NCT04221945 - 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) | Crick

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate PFS.

Time frame: Up to approximately 55 months

Overall Survival (OS)

OS is the time from randomization to death due to any cause. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate OS.

Time frame: Up to approximately 55 months

Secondary Outcomes

PFS Per 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. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate PFS.

Time frame: Up to approximately 55 months

PFS Per 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. The percentage of participants with PFS as assessed by the investigator is presented.

Time frame: 24 months

PFS Per RECIST 1.1 at Month 24 as Assessed by 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. The percentage of participants with PFS as assessed by BICR is presented.

Time frame: 24 months

Overall Survival (OS) at Month 36

OS is the time from randomization to death due to any cause. The analysis was performed via Kaplan-Meier approach to estimate the OS rate at Month 36. The percentage of participants with OS at Month 36 is presented.

Time frame: 36 months

Complete Response (CR) Rate Per 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. The percentage of participants with CR per RECIST 1.1 as assessed by the investigator at Week 12 is presented.

Time frame: 12 weeks

CR Rate Per RECIST 1.1 at Week 12 as Assessed by BICR

For participants who demonstrated a confirmed 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. The percentage of participants with CR per RECIST 1.1 as assessed by BICR at Week 12 is presented.

Time frame: 12 weeks

Objective Response Rate (ORR) Per 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.

Time frame: Up to approximately 55 months

ORR Per RECIST 1.1 as Assessed by BICR

Time frame: Up to approximately 55 months

PFS Per 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. PD-L1 positive participants have a combined positivity score (CPS) equal or greater than 1. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate PFS.

Time frame: Up to approximately 55 months

PFS Per RECIST 1.1 in PD-L1 Positive Participants as Assessed by 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. PD-L1 positive participants have a CPS equal or greater than 1. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate PFS.

Time frame: Up to approximately 55 months

OS in PD-L1 Positive Participants

OS is the time from randomization to death due to any cause. PD-L1 positive participants have a CPS equal or greater than 1. The Kaplan-Meier nonparametric product limit method for censored data was used to estimate OS.

Time frame: Up to approximately 55 months

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. PFS 2 is measured after next-line treatment following discontinuation of study treatment administration.

Time frame: Up to approximately 55 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.

Time frame: Baseline and week 36

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.

Time frame: Baseline and week 36

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. Total scores are linearly transformed and range from 0 (no symptoms) to 100 (most severe symptoms). The change from baseline in EORTC QLQ-CX24 score is presented, with negative scores representing an improvement from baseline and vice versa.

Time frame: Baseline and Week 36

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.

Time frame: Up to 55 months

Number of Participants Who Discontinue Study Treatment Due to an AE

Time frame: Up to 32 months

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)

Overview

Conditions

Interventions

Eligibility

Locations (176)

Outcomes

Primary Outcomes

Secondary Outcomes