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])

• ClinicalTrials.gov Identifier: NCT03517449
• Recruitment Status: Active, not recruiting
• First Posted: May 7, 2018
• Results First Posted: November 17, 2021
• Last Update Posted: October 18, 2023
• Sponsor: Eisai Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Eisai Inc.

Tracking Information

• First Submitted Date: April 25, 2018
• First Posted Date: May 7, 2018
• Results First Submitted Date: October 19, 2021
• Results First Posted Date: November 17, 2021
• Last Update Posted Date: October 18, 2023
• Actual Study Start Date: June 11, 2018
• Actual Primary Completion Date: October 26, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2021)

• Progression-free Survival (PFS) [ Time Frame: 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) ]
  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.
• Overall Survival (OS) [ Time Frame: 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) ]
  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.

Original Primary Outcome Measures (submitted: April 25, 2018)

• Progression Free Survival (PFS) [ Time Frame: Up to approximately 24 months ]
  PFS is defined as the time from randomization to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as determined by Blinded Independent Central Review (BICR) or death due to any cause, whichever occurred first.
• Overall Survival (OS) [ Time Frame: Up to approximately 27 months ]
  OS is defined as the time from date of randomization to date of death from any cause.

Current Secondary Outcome Measures (submitted: October 19, 2021)

• Objective Response Rate (ORR) [ Time Frame: 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) ]
  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.
• 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 [ Time Frame: 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) ]
  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).
• Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Immune-Related Adverse Events (irAEs) [ Time Frame: From the first dose of study drug up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months) ]
  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.
• Percentage of Participants Discontinued Study Treatment Due to TEAEs [ Time Frame: From the first dose of study drug up to data cutoff date 26 October 2020 (up to approximately 2 years 5 months) ]
  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 to Treatment Failure Due to Toxicity [ Time Frame: From the date of randomization to the date of discontinuation of study treatment due to TEAEs (up to 5 years 5 months) ]
  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).
• Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib [ 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) ]
  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.
• Model Predicted Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib [ 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) ]
  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.

Original Secondary Outcome Measures (submitted: April 25, 2018)

• Objective Response Rate (ORR) [ Time Frame: Up to approximately 24 months ]
  ORR is defined as the percentage of participants who have best overall response of either complete response (CR) or partial response (PR), as determined by BICR per RECIST 1.1.
• Health-Related Quality of Life (HRQoL) Score Using the European Organization for Research and Treatment (EORTC) Quality of Life (QoL) Questionnaire (QLQ-C30) Version 3.0 [ Time Frame: Baseline (prior to first dose of study treatment in Cycle 1) and at the end of follow-up (up to approximately 27 months) ]
  Change from baseline in HRQoL using the global score of EORTC QLQ-C30 will be determined. EORTC QLQ-C30 is a cancerspecific health-related quality-oflife (QoL) questionnaire, which contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and QoL scale. The score for each item and the overall score ranges from 0 to 100. A high overall scale and subscale scores represent improved health status. However, in case of individual symptoms, higher scores suggest increased perception of these symptoms.
• Number of Participants With Adverse Events (AE) [ Time Frame: Up to approximately 27 months ]
  The number of participants experiencing an AE will be assessed. An AE is defined as any unfavorable and unintended 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.
• Number of Participants With Serious Adverse Events (SAE) [ Time Frame: Up to approximately 27 months ]
  The number of participants experiencing an SAE will be assessed. A SAE is an AE that results in death, is life threatening, results in persistent or significant disability/incapacity, results in or prolongs an existing inpatient hospitalization, is a congenital anomaly/birth defect, is a cancer, is associated with an overdose, or is another important medical event.
• Number of Participants With Immune-related Adverse Events (irAE) [ Time Frame: Up to approximately 27 months ]
  The number of participants experiencing an irAE will be assessed. An irAE is 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.
• Number of Participants With Treatment Discontinuations Due to AEs [ Time Frame: Up to approximately 27 months ]
  The number of participants who discontinue study treatment due to an AE will be assessed.
• Time to Treatment Failure (TTF) Due to Treatment Emergent AEs [ Time Frame: Up to approximately 27 months ]
  Time to treatment failure due to toxicity, defined as the time from the date of randomization to the date that a participant discontinues study treatment due to AEs.
• Area Under the Concentration time Curve of Lenvatinib From Time 0 to Infinity (AUC 0-∞) [ Time Frame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycle 2 Day 1: predose and 0.5 - 4 hours and 6-10 hours postdose ]
• Apparent Total Body Clearance (Cl/F) of Lenvatinib [ Time Frame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycle 2 Day 1: predose and 0.5 - 4 hours and 6-10 hours postdose ]
• Apparent Total Body Volume of Distribution (Vd/F) of Lenvatinib [ Time Frame: Cycle 1 Day 1: 0.5-4 hours and 6-10 hours postdose; Cycle 1 Day 15: predose and 2-12 hours postdose; Cycle 2 Day 1: predose and 0.5 - 4 hours and 6-10 hours postdose ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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])
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Endometrial Neoplasms

