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Phase III

A Randomized, Phase 3, Double-Blind Study of Chemoradiotherapy With or Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer (KEYNOTE-A18 / ENGOT-cx11)

  • Study HIC#:2000028332
  • Last Updated:07/15/2021

The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus concurrent chemoradiotherapy compared to placebo plus concurrent chemoradiotherapy in participants with locally advanced cervical cancer.

The primary hypotheses are that pembrolizumab plus concurrent chemoradiotherapy is superior to placebo plus concurrent chemoradiotherapy with respect to progression-free survival and overall survival.

Once the study objectives have been met or the study has ended, participants will be discontinued from this study and will be enrolled in an extension study to continue protocol-defined assessments and treatment.

  • Start Date12/03/2020
  • End Date02/07/2024

Trial Purpose and Description

Primary Outcome Measures  :

  1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 38 months ]PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, or by histopathologic confirmation of disease progression, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. Unequivocal progression of non-target lesions is also considered PD.
  2. Overall Survival (OS) [ Time Frame: Up to approximately 46 months ]OS is the time from randomization to death due to any cause.

Eligibility Criteria

Inclusion Criteria:

  • Has high-risk locally advanced cervical cancer (LACC): The International Federation of Gynecology and Obstetrics (FIGO) 2014 Stage IB2-IIB (with node-positive disease) or FIGO 2014 Stages III-IVA
  • Has histologically-confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix
  • Has not previously received any definitive surgical, radiation, or systemic therapy for cervical cancer and is immunotherapy-naïve
  • Female participants must not be pregnant or breastfeeding, and agree to use highly effective contraception during the treatment period and for at least 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to the first dose of study treatment
  • Has provided a tissue sample from a core or excisional biopsy of a tumor lesion
  • Has radiographically evaluable disease, either measurable or non-measurable per RECIST 1.1, as assessed by the local site investigator/radiology
  • Has adequate organ within 7 days prior to the start of study treatment

Exclusion Criteria:

  • Has excluded subtypes of LACC
  • Has FIGO 2014 Stage IVB disease
  • Has undergone a previous hysterectomy defined as removal of the entire uterus or will have a hysterectomy as part of their initial cervical cancer therapy
  • Has bilateral hydronephrosis, unless at least one side has been stented or resolved by positioning of nephrostomy
  • Has anatomy or tumor geometry or any other reason or contraindication that cannot be treated with intracavitary brachytherapy or a combination of intracavitary and interstitial brachytherapy
  • Has received a live vaccine within 30 days prior to the first dose of study treatment
  • Has received treatment with systemic immunostimulatory agents such as bacterial or viral vaccines, colony stimulating factors, interferons, interleukins and vaccine combinations within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
  • Has received prior therapy with an anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137)
  • Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization
  • 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
  • Has any contraindication to the use of cisplatin.
  • 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 the first dose of study treatment
  • Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
  • Has severe hypersensitivity to pembrolizumab and/or any of its excipients
  • Has an active autoimmune disease that has required systemic treatment in past 2 years
  • 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 a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results, and in the judgment of the investigator or Sponsor, would make the participant inappropriate for entry into this study
  • Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
  • Is pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy
  • Has had an allogenic tissue/solid organ transplant