Lenvatinib in Combination With Pembrolizumab Versus Treatment of Physician's Choice in Participants With Advanced Endometrial Cancer (MK-3475-775/E7080-G000-309 Per Merck Standard Convention [KEYNOTE-775])

Study Overview
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Brief Summary
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This is a study of pembrolizumab (MK-3475, KEYTRUDA®) in combination with lenvatinib (E7080) versus treatment of physician's choice (doxorubicin or paclitaxel) for the treatment of advanced endometrial cancer. Participants will be randomly assigned to receive either pembrolizumab and lenvatinib or treatment of physician's choice. The primary study hypothesis is that pembrolizumab in combination with lenvatinib prolongs progression free survival (PFS) and overall survival (OS) when compared to treatment of physician's choice.

Official Title
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A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination With Pembrolizumab Versus Treatment of Physician's Choice in Participants With Advanced Endometrial Cancer

Conditions
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Endometrial Neoplasms

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Lenvatinib
* Drug: Paclitaxel
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically confirmed diagnosis of endometrial carcinoma (EC) Documented evidence of advanced, recurrent or metastatic EC. Has radiographic evidence of disease progression after 1 prior systemic, platinum-based chemotherapy regimen for EC. Participants may have received up to 1 additional line of platinum-based chemotherapy if given in the neoadjuvant or adjuvant treatment setting. Note: There is no restriction regarding prior hormonal therapy. Has historical or fresh tumor biopsy specimen for determination of mismatch repair (MMR) status. Has at least 1 measurable target lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and confirmed by Blinded Independent Central Review BICR. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days of starting study treatment. Is not pregnant, breastfeeding, and agrees to use a highly effective method of contraception during the treatment period and for at least 120 days (for participants treated with lenvatinib plus pembrolizumab) or at least 180 days (for participants treated with treatment of physician's choice [TPC]) after the last dose of study treatment. Exclusion Criteria: Has carcinosarcoma (malignant mixed mullerian tumor), endometrial leiomyosarcoma and endometrial stromal sarcomas. Has unstable central nervous system (CNS) metastases. Has active malignancy (except for endometrial cancer, definitively treated in-situ carcinomas [e.g. breast, cervix, bladder], or basal or squamous cell carcinoma of the skin) within 24 months of study start. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib. Has a pre-existing greater than or equal (>=) Grade 3 gastrointestinal or non-gastrointestinal fistula. Has radiographic evidence of major blood vessel invasion/infiltration. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study treatment. Has a history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability within 12 months of the first dose of study treatment. Has an active infection requiring systemic treatment. Has not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy. Is positive for Human Immunodeficiency Virus (HIV). Has active Hepatitis B or C. Has a history of (non-infectious) pneumonitis that required treatment with steroids, or has current pneumonitis. Has known psychiatric or substance abuse disorders 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 study start -Has an active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years. Is pregnant or breastfeeding. Has had an allogenic tissue/solid organ transplant. Has received >1 prior systemic chemotherapy regimen (other than adjuvant or neoadjuvant) for Endometrial Cancer. Participants may receive up to 2 regimens of platinum-based chemotherapy in total, as long as one is given in the neoadjuvant or adjuvant treatment setting. Has received prior anticancer treatment within 28 days of study start. All acute toxicities related to prior treatments must be resolved to Grade ≤1, except for alopecia and Grade ≤2 peripheral neuropathy. Has received prior treatment with any treatment targeting VEGF-directed angiogenesis, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has received prior treatment with an agent directed to a stimulatory or co-inhibitory T-cell receptor other than an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, and who has discontinued from that treatment due to a Grade 3 or higher immune-related adverse event. Has received prior radiation therapy within 21 days of study start with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks of study start. Participants must have recovered from all radiation-related toxicities and/or complications prior to randomization. Has received a live vaccine within 30 days of study start. Has a known intolerance to study treatment (or any of the excipients). Prior enrollment on a clinical study evaluating pembrolizumab and lenvatinib for endometrial carcinoma, regardless of treatment received. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of study start. Participants with urine protein ≥1 gram (g)/24 hour. Prolongation of corrected QT (QTc) interval to >480 milliseconds (ms). Left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).

