Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention
- Has known intolerance to study intervention (or any of the excipients)
- Has had an allogenic tissue/solid organ transplant
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 12 Apr 2019 | 10 |
 Belgium | Not Recruiting | 12 Apr 2019 | 9 |
 Germany | Not Recruiting | 12 Apr 2019 | 9 |
 Ireland | Not Recruiting | 12 Apr 2019 | 4 |
 Italy | Not Recruiting | 12 Apr 2019 | 37 |
 Poland | Not Recruiting | 12 Apr 2019 | 47 |
 Spain | Not Recruiting | 12 Apr 2019 | 27 |
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 | 200 | 156 | PRD4323105 |
Lenvatinib | Test | CAPSULE | ORAL | 20 | 156 | PRD9414231 |
CARBOPLATIN | Comparator | PHF00230MIG | INTRAVENOUS INFUSION | 6 | 42 | SCP28192792 |
PACLITAXEL | Comparator | PHF00016MIG | INTRAVENOUS INFUSION | 175 | 42 | SCP247399 |
Lenvatinib | Test | CAPSULE | ORAL | 20 | 156 | PRD9414230 |