NCT01704287 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE2
Status at capture: COMPLETED
Registry last update: 2020-05-18

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Progression-free Survival (PFS) - Initial Treatment Period

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outcome · POSTED

Interim Overall Survival (OS) - Initial Treatment Period

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outcome · POSTED

Final Overall Survival (OS) - Initial Treatment Period

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outcome · POSTED

Final Overall Survival (OS) By Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Status - Initial Treatment Period

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outcome · POSTED

Overall Response Rate (ORR) - Initial Treatment Period

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outcome · POSTED

Best Overall Response (BOR) - Initial Treatment Period

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outcome · POSTED

Best Overall Response (BOR) - Switch-to-Pembrolizumab Treatment Period

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outcome · POSTED

Duration of Response (DOR) - Initial Treatment Period

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outcome · POSTED

Number of Participants Who Experienced an Adverse Event (AE) - Overall Study

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outcome · POSTED

Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE) - Overall Study

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: 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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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 Names
Biological: Pembrolizumab
label
Pembrolizumab 2 mg/kg
type
EXPERIMENTAL
description
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 Names
Biological: Pembrolizumab
label
Pembrolizumab 10 mg/kg
type
EXPERIMENTAL
description
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)
intervention Names
Drug: Carboplatin
Drug: Paclitaxel
Drug: Dacarbazine
Drug: Temozolomide
label
Investigator-Choice Chemotherapy (ICC)
type
ACTIVE_COMPARATOR
description
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)
intervention Names
Biological: Pembrolizumab
Drug: Carboplatin
Drug: Paclitaxel
Drug: Dacarbazine
Drug: Temozolomide
label
ICC→Pembrolizumab 2 mg/kg
type
EXPERIMENTAL
description
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)
intervention Names
Biological: Pembrolizumab
Drug: Carboplatin
Drug: Paclitaxel
Drug: Dacarbazine
Drug: Temozolomide
label
ICC→Pembrolizumab 10 mg/kg
type
EXPERIMENTAL

interventions

arm Group Labels
ICC→Pembrolizumab 10 mg/kg
ICC→Pembrolizumab 2 mg/kg
Pembrolizumab 10 mg/kg
Pembrolizumab 2 mg/kg
description
IV infusion
name
Pembrolizumab
other Names
SCH 900475
MK-3475
KEYTRUDA®
type
BIOLOGICAL
arm Group Labels
ICC→Pembrolizumab 10 mg/kg
ICC→Pembrolizumab 2 mg/kg
Investigator-Choice Chemotherapy (ICC)
description
Carboplatin per institutional standard
name
Carboplatin
other Names
PARAPLATIN®
type
DRUG
arm Group Labels
ICC→Pembrolizumab 10 mg/kg
ICC→Pembrolizumab 2 mg/kg
Investigator-Choice Chemotherapy (ICC)
description
Paclitaxel per institutional standard
name
Paclitaxel
other Names
TAXOL®
type
DRUG
arm Group Labels
ICC→Pembrolizumab 10 mg/kg
ICC→Pembrolizumab 2 mg/kg
Investigator-Choice Chemotherapy (ICC)
description
Dacarbazine per institutional standard
name
Dacarbazine
other Names
DTIC
type
DRUG
arm Group Labels
ICC→Pembrolizumab 10 mg/kg
ICC→Pembrolizumab 2 mg/kg
Investigator-Choice Chemotherapy (ICC)
description
Temozolomide per institutional standard
name
Temozolomide
other Names
TEMODAR®
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: DOUBLE
who Masked: PARTICIPANT
INVESTIGATOR

primary Purpose

TREATMENT

Enrollment

count: 540
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
Progression-free Survival (PFS) - Initial Treatment Period
time Frame
Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
description
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.
measure
Interim Overall Survival (OS) - Initial Treatment Period
time Frame
Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
description
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.
measure
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)

secondary Outcomes

description
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.
measure
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)
description
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.
measure
Overall Response Rate (ORR) - Initial Treatment Period
time Frame
Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
description
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.
measure
Best Overall Response (BOR) - Initial Treatment Period
time Frame
Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
description
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.
measure
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)
description
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.
measure
Duration of Response (DOR) - Initial Treatment Period
time Frame
Up to approximately 36 months (Through Final Analysis database cutoff date of 16-Nov-2015)
description
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.
measure
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)
description
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.
measure
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)

Full study description

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.

Source references

references

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