Efficacy and Safety Study of First-line Treatment With Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy in Women With Persistent, Recurrent, or Metastatic Cervical Cancer (MK-3475-826/KEYNOTE-826)
Condition: Cervical Cancer
MeSH terms: Uterine Cervical Neoplasms
Intervention: Pembrolizumab; Paclitaxel; Cisplatin; Carboplatin; Bevacizumab; Placebo to pembrolizumab
Intervention description: IV infusion; IV infusion; IV infusion; IV infusion; IV infusion; IV infusion
Intervention MeSH terms: Paclitaxel; Bevacizumab; Carboplatin; Pembrolizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 617.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)

Summary:

      The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475)
      plus one of four platinum-based chemotherapy regimens compared to the efficacy and safety of
      placebo plus one of four platinum-based chemotherapy regimens in the treatment of adult women
      with persistent, recurrent, or metastatic cervical cancer. Possible chemotherapy regimens
      include: paclitaxel plus cisplatin with or without bevacizumab and paclitaxel plus
      carboplatin with or without bevacizumab.

      The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy is
      superior to placebo plus chemotherapy with respect to: 1) Progression-free Survival (PFS) per
      Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by the Investigator,
      or, 2) Overall Survival (OS).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous
             carcinoma, or adenocarcinoma of the cervix which has not been treated with systemic
             chemotherapy and is not amenable to curative treatment (such as with surgery and/or
             radiation). Prior chemotherapy utilized as a radiosensitizing agent and completed at
             least 2 weeks prior to randomization with resolution of all treatment-related
             toxicities is allowed. AEs due to previous treatments should be resolved to ≤ Grade 1
             or baseline. Participants with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are
             eligible.

          -  Not pregnant or breastfeeding, and at least one of the following conditions applies:
             a.) Not a woman of childbearing potential (WOCBP), b.) A WOCBP must agree to use
             effective contraception during the treatment period and for at least 120 days after
             the last dose of pembrolizumab/placebo and 210 days after the last dose of
             chemotherapy/bevacizumab

          -  Has measurable disease per RECIST 1.1 as assessed by the local site
             investigator/radiology

          -  Has provided archival tumor tissue sample or newly obtained core or excisional biopsy
             of a tumor lesion not previously irradiated for prospective determination of
             Programmed Cell Death-Ligand 1 (PD-L1) status prior to randomization

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within
             14 days prior to randomization

          -  Has adequate organ function

        Exclusion Criteria:

          -  A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Participants with known brain metastases may participate provided that the
             brain metastases have been previously treated (except with chemotherapy) and are
             radiographically stable.

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, transitional cell carcinoma of urothelial cancer,
             or carcinoma in situ (e.g. breast cancer) that have undergone potentially curative
             therapy are not excluded.

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in doses 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 that has required systemic treatment in past 2 years
             (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency) is not considered a form
             of systemic treatment and is allowed

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a known history of human immunodeficiency virus (HIV) infection

          -  Has a known history of Hepatitis B or known active Hepatitis C virus infection

          -  Has a known history of active tuberculosis (TB; Bacillus tuberculosis)

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.
             cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137)

          -  Has received prior systemic chemotherapy for treatment of cervical cancer.

          -  Has not recovered adequately from toxicity and/or complications from major surgery
             prior to randomization

          -  Has received prior radiotherapy within 2 weeks prior to randomization. Participants
             must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis.

          -  Has received a live vaccine within 30 days prior to randomization

          -  Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

          -  Has a contraindication or hypersensitivity to any component of cisplatin, carboplatin,
             paclitaxel, or bevacizumab

          -  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

          -  Is pregnant or breastfeeding or expecting to conceive within the projected duration of
             the study, starting with the screening visit through 120 days following last dose of
             pembrolizumab/placebo and 210 days following last dose of chemotherapy/bevacizumab

          -  Has had an allogeneic tissue/solid organ transplant