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Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)

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ClinicalTrials.gov Identifier: NCT01704287
Recruitment Status : Completed
First Posted : October 11, 2012
Results First Posted : March 28, 2017
Last Update Posted : May 18, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE October 8, 2012
First Posted Date  ICMJE October 11, 2012
Results First Submitted Date  ICMJE October 17, 2016
Results First Posted Date  ICMJE March 28, 2017
Last Update Posted Date May 18, 2020
Actual Study Start Date  ICMJE November 20, 2012
Actual Primary Completion Date November 16, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 16, 2019)
  • Progression-free Survival (PFS) - Initial Treatment Period [ Time Frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) ]
    PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Analysis of PFS was based on an integrated radiology and oncology (IRO) assessment and was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median PFS based on the product limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for PFS.
  • Interim Overall Survival (OS) - Initial Treatment Period [ Time Frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) ]
    OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the interim analysis for OS.
  • Final Overall Survival (OS) - Initial Treatment Period [ Time Frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) ]
    OS was defined as the time from randomization to death due to any cause. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data is presented. This was the final analysis for OS.
Original Primary Outcome Measures  ICMJE
 (submitted: October 8, 2012)
  • Overall response rate (ORR) at Week 12 [ Time Frame: Week 12 ]
  • Progression-free Survival (PFS) [ Time Frame: Up to 24 months ]
  • Overall Survival (OS) [ Time Frame: Up to 24 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 16, 2019)
  • Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period [ Time Frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) ]
    OS was defined as the time from randomization to death due to any cause. Participants with an Allred Proportion Score (APS) ≥2 (membranous staining in ≥1% of cells for PD-L1) were considered to be PD-L1 Positive and participants with an APS of 0 or 1 were considered to be PD-L1 Negative. Analysis of OS was not planned or conducted for the switch-to-pembrolizumab treatment groups. Median OS duration based on the product-limit (Kaplan-Meier) method for censored data by PD-L1 tumor expression status is presented.
  • Overall Response Rate (ORR) - Initial Treatment Period [ Time Frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) ]
    ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. Analysis of ORR was not planned or conducted for the switch-to-pembrolizumab treatment groups. The percentage of participants who experienced a CR or PR is presented. This was the final analysis for ORR.
  • Best Overall Response (BOR) - Initial Treatment Period [ Time Frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) ]
    BOR was assessed by independent radiology review using RECIST 1.1 and was recorded from randomization until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. BOR for the Initial Treatment Period was based on IRO. BOR for participants during the Initial Treatment Period is presented.
  • Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period [ Time Frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) ]
    The BOR was assessed using RECIST 1.1 and was recorded from the start of the second line of study drug (pembrolizumab) until the last imaging assessment in this period. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. For the switch-to-pembrolizumab treatment groups, BOR was based on independent review committee (IRC) assessment. The BOR for switched-to pembrolizumab treatment groups is presented.
  • Duration of Response (DOR) - Initial Treatment Period [ Time Frame: Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015) ]
    For participants who demonstrated a confirmed response (Complete Response [CR]: disappearance of all target lesions or Partial Response [PR]: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. DOR analysis was based on IRO assessment. Analysis of DOR was not planned or analyzed for the switch-to-pembrolizumab treatment groups. Median DOR for participants who demonstrated a confirmed response is presented.
  • Number of Participants Who Experienced an Adverse Event (AE) - Overall Study [ Time Frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) ]
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study drug, was also an AE. Participants were included in the treatment group in which an AE was experienced. The number of participants who experienced at least one AE is presented.
  • Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study [ Time Frame: Up to approximately 75 months (Through End of Trial Analysis database cutoff date of 31-Jan-2019) ]
    An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, was also an AE. The number of participants who discontinued study drug due to an AE is presented.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 8, 2012)
  • Disease control rate (DCR) at Week 12 [ Time Frame: Week 12 ]
  • Overall survival rate at Week 12 [ Time Frame: Week 12 ]
  • Response Duration [ Time Frame: Up to 24 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (MK-3475-002/P08719/KEYNOTE-002)
Official Title  ICMJE Randomized, Phase II Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Patients With Advanced Melanoma (KEYNOTE 002)
Brief Summary

This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after prior therapy.

Initial Treatment Period:

Participants were initially randomized to receive either low-dose (2 mg/kg) pembrolizumab, higher dose (10 mg/kg) pembrolizumab or Investigator-choice chemotherapy (ICC). The four standard chemotherapy choices were: carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide. The randomization to either pembrolizumab or ICC was conducted in an open-label fashion.

The starting pembrolizumab dose was initially blinded to Investigators and participants until Amendment 03. With Amendment 03, all ongoing pembrolizumab participants were to be treated with open label, fixed dose pembrolizumab 200 mg, instead of a weight-based dosing of pembrolizumab.

