Melanoma
Conditions
Keywords
Programmed Cell Death-1 (PD-1), Programmed Cell Death 1 (PD1), Programmed Cell Death-Ligand 1 (PD-L1, PDL1), Programmed Cell Death-Ligand 2 (PD-L2, PDL2)
Brief summary
This study will assess whether post-surgery therapy with pembrolizumab improves recurrence-free survival (RFS) as compared to placebo for high-risk participants with melanoma (Stage IIIA \[\> 1 mm metastasis\], IIIB and IIIC). The study will also assess whether pembrolizumab improves RFS versus placebo in the subgroup of participants with programmed cell death-ligand 1 (PD-L1)-positive tumor expression. Participants will be stratified for stage of disease and region and then will be randomly assigned to receive either pembrolizumab or placebo as post-surgery therapy in Part 1. In Part 2, participants who experience a disease recurrence are eligible for pembrolizumab treatment (if treated with placebo in Part 1) or pembrolizumab rechallenge (if treated with pembrolizumab in Part 1).
Detailed description
As of Amendment 8, enrollment in Part 2 has closed, and an optional pembrolizumab extension study will not be available to participants after study closure.
Interventions
BIOLOGICALpembrolizumab
Pembrolizumab 200 mg administered intravenously (IV) on Day 1 of each 21-day cycle
DRUGplacebo
Normal saline solution administered IV on Day 1 of each 21-day cycle
Sponsors
Merck Sharp & Dohme LLC
European Organisation for Research and Treatment of Cancer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Completely resected Stage III melanoma * Tumor tissue available for evaluation of PD-L1 expression * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Adequate organ function * No prior therapy for melanoma except surgery for primary melanoma lesions (or previously treated with interferon for thick primary melanomas without evidence of lymph node involvement are eligible) * Female participants of childbearing potential should be willing to use adequate methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication * Male participants should agree to use an adequate method of birth control starting with the first dose of study therapy through 120 days after the last dose of study medication
Exclusion criteria
* Mucosal or ocular melanoma * History of (non-infectious) pneumonitis that required steroids or current pneumonitis * History of or current interstitial lung disease * History of hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5 years * Active autoimmune disease that has required systemic treatment in past 2 years * Active infection requiring therapy * Unstable hyperthyroidism or hypothyroidism * Diagnosis of immunodeficiency * Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication * Known history of human immunodeficiency virus (HIV), active Hepatitis B or C * Treatment with live vaccine within 30 days prior to the first dose of study medication are not eligible * Prior treatment with any anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody or anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent, or prior participation in any Merck pembrolizumab clinical trial * Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study medication * Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication * Participant is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial without prospective Institutional Review Board approval (by chair or designee) is given
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among All Participants | 6 months | RFS was defined as the time between the date of randomization and the date of first melanoma recurrence (local, regional, distant metastasis) or death (whatever the cause), whichever occurred first. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments. The percentage of participants with RFS at Month 6 was reported for all participants in both treatment arms of Part 1. |
| Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among Participants With PD-L1-positive Tumor Expression | 6 months | RFS was defined as the time between the date of randomization and the date of first melanoma recurrence (local, regional, distant metastasis) or death (whatever the cause), whichever occurred first. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments. The percentage of participants with RFS at Month 6 was reported for all participants with PD-L1-positive tumors in both treatment arms of Part 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Distant Metastases-free Survival (DMFS) in All Participants | Up to approximately 11 years | DMFS will be defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last visit/contact with disease assessments. The percentage of participants with DMFS will be reported for all participants in both treatment arms. |
| Distant Metastases-free Survival (DMFS) for Participants With PD-L1-positive Tumor Expression | Up to approximately 11 years | Description: DMFS will be defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last visit/contact with disease assessments. The percentage of participants with DMFS will be reported for all participants with PD-L1-positive tumors in both treatment arms. |
| Overall Survival (OS) for All Participants | Up to approximately 11 years | OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last visit/contact. OS will be reported for all participants in both treatment arms. |
| Overall Survival (OS) for Participants With PD-L1-positive Tumor Expression | Up to approximately 11 years | OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last visit/contact. OS will be reported for all participants with PD-L1-positive tumors in both treatment arms. |
