Clinical Trials /

Study of Chemoradiotherapy With or Without Pembrolizumab (MK-3475) For The Treatment of Locally Advanced Cervical Cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11)

NCT04221945

Description:

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.

Related Conditions:
  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Carcinoma
  • Cervical Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study of Chemoradiotherapy With or Without Pembrolizumab (MK-3475) For The Treatment of Locally Advanced Cervical Cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-A18
  • SECONDARY ID: 2019-003152-37
  • SECONDARY ID: MK-3475-A18
  • SECONDARY ID: KEYNOTE-A18
  • SECONDARY ID: ENGOT-cx11
  • SECONDARY ID: 205189
  • NCT ID: NCT04221945

Conditions

  • Uterine Cervical Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabKEYTRUDA®, MK-3475chemoradiotherapy + pembrolizumab
Placebo for pembrolizumabchemoradiotherapy + placebo for pembrolizumab
CisplatinPlatinol®, Platinol®-AQchemoradiotherapy + pembrolizumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
chemoradiotherapy + pembrolizumabExperimentalParticipants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for 5 cycles followed by pembrolizumab 400 mg IV on Day 1 of each 6-week cycle (Q6W) for an additional 15 cycles. During the Q3W dosing period of pembrolizumab, participants receive concurrent chemoradiotherapy. The standard of care chemoradiotherapy regimen includes cisplatin 40 mg/m^2 IV once per week (QW) for 5 weeks plus 45-50 Gray units (Gy) of external beam radiotherapy (EBRT) given over 40 days followed by 25-30 Gy of brachytherapy given with the total duration of radiation treatment not to exceed 56 days.
  • Pembrolizumab
  • Cisplatin
chemoradiotherapy + placebo for pembrolizumabExperimentalParticipants receive placebo for pembrolizumab IV on Day 1 of each 3-week cycle (Q3W) for 5 cycles followed by placebo IV on Day 1 of each 6-week cycle (Q6W) for an additional 15 cycles. During the Q3W dosing period of placebo, participants receive concurrent chemoradiotherapy. The standard of care chemoradiotherapy regimen includes cisplatin 40 mg/m^2 IV once per week (QW) for 5 weeks plus 45-50 Gray units (Gy) of external beam radiotherapy (EBRT) given over 40 days followed by 25-30 Gy of brachytherapy given with the total duration of radiation treatment not to exceed 56 days.
  • Placebo for pembrolizumab
  • Cisplatin

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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. PFS data will be cumulated to a certain cut-off date and the analysis will be performed via Kaplan-Meier approach to estimate the PFS rate at Month 24 using the entire PFS data up to the cut-off date. The cut-off date is event-driven and estimated to be approximately 38 months.
Measure:Overall Survival (OS) at Month 36
Time Frame:Up to approximately 46 months
Safety Issue:
Description:OS is the time from randomization to death due to any cause. OS data will be cumulated to a certain cut-off date and the analysis will be performed via Kaplan-Meier approach to estimate the OS rate at Month 36 using the entire OS data up to the cut-off date. The cut-off date is event-driven and estimated to be approximately 46 months.
Measure:Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12
Time Frame:Up to approximately 38 months
Safety Issue:
Description:For participants who demonstrated a confirmed Complete Response (CR: Disappearance of all target and non-target lesions and also includes reduction of all nodal lesions to <10mm) per RECIST 1.1, CR rate is defined as the percentage of participants who experienced a CR. CR data will be cumulated to a certain cut-off date and the analysis will be performed to estimate the CR rate at Week 12 using the entire CR data up to the cut-off date. The cut-off date is estimated to be approximately 38 months.
Measure:Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Time Frame:Up to approximately 46 months
Safety Issue:
Description:ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target and non-target lesions and also includes reduction of all nodal lesions to <10mm) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions and includes no unequivocal progression in non-target lesions) per RECIST 1.1.
Measure:Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants
Time Frame:Up to approximately 38 months
Safety Issue:
Description: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.
Measure:Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants
Time Frame:Up to approximately 46 months
Safety Issue:
Description:OS is the time from randomization to death due to any cause.
Measure:Progression-Free Survival (PFS) After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment
Time Frame:Up to approximately 46 months
Safety Issue:
Description:PFS is defined as the time from randomization to the first documented progressive disease (PD) on next-line treatment or death due to any cause, whichever occurs first, as assessed by the investigator.
Measure:Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status Score
Time Frame:Baseline and up to approximately 46 months
Safety Issue:
Description:The EORTC QLQ-C30 is a questionnaire 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. Global scores are converted to a score of 0 to 100, with a higher score indicating improved health status. The change from baseline in EORTC QLQ-C30 score will be presented.
Measure:Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score
Time Frame:Baseline and up to approximately 46 months
Safety Issue:
Description:The EORTC QLQ-C30 is a questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=not at all to 4=very much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better quality of life. The change from baseline in physical function (EORTC QLQ-C30 Items 1-5) score will be presented.
Measure:Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Symptom Specific Scale for Cervical Cancer (EORTC QLQ-CX24) Score
Time Frame:Baseline and up to approximately 46 months
Safety Issue:
Description:The EORTC QLQ-CX24 is a questionnaire that rates the symptoms common to women with cervical cancer and evaluates the impact of disease and/or treatments. The 24 items use a 4-point scale (1=not at all to 4=very much) and are classified into 3 multi-item scales, 11 items with symptom experience, 3 items with body image, and 4 items with sexual/ vaginal functioning. The other items of the questionnaire are lymphedema, peripheral neuropathy, menopausal symptom, sexual worry, sexual activity, and sexual enjoyment. The change from baseline in EORTC QLQ-CX24 score will be presented.
Measure:Number of Participants Who Experience One or More Adverse Events (AEs)
Time Frame:Up to approximately 46 months
Safety Issue:
Description:An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.
Measure:Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
Time Frame:Up to approximately 46 months
Safety Issue:
Description:An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • Programmed Cell Death Receptor 1 (PD-1, PD1)
  • Programmed Cell Death Receptor Ligand 1 (PD-L1, PDL1)
  • Programmed Cell Death Receptor Ligand 2 (PD-L2, PDL2)

Last Updated

July 23, 2020