Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) Versus Chemotherapy for Endometrial Carcinoma (ENGOT-en9 / MK-7902-001)

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of pembrolizumab + lenvatinib to chemotherapy in female participants with Stage III, IV, or recurrent endometrial carcinoma. It is hypothesized that the combination of pembrolizumab + lenvatinib will be superior to chemotherapy for progression-free survival (PFS) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR). It is also hypothesized that the combination of pembrolizumab + lenvatinib will be superior to chemotherapy for overall survival (OS).

Official Title
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A Phase 3 Randomized, Open-Label, Study of Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) Versus Chemotherapy for First-line Treatment of Advanced or Recurrent Endometrial Carcinoma (LEAP-001)

Conditions
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Endometrial Neoplasms

Intervention / Treatment
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* Drug: Lenvatinib
* Biological: Pembrolizumab
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenvatinib + Pembrolizumab<br>Participants receive lenvatinib daily and pembrolizumab once at the start of each 3-week treatment cycle. | Drug: Lenvatinib<br>* Lenvatinib 4 mg or 10 mg capsules at a total daily dose of 20 mg taken by mouth once per day.<br>* Other names: E7080, MK-7902, LENVIMA®;Biological: Pembrolizumab<br>* Pembrolizumab 200 mg IV infusion given on Day 1 of each cycle.<br>* Other names: MK-3475, KEYTRUDA®;|
| Active Comparator: Paclitaxel + Carboplatin<br>Participants receive paclitaxel and carboplatin once at the start of each 3-week treatment cycle. | Drug: Paclitaxel<br>* Paclitaxel 175 mg/m^2 IV infusion given on Day 1 of each cycle.<br>* Other names: TAXOL®, ONXAL®;Drug: Carboplatin<br>* Carboplatin 10 mg/mL IV infusion at a total dose of are-under-the-curve (AUC) 6 (per Calvert's formula) given on Day 1 of each cycle.<br>* Other names: PARAPLATIN®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR) | Progression-free survival based on RECIST 1.1 as assessed by BICR. Progression-free survival is measured from the time of randomization to the first documented disease progression or death due to any cause, whichever occurs first. | Up to approximately 31 months | 
| Overall Survival (OS) | Overall survival is measured from the time of randomization up to death due to any cause. | Up to approximately 45 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR ) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent review (BICR) | The ORR (either confirmed complete response [CR] or partial response [PR]) based on RECIST 1.1 and assessed by BICR will be determined in mismatch repair proficient (pMMR) participants and in all-comer participants who have measurable disease at study entry. | Up to approximately 31 months | 
| Mean change from baseline in the global health status/quality of life 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 | The EORTC QLQ-C30 was developed to assess the quality of life of patients with cancer. It contains 30 questions (items), 24 of which aggregate into nine multi-item scales representing various aspects, or dimensions, of quality of life (QoL): one global scale, five functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea, pain), and six additional single-symptom items assessing additional symptoms commonly reported by cancer patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease. Individual items are scored on a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Raw scores for each scale are standardized into a range of 0 to 100 by linear transformation; a higher score on the global and functional scales represents a higher (better) level of functioning, and a higher score on the symptom scale represents a higher (worse) level of symptoms. | Baseline and designated time points up to 27 months | 
| Percentage of participants experiencing an 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. | Up to approximately 27 months (through 90 days after the last dose of study treatment) | 
| Percentage of participants experiencing a serious adverse event (SAE) | An SAE is an AE that results in death, is life-threatening, requires or prolongs hospitalization, results in persistent or significant disability, is a congenital birth defect, or is another important medical event. | Up to approximately 28 months (through 120 days after the last dose of study treatment) | 
| Percentage of participants experiencing an immune-related AE (irAE) | Immune-related AEs will be monitored in both arms. | Up to approximately 27 months (through 90 days after the last dose of study treatment) | 
| Percentage of participants discontinuing from study treatment due to an AE(s) | Discontinuations related to AEs will be monitored in both arms. | Up to approximately 24 months (through the last dose of study treatment) |