Pembrolizumab (MK-3475) Versus Placebo Following Surgery and Radiation in Participants With Locally Advanced Cutaneous Squamous Cell Carcinoma (MK-3475-630/KEYNOTE-630)

Study Overview
=================
Brief Summary
-----------------
This is a randomized, double-blind, study that compares pembrolizumab (MK-3475) with placebo given as adjuvant therapy in participants with high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC) that have undergone surgery with curative intent in combination with radiotherapy. The primary hypothesis is that pembrolizumab is superior to placebo in increasing recurrence free survival (RFS).

Official Title
-----------------
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Pembrolizumab Versus Placebo as Adjuvant Therapy Following Surgery and Radiation in Participants With High-risk Locally Advanced Cutaneous Squamous Cell Carcinoma (LA cSCC) (KEYNOTE-630)

Conditions
-----------------
Carcinoma, Squamous Cell

Intervention / Treatment
-----------------
* Biological: Pembrolizumab 400 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has histologically confirmed cutaneous squamous cell carcinoma (cSCC) as the primary site of malignancy (metastatic skin involvement from another type of primary cancer or from an unknown primary cancer is not permitted) Has histologically confirmed LA cSCC with ≥1 high-risk feature(s) as the primary site of malignancy Has undergone complete macroscopic resection of all known cSCC disease with or without microscopic positive margins. For those participants with residual microscopic positive margin involvement, confirmation that additional re-excision is not possible must be provided Has completed adjuvant radiotherapy (RT) for LA cSCC with last dose of RT ≥4 weeks and ≤16 weeks from randomization Has received an adequate post-op dose of RT (either hypofractionated or conventional) Is disease free as assessed by the investigator with complete radiographic staging assessment ≤28 days from randomization Is not pregnant or breastfeeding Is not a person of childbearing potential (POCBP) Has a negative pregnancy test ≤72 hours before the first dose of study intervention. Has provided an archival or newly-obtained tumor tissue sample adequate for Programmed Cell Death Ligand 1 (PD-L1) testing as determined by central laboratory testing Has a life expectancy of >3 months Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 ≤10 days prior to the first dose of study intervention. Exclusion Criteria: Has macroscopic residual cSCC after surgery and/or recurrence with active cSCC disease before randomization Has any other histologic type of skin cancer other than invasive cSCC (eg, basal cell carcinoma) that has not been definitively treated with surgery or radiation; Bowen's disease; Merkel cell carcinoma; or melanoma Has received prior therapy with an anti-programmed cell death receptor 1(PD-1), anti-PD-L1, or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another costimulatory or coinhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137) Has received prior systemic anticancer therapy including investigational agents for cSCC ≤4 weeks prior to before start of study intervention. Has not recovered from all radiation-related toxicities and has not had radiation pneumonitis Has received a live vaccine ≤30 days prior to the first dose of study intervention Has received an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Has known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Other exceptions may be considered with Sponsor consultation. Note: Participants with low risk early-stage prostate cancer defined as below are not excluded: Stage T1c or T2a with a Gleason score ≤6 and a prostate-specific antigen (≤10 ng/ml) either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study allocation. Early stage asymptomatic CLL without prior treatment and without any of the risk features (unmutated IGHV, lymphocytes >15,000μL, palpable lymph nodes) will be eligible for the study Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid). Has a history of (noninfectious) 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 (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV; defined as HCV RNA [qualitative] is detected) infection Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention Has had an allogeneic tissue/solid organ transplant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>Participants receive 400 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of each 42-day cycle (Q6W) for up to 9 cycles. Participants that complete 9 cycles of pembrolizumab and experience biopsy-proven-disease recurrence may be eligible to receive up to 18 additional cycles of pembrolizumab in an open-label design. | Biological: Pembrolizumab 400 mg<br>* Administered by IV infusion on Day 1 of each 42-day cycle<br>* Other names: MK-3475;|
| Placebo Comparator: Placebo<br>Participants receive placebo by IV infusion administered on Day 1 of each 42-day cycle (Q6W) for up to 9 cycles. Participants treated with placebo who experience biopsy-proven-disease recurrence may be eligible to receive up to 18 cycles of pembrolizumab in an open-label design. | Drug: Placebo<br>* Administered by IV infusion on Day 1 of each 42-day cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-Free Survival (RFS) as Assessed by the Investigator and Confirmed by Biopsy | RFS was defined as the time between the date of randomization to the date of first local or regional recurrence of the index lesion, distant metastasis, or death due to any cause; whichever occurred first. | Up to approximately 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is the time from randomization to death due to any cause. | Up to approximately 60 months | 
| Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score | Change from baseline in the score of EORTC QLQ-C30 is reported. The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire, which contains 30 items and measures 5 functioning dimensions (physical, role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and QoL scale. Scores ranged from 0 -100. For functional and global quality of life (QoL) scales, higher scores meant a better level of function. For symptom-oriented scales, a higher score meant more severe symptoms and a decrease in QoL. | Baseline and up to approximately 60 months | 
| Change From Baseline in Physical Functioning Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1-5 Score | Change from baseline in the score of EORTC QLQ-C30 Items 1-5 is reported. The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. 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. Higher scores meant a better level of function. | Baseline and up to approximately 60 months | 
| Percentage of Participants Who Experience an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The percentage of participants who experience at least one AE will be presented. | Up to approximately 63 months | 
| Percentage of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The percentage of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 38 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Programmed Cell Death-1 (PD-1), Programmed Cell Death 1, PD1, Programmed Cell Death Ligand 1 (PD-L1), Programmed Cell Death Ligand 2 (PD-L2), PDL1, PDL2