Study of Pembrolizumab (MK-3475) in Platinum Pre-treated Recurrent/Metastatic Nasopharyngeal Cancer (MK-3475-122/KEYNOTE-122)

Study Overview
=================
Brief Summary
-----------------
This is a study of pembrolizumab (MK-3475) versus standard treatment (capecitabine, gemcitabine, or docetaxel) for the treatment of recurrent or metastatic nasopharyngeal cancer (NPC). Participants will be randomly assigned to receive either pembrolizumab or Investigator's choice of standard treatment. The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment. With Amendment 7 (effective 2-March-2022), upon study completion, participants will be discontinued and may be enrolled in an extension study.

Official Title
-----------------
A Two-arm, Open-label, Randomized Phase III Study of Pembrolizumab (MK-3475) Monotherapy Versus Standard Chemotherapy in Platinum Pre-treated, Recurrent or Metastatic Nasopharyngeal Cancer (NPC) (Keynote-122)

Conditions
-----------------
Nasopharyngeal Neoplasms

Intervention / Treatment
-----------------
* Biological: Pembrolizumab
* Drug: Capecitabine
* Drug: Gemcitabine
* Drug: Docetaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed non-keratinizing differentiated NPC or undifferentiated NPC Metastatic disease or incurable locally recurrent disease Treatment with prior platinum therapy Tumor tissue available for programmed cell death ligand 1 (PD-L1) testing Measurable disease based on RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate organ function Male or female participants of childbearing potential must be willing to use an adequate method of contraception starting with the first dose of study drug through 180 days after the last dose of study drug Life expectancy of at least 3 months Exclusion Criteria: Disease is suitable for local therapy administered with curative intent Participants previously treated in the recurrent/metastatic setting with any 1 of the 3 standard therapies in this study (i.e., docetaxel, capecitabine, or gemcitabine) may not receive the same therapy if randomized to the Standard Treatment arm. Additionally, participants previously treated in the recurrent/metastatic setting with all 3 standard therapies are excluded from this study Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of study drug Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug Not recovered from adverse events due to therapy more than 4 weeks earlier Prior anti-cancer monoclonal antibody (mAb) therapy within 4 weeks prior to Study Day 1, or not recovered from adverse events Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 Diagnosed and/or treated additional malignancy within 5 years of randomization, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin, and/or curatively-resected in situ cervical and/or breast carcinoma Active autoimmune disease that has required systemic therapy in the past 2 years with modifying agents, corticosteroids, or immunosuppressive agents Active central nervous system metastases and/or carcinomatous meningitis Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Active infection requiring systemic therapy Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of trial treatment for the chemotherapy arm or 120 days after the last dose of trial treatment for the pembrolizumab arm Prior therapy with an anti-PD-1 or anti-PD1-L1 or -L2 therapy or previously participated in a Merck pembrolizumab (MK-3475) study Human immunodeficiency virus (HIV) positive Hepatitis B or C positive Live vaccine within 30 days of planned start of study drug

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;|
| Active Comparator: Standard Treatment<br>Participants receive capecitabine 1000 mg/m^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity. | Drug: Capecitabine<br>* oral tablet<br>* Other names: XELODA®;Drug: Gemcitabine<br>* IV infusion<br>* Other names: GEMZAR®;Drug: Docetaxel<br>* IV infusion<br>* Other names: TAXOTERE®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. OS was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020. | Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020) | 

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) | PFS was defined as the time from randomization to the first documented progressive disease (PD) per RECIST 1.1 based on blinded independent central review (BICR), or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. PFS was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020. | Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020) | 
| Objective Response Rate (ORR) Per RECIST 1.1 | ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. based upon BICR. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. ORR was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020. | Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020) | 
| Duration of Response (DOR) Per RECIST 1.1 | For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by BICR, DOR was defined as the time from first documented evidence of confirmed CR or PR until PD or death due to any cause, whichever occurred first. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. DOR was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020. | Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020) | 
| Percentage of Participants Surviving (OS Rate) at 12 Months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. The percentage of participants surviving (OS rate) at 12 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020. | 12 months | 
| Percentage of Participants Surviving (OS Rate) at 24 Months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last known contact. The percentage of participants surviving (OS rate) at 24 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020. | 24 months | 
| Percentage of Participants With PFS (PFS Rate) at 6 Months | PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. The percentage of participants with PFS (PFS rate) at 6 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020. | 6 months | 
| Percentage of Participants With PFS (PFS Rate) at 12 Months | PFS was defined as the time from randomization to the first documented PD per RECIST 1.1 based on BICR, or death due to any cause, whichever occurs earlier. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. The sponsor allowed a maximum of 10 target lesions in total and 5 per organ on this study. The percentage of participants with PFS (PFS rate) at 12 months is reported for each treatment arm based on the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm, with a protocol-specified analysis data cut-off date of 30-Nov-2020. | 12 months | 
| Percentage of Participants Who Experience One or More Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable 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 medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm. | Up to approximately 73 months | 
| Percentage of Participants Who Discontinue Study Treatment Due to an AE | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable 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 medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. The percentage of participants that discontinued study treatment due to an AE was reported for each treatment arm. Per protocol, analysis for this outcome measure was performed for the first pembrolizumab course and for the standard treatment arm. | Up to approximately 72 months | 

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