| Number of Participants Who Experienced At Least 1 Adverse Event (AE) | Up to 22 months | An AE is defined as "any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment". An AE can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product. The number of participants who experienced at least 1 AE was reported for all participants in each treatment arm. |
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | Up to 22 months | An AE is defined as "any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment". An AE can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product. The number of participants who discontinued study treatment due to an AE was reported for all participants in each treatment arm. |
| Clearance (CL) of Pembrolizumab | Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks. | Blood samples were to be collected at pre-specified time points and plasma isolated for analysis of pembrolizumab CL, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following IV pembrolizumab administration. Samples were not collected and this analysis was not performed. |
| Volume of Distribution (V) of Pembrolizumab | Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks. | Blood samples were to be collected at pre-specified time points and plasma isolated for analysis of pembrolizumab V, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. Samples were not collected and this analysis was not performed. |
| Number of Participants Positive for Anti-Drug Antibodies (ADA) After Pembrolizumab Treatment | Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks. | Pre- and post-baseline serum samples from participants treated with pembrolizumab were analyzed for ADA by means of a neutralizing antibody assay which assessed the ability of ADA to block (neutralize) binding of pembrolizumab to Programmed Cell Death-1 (PD-1) protein. Overall immunogenicity was defined as the number of treatment emergent positive participants based on the total number of evaluable participants (treatment emergent positive, non-treatment emergent positive and negative immunogenicity status). |
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
As of the 02-Oct-2017 interim database cut-off date, of the 1019 randomized participants in Part 1, 544 had completed Part 1 and 62 were continuing in Part 1. This interim results disclosure is for Part 1 only.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab In Part 1, participants received pembrolizumab 200 mg IV as post-surgery therapy Q3W for up to 1 year. | 514 |
| Placebo In Part 1, participants received placebo IV as post-surgery therapy Q3W. | 505 |
| Total | 1,019 |
Baseline characteristics
| Characteristic | Total | Placebo | Pembrolizumab |
|---|---|---|---|
| Age, Continuous | 53.8 Years STANDARD_DEVIATION 13.9 | 53.7 Years STANDARD_DEVIATION 14.2 | 53.9 Years STANDARD_DEVIATION 13.6 |
| Melanoma Stage Stage IIIA (> 1 mm) | 160 Participants | 80 Participants | 80 Participants |
| Melanoma Stage Stage IIIB | 467 Participants | 230 Participants | 237 Participants |
| Melanoma Stage Stage IIIC (1-3 LN+) | 188 Participants | 93 Participants | 95 Participants |
| Melanoma Stage Stage IIIC (≥4 LN+) | 204 Participants | 102 Participants | 102 Participants |
| Programmed Death-Ligand 1 (PD-L1) Tumor Status PD-L1 Negative | 116 Participants | 57 Participants | 59 Participants |
| Programmed Death-Ligand 1 (PD-L1) Tumor Status PD-L1 Positive | 853 Participants | 425 Participants | 428 Participants |
| Programmed Death-Ligand 1 (PD-L1) Tumor Status Undetermined | 50 Participants | 23 Participants | 27 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment Australia/New Zealand | 223 Participants | 112 Participants | 111 Participants |
| Region of Enrollment Europe | 677 Participants | 336 Participants | 341 Participants |
| Region of Enrollment North America | 75 Participants | 37 Participants | 38 Participants |
| Region of Enrollment Other | 44 Participants | 20 Participants | 24 Participants |
| Sex: Female, Male Female | 391 Participants | 201 Participants | 190 Participants |
| Sex: Female, Male Male | 628 Participants | 304 Participants | 324 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 25 / 514 | 35 / 505 |
| other Total, other adverse events | 443 / 509 | 409 / 502 |
| serious Total, serious adverse events | 128 / 509 | 82 / 502 |
Outcome results
Primary
Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among All Participants
RFS was defined as the time between the date of randomization and the date of first melanoma recurrence (local, regional, distant metastasis) or death (whatever the cause), whichever occurred first. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments. The percentage of participants with RFS at Month 6 was reported for all participants in both treatment arms of Part 1.
Time frame: 6 months
Population: All randomized participants in Part 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among All Participants | 82.2 Percentage of Participants |
| Placebo | Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among All Participants | 73.3 Percentage of Participants |
Comparison: Comparison of RFS time-to-event distribution between the 2 treatment arms was based on Cox regression model with treatment as a covariate stratified by stage (IIIA \[\>1 mm metastasis\] vs. IIIB vs. IIIC 1-3 nodes vs. IIIC ≥4 nodes) as indicated at randomization.p-value: <0.000198.4% CI: [0.43, 0.74]Regression, Cox
Primary
Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among Participants With PD-L1-positive Tumor Expression
RFS was defined as the time between the date of randomization and the date of first melanoma recurrence (local, regional, distant metastasis) or death (whatever the cause), whichever occurred first. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments. The percentage of participants with RFS at Month 6 was reported for all participants with PD-L1-positive tumors in both treatment arms of Part 1.