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 20 mg + Pembrolizumab 200 mg<br>Participants will receive pembrolizumab 200 milligram (mg) administered by intravenous (IV) infusion on Day 1 of each 21-day cycle plus lenvatinib 20 mg administered orally (PO) once daily (QD) during each 21-day cycle for up to 35 cycles. | Drug: Pembrolizumab<br>* 200 mg administered by IV infusion on Day 1 of each 21-day cycle.<br>* Other names: MK-3475;Drug: Lenvatinib<br>* 20 mg administered orally (PO) QD during each 21-day cycle.<br>* Other names: LENVIMA®;|
| Active Comparator: Treatment of Physician's Choice<br>Participants will receive either of the following treatments: doxorubicin 60 milligram per square meter (mg/m^2) administered by IV on Day 1 of each 21-day cycle for up to a maximum cumulative dose of 500 mg/m^2 OR paclitaxel 80 mg/m^2 administered by IV on a 28-day cycle: 3 weeks receiving paclitaxel once a week and 1 week not receiving paclitaxel. | Drug: Paclitaxel<br>* 80 mg/m^2 administered by IV on a 28-day cycle: 3 weeks receiving paclitaxel once a week and 1 week not receiving paclitaxel.<br>* Other names: TAXOL®;Drug: Doxorubicin<br>* 60 mg/m^2 administered by IV on Day 1 of each 21-day cycle.<br>* Other names: ADRIAMYCIN®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from the date of randomization to the date of the first documentation of disease progression, as determined by Blinded Independent Central Review (BICR) per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method. | From the date of randomization to the date of the first documentation of disease progression or death, whichever occurred first or up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months) | 
| Overall Survival (OS) | OS was defined as the time from the date of randomization to the date of death due to any cause. Participants who were lost to follow-up and those who were alive at the date of data cut-off were censored at the date the participant was last known alive, or date of data cut-off, whichever occurred first. | From the date of randomization until the date of death from any cause or up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants who had best overall response of either complete response (CR) or partial response (PR) as determined by BICR per RECIST 1.1. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From date of randomization up to first documentation of PD or date of death, whichever occurred first up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months) | 
| Health-Related Quality of Life (HRQoL) Assessed by European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQC30) Score | EORTC QLQ-C30 was a questionnaire which included 30 questions that rates the overall quality of life in cancer participants. The first 28 questions use a 4-point scale (1=not at all to 4=very much) for evaluating function (physical, role, social, cognitive, emotional), symptoms (diarrhea, fatigue, dyspnea, appetite loss, insomnia, nausea/vomiting, constipation, and pain) and financial difficulties. The last 2 questions use a 7-point scale (1=very poor to 7=excellent) to evaluate overall health and quality of life. Scores are transformed to a range of 0 to 100 using a standard EORTC algorithm. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/quality of life (QoL) represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problem. Data for this outcome measure will be reported after study completion (anticipated study completion date is November 2023). | At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length of either 21 or 28 days), and at the post-treatment visit (up to 5 years and 5 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs) | TEAEs was defined as AEs that occurred (or worsened, if present at Baseline) after the first dose of study drug through 28 days after the last dose of study drug. AE was defined as any untoward medical occurrence in a participants or clinical study participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. A SAE was defined as any untoward medical occurrence at any dose if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. irAE was defined as any unfavorable and unintended immune-related sign, symptom, or disease (new or worsening) temporally associated with the use of study therapy, regardless of whether or not a causal relationship with the study therapy can be determined. | From the first dose of study drug up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months) | 
| Percentage of Participants Discontinued Study Treatment Due to TEAEs | TEAEs was defined as those AEs that occurred (or worsened, if present at Baseline) after the first dose of study drug through 30 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a participants or clinical study participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. | From the first dose of study drug up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months) | 
| Time to Treatment Failure Due to Toxicity | Time to treatment failure due to toxicity was defined as the time from the date of randomization to the date a participant discontinued study treatment due to TEAEs. Data for this outcome measure will be reported after study completion (anticipated study completion date is November 2023). | From the date of randomization to the date of discontinuation of study treatment due to TEAEs (up to 5 years 5 months) | 
| Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib | Sparse pharmacokinetic (PK) samples were collected and analyzed using a population PK approach to estimate PK parameters. Individual predicted CL/F for lenvatinib was then derived from the PK model. The data was collected and analyzed for lenvatinib plus pembrolizumab arm only. | Cycle 1 Day 1: 0.5-10 hours post-dose; Cycle 1 Day 15: 0-12 hours post-dose; Cycle 2 Day 1: 0.5-10 hours post-dose (each cycle length=21 days) | 
| Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib | Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Individual predicted AUC for lenvatinib was then derived from the PK model. The data was collected and analyzed for lenvatinib plus pembrolizumab arm only. | Cycle 1 Day 1: 0.5-10 hours post-dose; Cycle 1 Day 15: 0-12 hours post-dose; Cycle 2 Day 1: 0.5-10 hours post-dose (each cycle length=21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1), programmed cell death ligand 2 (PD-L2, PDL2), vascular endothelial growth factor (VEGF) receptors, lenvatinib, pembrolizumab, doxorubicin, paclitaxel, phase 3 endometrial cancer