Study of Chemoradiotherapy With or Without Pembrolizumab (MK-3475) For The Treatment of Locally Advanced Cervical Cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11/GOG-3047)

Study Overview
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Brief Summary
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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.

Official Title
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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/GOG-3047)

Conditions
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Uterine Cervical Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Placebo for pembrolizumab
* Drug: Cisplatin
* Radiation: External Beam Radiotherapy (EBRT)
* Radiation: Brachytherapy


Participation Criteria
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Eligibility Criteria
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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, including investigational agents, 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 and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. Female participants must abstain from breastfeeding during the study intervention 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 incisional 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 function 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 or considered mild and not clinically significant in the opinion of the investigator 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, 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/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease 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 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 Has had an allogenic tissue/solid organ transplant Has evidence of metastatic disease per RECIST 1.1 including lymph nodes above the first lumbar vertebra (L1) cephalad body, in the inguinal region

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: chemoradiotherapy + pembrolizumab<br>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 or 6 weeks plus external beam radiotherapy (EBRT) followed by brachytherapy with minimum total radiotherapy dose of 80 Gray Units (Gy) for volume-directed and 75 Gy for point-directed given with the total duration of radiation treatment not to exceed 50 days (with an extension to a maximum of 56 days for unforeseen delays). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;Drug: Cisplatin<br>* IV infusion<br>* Other names: Platinol®-AQ;Radiation: External Beam Radiotherapy (EBRT)<br>* Given as a total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed<br>Radiation: Brachytherapy<br>* Given as a total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed<br>|
| Experimental: chemoradiotherapy + placebo for pembrolizumab<br>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 or 6 weeks plus external beam radiotherapy (EBRT) followed by brachytherapy with minimum total radiotherapy dose of 80 Gray Units (Gy) for volume-directed and 75 Gy for point-directed given with the total duration of radiation treatment not to exceed 50 days (with an extension to a maximum of 56 days for unforeseen delays). | Drug: Placebo for pembrolizumab<br>* IV infusion<br>Drug: Cisplatin<br>* IV infusion<br>* Other names: Platinol®-AQ;Radiation: External Beam Radiotherapy (EBRT)<br>* Given as a total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed<br>Radiation: Brachytherapy<br>* Given as a total radiotherapy dose of 80 Gy for volume-directed and 75 Gy for point-directed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator | 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 suspected 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. | Up to approximately 38 months | 
| Overall Survival (OS) | OS is the time from randomization to death due to any cause. | Up to approximately 46 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 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, 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. | Up to approximately 38 months | 
| Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24 as Assessed by the Investigator | 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 suspected 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. | Up to approximately 38 months | 
| Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24 as Assessed by Blinded Independent Central Review (BICR) | 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, 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. | Up to approximately 38 months | 
| Overall Survival (OS) at Month 36 | 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. | Up to approximately 46 months | 
| Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12 as Assessed by the Investigator | 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. | Up to approximately 38 months | 
| Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12 as Assessed by Blinded Independent Central Review (BICR) | 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. | Up to approximately 38 months | 
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator | 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. | Up to approximately 46 months | 
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 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. | Up to approximately 46 months | 
| 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 as Assessed by the Investigator | 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 suspected 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. | Up to approximately 38 months | 
| 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 as Assessed by Blinded Independent Central Review (BICR) | 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, 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. | Up to approximately 38 months | 
| Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator | OS is the time from randomization to death due to any cause. | Up to approximately 46 months | 
| Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by Blinded Independent Central Review (BICR) | OS is the time from randomization to death due to any cause. | Up to approximately 46 months | 
| Progression-Free Survival (PFS) After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment | 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. | Up to approximately 46 months | 
| 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 | 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. | Baseline and up to approximately 46 months | 
| Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score | 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. | Baseline and up to approximately 46 months | 
| 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 | 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. | Baseline and up to approximately 46 months | 
| Number of Participants Who Experience One or More Adverse Events (AEs) | 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. | Up to approximately 46 months | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | 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. | Up to approximately 46 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)