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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)

PHRR160616-001275

MK-3475-122, Keynote-122; PFDA: 2016-CT0339; CT.gov: NCT02611960

2016-CT0339

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)

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.

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2016-09-26 78 2023-03-26 2023-02-01

Completed

Institution Classification Region LTO #
Merck Sharp & Dohme (I.A.) LLC Private Business NCR CDRR-NCR-S-16
Institution Region
Merck Sharp & Dohme (I.A.) LLC NCR
Name E-Mail Institution and Institution Address
Priscila Perez priscila.d.perez@merck.com 26/F Philamlife Tower Paseo De Roxas Makati City
Name E-Mail Institution and Institution Address
Priscila Perez priscila.d.perez@merck.com 26/F Philamlife Tower Paseo De Roxas Makati City
Name Expertise Affiliation
Felycette Gay Martinez-Lapus, MD Medical Oncology Davao Doctors Hospital
Ma. Luisa Abesamis-Tiambeng, MD Medical Oncology Cardinal Santos Medical Center
Ma. Noemi Alsay-Uy, MD Medical Oncology Cebu Doctors' University Hospital
Priscilla B. Caguioa, MD Hematology-Oncology St. Luke's Medical Center - Quezon City
Project Location Institutional Ethics Review Board
Davao Doctors Hospital Davao Doctors Hospital Ethics Review Committee
Cardinal Santos Medical Center Cardinal Santos Medical Center Ethics Review Committee
Cebu Doctors' University Hospital Cebu Doctors' University Hospital - Institutional Ethics Review Committee
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Board

Nasopharyngeal Neoplasms

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.

  1. Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020) ]
    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.
  2. Objective Response Rate (ORR) Per RECIST 1.1 [ Time Frame: Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020) ]
    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.
  3. Duration of Response (DOR) Per RECIST 1.1 [ Time Frame: Up to approximately 53 months (through analysis cut-off date of 30-Nov-2020) ]
    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.
  4. Percentage of Participants Surviving (OS Rate) at 12 Months [ Time Frame: 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.
  5. Percentage of Participants Surviving (OS Rate) at 24 Months [ Time Frame: 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.
  6. Percentage of Participants With PFS (PFS Rate) at 6 Months [ Time Frame: 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.
  7. Percentage of Participants With PFS (PFS Rate) at 12 Months [ Time Frame: 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.
  8. Percentage of Participants Who Experience One or More Adverse Events (AEs) [ Time Frame: Up to approximately 52 months ]
    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.
  9. Percentage of Participants Who Discontinue Study Treatment Due to an AE [ Time Frame: Up to approximately 51 months ]
    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.

Completed

  • Australia
  • Canada
  • Hong Kong
  • Malaysia
  • Philippines
  • Singapore
  • South Korea
  • Taiwan
  • Thailand
  • United States

Clinical Trial

MK-3475-122, Keynote-122; PFDA: 2016-CT0339; CT.gov: NCT02611960

DTN 20160121164730

2016-05-18

0000-00-00

20

20

Not Applicable

2016-09-26

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
 

Interventional

Biological: Pembrolizumab IV infusion Other Names: MK-3475 KEYTRUDA® Drug: Capecitabine oral tablet Other Name: XELODA® Drug: Gemcitabine IV infusion Other Name: GEMZAR® Drug: Docetaxel IV infusion Other Name: TAXOTERE®

Experimental: Pembrolizumab
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).
 
 
Intervention: Biological: pembrolizumab
 
Active Comparator: Standard Treatment
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.
 
 
Interventions:
◦Drug: capecitabine
◦Drug: gemcitabine
◦Drug: docetaxel
 

Date Amendment Classification Reason
2016-08-24 Amendments related to the protocol 1. The change to Capecitabine dose (changed to 1000 mg/m2 BID) was made to align with US standard of care practices. The change to gemcitabine dose (increased to 1250 mg/m2) was made to align with the US label. 2. Revisions to Tables of Dose Modifications for Capecitabine, Gemcitabine and Docetaxel to provide clarifications and due to FDA requests and to match with USPIs. 3. FDA recommendation to control type I error to one-sided 2.5% and have power to test OS to be at least 80%
2017-04-17 Amendments related to the protocol 1. To include an optional sub-study, which allows for exploratory analyses for EBV-specific CD8+ T-cells in peripheral blood. 2. To update the Dose Modification table for Pembrolizumab (MK-3475) in order to better align with the updated SmPC Table. 3. To remove the head and brain imaging requirements in the study, unless clinically indicated.
2017-11-29 Amendments related to the protocol 1. To increase the number of trial subjects (sample size) from 160 to 230 subjects.
2018-03-19 Amendments related to the protocol 1. To update the Pembrolizumab (MK-3475) Dose Modification Table to include myocarditis-specific guidelines and to align with the current label 2. To clarify that subjects should be contacted approximately every 12 weeks in the Survival Follow-up Phase 3. To enable survival follow-up activities throughout the course of the study (i.e., Treatment Phase, Follow-up Phase, etc.) upon the request of the Sponsor to ensure that current and complete survival data are available at the time of database locks
2019-08-19 Amendments related to the protocol 1. Modified the primary objective/hypothesis/endpoint to be OS only and definition of trial success from “at least one of the two endpoints (OS and PFS) is shown to be successful” to “OS is shown to be successful.” Updated duration of trial, multiplicity, interim analysis, and power accordingly. 2. Addition of newly available clinical trial data 3. Addition of ‘efficacy’ in paragraph for Section 7.3.2 Data Monitoring Committee 4. Demoted PFS to a secondary endpoint
2021-09-02 Amendments related to the protocol PN 122-06 amendment dated 19-Jul-2021; To update the dose modification and toxicity management guidelines for irAEs in the MK-3475 Dose Modification Table, to allow site Investigators to follow the local/standard imaging schedule, to remove blood collection for Plasma EBV DNA beyond Cycle 80, to remove blood collection for Correlative Studies at the Discontinuation Visit, to remove ePRO administration at the Discontinuation/EOT and 30-Day Safety Follow-Up Visits, and to remove blood collection at time of progression after Cycle 80 for the sub-study.
2022-03-24 Amendments related to the protocol PN 122-07 amendment dated 02-Mar-2022 To add language to give ongoing study participants the option to discontinue this study and transition into a pembrolizumab extension study.

Randomized

Open Label

Unspecified

Parallel

Treatment

Phase III

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