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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
827
200 mg administered by IV infusion on Day 1 of each 21-day cycle.
20 mg administered orally (PO) QD during each 21-day cycle.
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.
60 mg/m\^2 administered by IV on Day 1 of each 21-day cycle.
Arizona Oncology Associates, PC- HAL
Phoenix, Arizona, United States
University of California San Francisco
San Francisco, California, United States
University of California Los Angeles
Santa Monica, California, United States
Smilow Cancer Hospital at Yale New Haven
New Haven, Connecticut, United States
University of Miami Health System
Miami, Florida, United States
Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on Blinded Independent Central Review (BICR) in Mismatch Repair Proficient (pMMR) Participants
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.
Time frame: Up to approximately 27 months
PFS Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on BICR in All-comer Participants
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.
Time frame: Up to approximately 27 months
Overall Survival (OS) in pMMR Participants
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.
Time frame: Up to approximately 43 months
OS in All-comer Participants
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.
Time frame: Up to approximately 43 months
Objective Response Rate (ORR) in pMMR Participants
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.
Time frame: Up to approximately 80 months
ORR in All-comer Participants
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.
Time frame: Up to approximately 80 months
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) in pMMR Participants
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.
Time frame: Baseline, Week 12
Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) in All-comer Participants
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Florida Hospital Cancer Institute
Orlando, Florida, United States
Georgia Cancer Center at Augusta University
Augusta, Georgia, United States
North Shore University Health System
Evanston, Illinois, United States
University Medical Center New Orleans
New Orleans, Louisiana, United States
Greater Baltimore Medical Center
Baltimore, Maryland, United States
...and 159 more locations
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.
Time frame: Baseline, Week 12
Number of Partricipants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Immune-Related Adverse Events (irAEs)
TEAEs were AEs that occurred (or worsened, if present at baseline) after the first dose of study drug through 28 days after the last dose. An AE was any untoward medical occurrence in a participant temporally associated with use of study treatment, whether or not related to the treatment. An SAE was any untoward medical occurrence at any dose that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, or was a congenital anomaly/birth defect. An irAE was any unfavorable and unintended immune-related sign, symptom, or disease (new or worsening) temporally associated with study therapy, regardless of whether a causal relationship with the therapy could be determined.
Time frame: Up to approximately 77 months
Number of Participants Who Discontinued Study Treatment Due to a TEAE in pMMR Participants
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.
Time frame: Up to approximately 77 months
Number of Participants Who Discontinued Study Treatment Due to a TEAE in All-comer Participants
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.
Time frame: Up to approximately 77 months
Time to Treatment Failure Due to Toxicity in pMMR Participants
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.
Time frame: Up to approximately 77 months
Time to Treatment Failure Due to Toxicity in All-comer Participants
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.
Time frame: Up to approximately 77 months
Plasma Concentration of Lenvatinib Versus Time in All-comer Participants
Pharmacokinetic (PK) samples were collected and analyzed using a population PK approach to estimate PK parameters. Individual predicted plasma concentration of lenvatinib was then derived from the PK model.
Time frame: Cycle 1 day 1 0.5-4 hours (h), 6-10 postdose; Cycle 1 day 15 predose; Cycle 1 day 15 2-12h postdose, Cycle 2 day 1 predose, 0.5-4h, 6-10 h (Each cycle is 21 days)
Plasma Concentration of Lenvatinib Versus Time in pMMR Participants
PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Individual predicted plasma concentration of lenvatinib was then derived from the PK model.
Time frame: Cycle 1 day 1 0.5-4 hour (h), 6-10 postdose; Cycle 1 day 15 predose; Cycle 1 day 15 2-12h postdose, Cycle 2 day 1 predose, 0.5-4h, 6-10 h (Each cycle is 21 days)
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.
Time frame: 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.
Time frame: 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)