Switch-to-Pembrolizumab Treatment Period:

Participants who were initially randomized to receive ICC and experienced progressive disease (PD) may have been eligible to switch to receiving pembrolizumab provided they met protocol-specified requirements for switching. Qualified participants were re-randomized to receive either pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg in a double-blind fashion. Participants who qualified to switch to pembrolizumab must have completed a washout period of ≥28 days from last dose of chemotherapy before receiving pembrolizumab. With Amendment 03, all switched-to-pembrolizumab participants were to be treated with open-label, fixed dose pembrolizumab 200 mg instead of a weight-based dosing of pembrolizumab.

Detailed Description

Two interim and one final statistical analyses were planned for and conducted during this study:

  • Interim Analysis 1 (futility analysis),
  • Interim Analysis 2 (~18 months into study): database cutoff date 12-May-2014, and
  • Final Analysis (~36 months into study): database cutoff date 16-Nov-2015. The End of Trial Analysis for the study was conducted at ~75 months into the study: database cutoff date 31-Jan-2019.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Malignant Melanoma
Intervention  ICMJE
  • Biological: Pembrolizumab
    IV infusion
    Other Names:
    • SCH 900475
    • MK-3475
    • KEYTRUDA®
  • Drug: Carboplatin
    Carboplatin per institutional standard
    Other Name: PARAPLATIN®
  • Drug: Paclitaxel
    Paclitaxel per institutional standard
    Other Name: TAXOL®
  • Drug: Dacarbazine
    Dacarbazine per institutional standard
    Other Name: DTIC
  • Drug: Temozolomide
    Temozolomide per institutional standard
    Other Name: TEMODAR®
Study Arms  ICMJE
  • Experimental: Pembrolizumab 2 mg/kg
    Participants were initially randomized to receive pembrolizumab 2 mg/kg intravenously (IV) once every 3 weeks (Q3W). With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
    Intervention: Biological: Pembrolizumab
  • Experimental: Pembrolizumab 10 mg/kg
    Participants were initially randomized to receive pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
    Intervention: Biological: Pembrolizumab
  • Active Comparator: Investigator-Choice Chemotherapy (ICC)
    Participants were initially randomized to receive 1 of 4 possible chemotherapy regimens decided at the treating institution (carboplatin+paclitaxel, paclitaxel alone, dacarbazine, or temozolomide). Participants were to receive study drug until discontinuation due to progression of disease, toxicity, or choice. (Up to ~66 months)
    Interventions:
    • Drug: Carboplatin
    • Drug: Paclitaxel
    • Drug: Dacarbazine
    • Drug: Temozolomide
  • Experimental: ICC→Pembrolizumab 2 mg/kg
    Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 2 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Carboplatin
    • Drug: Paclitaxel
    • Drug: Dacarbazine
    • Drug: Temozolomide
  • Experimental: ICC→Pembrolizumab 10 mg/kg
    Participants who were initially randomized to ICC, subsequently experienced confirmed progressive disease (PD) and met all switching criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg. Participants received pembrolizumab 10 mg/kg IV Q3W. With Amendment 03, this dosing was discontinued and all study participants were to be treated with fixed-dose open label pembrolizumab 200 mg IV Q3W. Participants were to receive study drug until discontinuation due to PD, toxicity, or choice. (Up to ~66 months)
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Carboplatin
    • Drug: Paclitaxel
    • Drug: Dacarbazine
    • Drug: Temozolomide
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 24, 2016)
540
Original Estimated Enrollment  ICMJE
 (submitted: October 8, 2012)
510
Actual Study Completion Date  ICMJE January 31, 2019
Actual Primary Completion Date November 16, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic MEL not amenable to local therapy
  • Participants must be refractory to ipilimumab
  • Participants with BRAF gene mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor
  • Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy specimen (or specimen obtained within 60 days of consenting)
  • Radiographically measurable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

  • Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from the AEs due to cancer therapies administered more than 4 weeks earlier
  • Disease progression within 24 weeks of last dose of ipilimumab
  • Participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug
  • Expected to require any other form of systemic or localized antineoplastic therapy while on study
  • Chronic systemic steroid therapy within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication
  • Known history of any other than the current malignancy excepting adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, breast cancer, or other in situ cancers
  • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
  • Prior treatment with any other anti-programmed cell death (PD) agent
  • Active infection requiring systemic therapy
  • Known history of Human Immunodeficiency Virus (HIV)
  • Active Hepatitis B or Hepatitis C
  • Regular user (including recreational use of) illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
  • Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study through 120 days after last dose of study drug
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Argentina,   Australia,   Germany,   Israel,   Italy,   Netherlands,   Norway,   Spain,   Sweden,   Switzerland,   United States
 
Administrative Information
NCT Number  ICMJE NCT01704287
Other Study ID Numbers  ICMJE P08719
MK-3475-002 ( Other Identifier: Merck )
2012-003030-17 ( EudraCT Number )
KEYNOTE-002 ( Other Identifier: Merck )
P08719 ( Other Identifier: Schering Plough )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP