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

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ClinicalTrials.gov Identifier: NCT04221945
Recruitment Status : Not yet recruiting
First Posted : January 9, 2020
Last Update Posted : January 18, 2020
Sponsor:
Collaborator:
European Network for Gynaecological Oncological Trial Groups
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Uterine Cervical Neoplasms Biological: Pembrolizumab Drug: Placebo for pembrolizumab Drug: Cisplatin Radiation: External Beam Radiotherapy (EBRT) Radiation: Brachytherapy Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 980 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Estimated Study Start Date : February 25, 2020
Estimated Primary Completion Date : February 7, 2024
Estimated Study Completion Date : December 7, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cervical Cancer

Arm Intervention/treatment
Experimental: chemoradiotherapy + pembrolizumab
Participants 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.
Biological: Pembrolizumab
IV infusion
Other Names:
  • KEYTRUDA®
  • MK-3475

Drug: Cisplatin
IV infusion
Other Names:
  • Platinol®
  • Platinol®-AQ

Radiation: External Beam Radiotherapy (EBRT)
Given as 23-28 fractions (1.8 Gy to 2 Gy per fraction)

Radiation: Brachytherapy
Given as 4-6 fractions (5 to 7 Gy per fraction)

Experimental: chemoradiotherapy + placebo for pembrolizumab
Participants 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.
Drug: Placebo for pembrolizumab
IV infusion

Drug: Cisplatin
IV infusion
Other Names:
  • Platinol®
  • Platinol®-AQ

Radiation: External Beam Radiotherapy (EBRT)
Given as 23-28 fractions (1.8 Gy to 2 Gy per fraction)

Radiation: Brachytherapy
Given as 4-6 fractions (5 to 7 Gy per fraction)




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.


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. Overall Survival (OS) at Month 36 [ Time Frame: Up to approximately 46 months ]
    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.

  3. 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 ]
    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.

  4. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 46 months ]
    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.

  5. 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 ]
    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.

  6. Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants [ Time Frame: Up to approximately 46 months ]
    OS is the time from randomization to death due to any cause.

  7. Progression-Free Survival (PFS) After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment [ Time Frame: Up to approximately 46 months ]
    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.

  8. 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 ]
    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.

  9. 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 ]
    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.

  10. 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 ]
    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.

  11. Number of Participants Who Experience One or More Adverse Events (AEs) [ Time Frame: Up to approximately 46 months ]
    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.

  12. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 46 months ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04221945


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
European Network for Gynaecological Oncological Trial Groups
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT04221945    
Other Study ID Numbers: 3475-A18
2019-003152-37 ( EudraCT Number )
MK-3475-A18 ( Other Identifier: Merck )
KEYNOTE-A18 ( Other Identifier: Merck )
ENGOT-cx11 ( Other Identifier: European Network for Gynaecological Oncological Trial groups )
First Posted: January 9, 2020    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
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)
Additional relevant MeSH terms:
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Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Cisplatin
Pembrolizumab
Antineoplastic Agents
Antineoplastic Agents, Immunological