Time frame: 6 months
Population: All randomized participants in Part 1 with PD-L1-positive tumors.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among Participants With PD-L1-positive Tumor Expression | 83.8 Percentage of Participants |
| Placebo | Part 1: Percentage of Participants With Recurrence-Free Survival (RFS) At 6 Months Among Participants With PD-L1-positive Tumor Expression | 75.4 Percentage of Participants |
Comparison: Comparison of RFS time-to-event distribution between the 2 treatment arms (PD-L1-positive participants) was based on Cox regression model with treatment as a covariate stratified by stage (IIIA \[\>1 mm metastasis\] vs. IIIB vs. IIIC 1-3 nodes vs. IIIC ≥4 nodes) as indicated at randomization.p-value: <0.000195% CI: [0.42, 0.69]Regression, Cox
Secondary
Clearance (CL) of Pembrolizumab
Blood samples were to be collected at pre-specified time points and plasma isolated for analysis of pembrolizumab CL, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following IV pembrolizumab administration. Samples were not collected and this analysis was not performed.
Time frame: Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks.
Population: As pre-specified by the protocol, pembrolizumab CL was not analyzed as planned and no data were collected since by the time of the interim analysis, pembrolizumab pharmacokinetics (PK) in melanoma patients had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Secondary
Distant Metastases-free Survival (DMFS) for Participants With PD-L1-positive Tumor Expression
Description: DMFS will be defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last visit/contact with disease assessments. The percentage of participants with DMFS will be reported for all participants with PD-L1-positive tumors in both treatment arms.
Time frame: Up to approximately 11 years
Secondary
Distant Metastases-free Survival (DMFS) in All Participants
DMFS will be defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last visit/contact with disease assessments. The percentage of participants with DMFS will be reported for all participants in both treatment arms.
Time frame: Up to approximately 11 years
Secondary
Number of Participants Positive for Anti-Drug Antibodies (ADA) After Pembrolizumab Treatment
Pre- and post-baseline serum samples from participants treated with pembrolizumab were analyzed for ADA by means of a neutralizing antibody assay which assessed the ability of ADA to block (neutralize) binding of pembrolizumab to Programmed Cell Death-1 (PD-1) protein. Overall immunogenicity was defined as the number of treatment emergent positive participants based on the total number of evaluable participants (treatment emergent positive, non-treatment emergent positive and negative immunogenicity status).
Time frame: Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks.
Population: All randomized participants in Part 1 who had at least one ADA sample available after treatment with pembrolizumab and who had treatment emergent positive, non-treatment emergent positive, or negative immunogenicity status. Participants receiving Placebo treatment in Part 1 were not analyzed for ADA.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab | Number of Participants Positive for Anti-Drug Antibodies (ADA) After Pembrolizumab Treatment | Treatment emergent positive | 17 Participants |
| Pembrolizumab | Number of Participants Positive for Anti-Drug Antibodies (ADA) After Pembrolizumab Treatment | Negative | 473 Participants |
| Pembrolizumab | Number of Participants Positive for Anti-Drug Antibodies (ADA) After Pembrolizumab Treatment | Non-Treatment emergent positive | 5 Participants |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product. The number of participants who discontinued study treatment due to an AE was reported for all participants in each treatment arm.
Time frame: Up to 22 months
Population: All randomized participants in Part 1 who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 70 Participants |
| Placebo | Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | 18 Participants |
Secondary
Number of Participants Who Experienced At Least 1 Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a participant which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product. The number of participants who experienced at least 1 AE was reported for all participants in each treatment arm.
Time frame: Up to 22 months
Population: All randomized participants in Part 1 who received at least 1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Experienced At Least 1 Adverse Event (AE) | 475 Participants |
| Placebo | Number of Participants Who Experienced At Least 1 Adverse Event (AE) | 453 Participants |
Secondary
Overall Survival (OS) for All Participants
OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last visit/contact. OS will be reported for all participants in both treatment arms.
Time frame: Up to approximately 11 years
Secondary
Overall Survival (OS) for Participants With PD-L1-positive Tumor Expression
OS will be defined as the time from the date of randomization to the date of death, whatever the cause. The follow-up of participants still alive will be censored at the moment of last visit/contact. OS will be reported for all participants with PD-L1-positive tumors in both treatment arms.
Time frame: Up to approximately 11 years
Secondary
Volume of Distribution (V) of Pembrolizumab
Blood samples were to be collected at pre-specified time points and plasma isolated for analysis of pembrolizumab V, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. Samples were not collected and this analysis was not performed.
Time frame: Pre-dose on Day 1 of Cycles 1, 2, 4, 6, and 8, and then Day 1 of cycle for every 4 cycles afterwards (up to approximately 16 months). Each cycle is 3 weeks.
Population: As pre-specified by the protocol, pembrolizumab V was not analyzed as planned and no data were collected since by the time of the interim analysis, pembrolizumab PK in melanoma patients had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.