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])
Condition: Endometrial Neoplasms
MeSH terms: Endometrial Neoplasms
Intervention: Pembrolizumab; Lenvatinib; Paclitaxel; Doxorubicin
Intervention description: 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.
Intervention MeSH terms: Paclitaxel; Doxorubicin; Pembrolizumab; Lenvatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 827.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: 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

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.
    

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).