Intervention

• Drug: Pembrolizumab
  200 mg administered by IV infusion on Day 1 of each 21-day cycle.
  Other Names:

  • KEYTRUDA®
  • MK-3475
• Drug: Lenvatinib
  20 mg administered orally (PO) QD during each 21-day cycle.
  Other Name: LENVIMA®
• Drug: 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.
  Other Name: TAXOL®
• Drug: Doxorubicin
  60 mg/m^2 administered by IV on Day 1 of each 21-day cycle.
  Other Name: ADRIAMYCIN®

Study Arms

• Experimental: Lenvatinib 20 mg + Pembrolizumab 200 mg
  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.
  Interventions:

  • Drug: Pembrolizumab
  • Drug: Lenvatinib
• Active Comparator: Treatment of Physician's Choice
  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.
  Interventions:

  • Drug: Paclitaxel
  • Drug: Doxorubicin

• Publications *: Makker V, Colombo N, Casado Herraez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim YM, Guerra EM, Sanli UA, McCormack MM, Smith AD, Keefe S, Bird S, Dutta L, Orlowski RJ, Lorusso D; Study 309-KEYNOTE-775 Investigators. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448. doi: 10.1056/NEJMoa2108330. Epub 2022 Jan 19.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 2, 2020): 827
• Original Estimated Enrollment (submitted: April 25, 2018): 780
• Estimated Study Completion Date: October 7, 2024
• Actual Primary Completion Date: October 26, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Has a histologically confirmed diagnosis of endometrial carcinoma (EC)
2. Documented evidence of advanced, recurrent or metastatic EC.

3. 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.

4. Has historical or fresh tumor biopsy specimen for determination of mismatch repair (MMR) status.
5. 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.
6. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days of starting study treatment.
7. 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:

1. Has carcinosarcoma (malignant mixed mullerian tumor), endometrial leiomyosarcoma and endometrial stromal sarcomas.
2. Has unstable central nervous system (CNS) metastases.
3. 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.
4. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
5. Has a pre-existing greater than or equal (>=) Grade 3 gastrointestinal or non-gastrointestinal fistula.
6. Has radiographic evidence of major blood vessel invasion/infiltration.
7. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study treatment.
8. 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.
9. Has an active infection requiring systemic treatment.
10. Has not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
11. Is positive for Human Immunodeficiency Virus (HIV).
12. Has active Hepatitis B or C.
13. Has a history of (non-infectious) pneumonitis that required treatment with steroids, or has current pneumonitis.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
15. 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.
16. Is pregnant or breastfeeding.
17. Has had an allogenic tissue/solid organ transplant.
18. 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.
19. 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.
20. Has received prior treatment with any treatment targeting VEGF-directed angiogenesis, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
21. 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.
22. 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.
23. Has received a live vaccine within 30 days of study start.
24. Has a known intolerance to study treatment (or any of the excipients).
25. Prior enrollment on a clinical study evaluating pembrolizumab and lenvatinib for endometrial carcinoma, regardless of treatment received.
26. 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.
27. Participants with urine protein ≥1 gram (g)/24 hour.
28. Prolongation of corrected QT (QTc) interval to >480 milliseconds (ms).
29. Left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, Canada, Colombia, France, Germany, Ireland, Israel, Italy, Japan, Korea, Republic of, Mexico, New Zealand, Poland, Russian Federation, Spain, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03517449
• Other Study ID Numbers: E7080-G000-309; 2017-004387-35 ( EudraCT Number ); MK3475-775 ( Other Identifier: Merck Protocol Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eisai Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Eisai Inc.
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Eisai Inc.

• PRS Account: Eisai Inc.
• Verification Date: October 2023