Melanoma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1(PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Brief summary
This 2-part study will evaluate the safety and efficacy of pembrolizumab (MK-3475) compared to placebo in participants with surgically resected high-risk Stage II melanoma. Participants in Part 1 will receive either pembrolizumab or placebo in a double-blind design every 3 weeks (Q3W) for up to 17 cycles/\ 1 year (each cycle = 21 days). Participants who complete the initial treatment of 17 cycles of pembrolizumab in Part 1 and experience disease recurrence may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \ 2 years) in Part 2 in an open label design. Participants who complete the initial treatment of placebo and experience disease recurrence may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \ 2 years) in Part 2 in an open label design. The primary hypothesis of this study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo. Per protocol, response/ progression or adverse events (AEs) during re-challenge/switch-over in Part 2 will not be counted towards the RFS outcome measure or safety outcome measures respectively.
Interventions
BIOLOGICALPembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
OTHERPlacebo
Administered as an IV infusion every 3 weeks (Q3W)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Participants and Investigators will be blinded in Part 1 and unblinded in Part 2, if done.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion: * Has surgically resected and histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer (AJCC) 8th edition guidelines * Has not been previously treated for melanoma beyond complete surgical resection * Has ≤12 weeks between final surgical resection and randomization * Has no evidence of metastatic disease on imaging as determined by investigator * Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale or Lansky Play-Performance Scale (LPS) score ≥50 for participants ≤16 years old, or a Karnofsky Performance Scale (KPS) score ≥50 for participants \>16 and \<18 years old * Has recovered adequately from toxicity and/or complications from surgery prior to study start * Female participants must not be pregnant or breastfeeding, and must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment if they are women of childbearing potential (WOCBP) Exclusion: * Has a known additional malignancy that is progressing or has required active antineoplastic therapy (including hormonal) within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment * WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Has received prior therapy with an 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 with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137) * Has received prior systemic anti-cancer therapy for melanoma including investigational agents * Has received a live vaccine within 30 days prior to the first dose of study treatment * Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Has severe hypersensitivity (≥Grade 3) to any excipients of pembrolizumab * Has an active autoimmune disease that has required systemic treatment in the past 2 years * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has an active infection requiring systemic therapy * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of hepatitis B (defined as hepatitis B surface antigen reactive) or known active hepatitis C virus (defined as hepatitis C virus ribonucleic acid \[RNA\] \[qualitative\] is detected) infection * Has a history of active tuberculosis (Bacillus tuberculosis) * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator * Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study * Has had an allogeneic tissue/solid organ transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-free Survival (RFS) | Up to ~32.7 months | RFS was defined as the time from randomization to any of the following events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or death due to any cause, whichever occurs first. Per protocol, final analysis for this primary outcome measure was performed using the initial pembrolizumab or placebo treatment with a protocol-specified analysis data cut-off date of June-21-2021. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Distant Metastasis-free Survival (DMFS) | Up to ~9 years | DMFS will be defined as the time from randomization to the first diagnosis of a distant metastasis per RECIST 1.1. Distant metastasis will refer to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes. DMFS will be reported for randomized participants. |
| Overall Survival (OS) | Up to ~15 years | OS will be defined as the time from randomization to death due to any cause. OS will be reported for randomized participants. |
| Number of Participants Who Experienced at Least One Adverse Event (AE) | Up to ~19.3 months | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to ~19.3 months | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment. |
Countries
Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
Per protocol, response/progression or adverse events (AEs) during re-challenge/switch-over in Part 2 were not counted towards the recurrence-free survival (RFS) outcome measure or safety outcome measures respectively.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Participants received 200 mg pembrolizumab (2 mg/kg for a maximum of 200 mg in pediatric participants) by intravenous (IV) infusion once every 3 weeks (Q3W; 21-day cycles) for up to 17 cycles (up to \
1 year) in Part 1. Participants who completed the initial treatment of 17 cycles of pembrolizumab and experienced disease recurrence may have been eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \
2 years) in Part 2. | 487 |
| Placebo Participants received saline placebo by IV infusion Q3W (21-day cycles) for up to 17 cycles (up to \
1 year) in Part 1. Participants who completed the initial treatment of 17 cycles of placebo and experienced disease recurrence may have been eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to \
2 years) in Part 2. | 489 |
| Total | 976 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 17 | 17 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Ongoing in Study | 460 | 459 |
| Overall Study | Withdrawal by Subject | 9 | 10 |
Baseline characteristics
| Characteristic | Placebo | Total | Pembrolizumab |
|---|---|---|---|
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 13.3 | 59.3 Years STANDARD_DEVIATION 12.9 | 59.0 Years STANDARD_DEVIATION 12.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 30 Participants | 79 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 409 Participants | 799 Participants | 390 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 50 Participants | 98 Participants | 48 Participants |
| Melanoma Primary Tumor (T) Stage T3a | 0 Participants | 2 Participants | 2 Participants |
| Melanoma Primary Tumor (T) Stage T3b | 201 Participants | 401 Participants | 200 Participants |
| Melanoma Primary Tumor (T) Stage T4a | 116 Participants | 229 Participants | 113 Participants |
| Melanoma Primary Tumor (T) Stage T4b | 172 Participants | 344 Participants | 172 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 45 Participants | 87 Participants | 42 Participants |
| Race (NIH/OMB) White | 439 Participants | 874 Participants | 435 Participants |
| Sex: Female, Male Female | 200 Participants | 387 Participants | 187 Participants |
| Sex: Female, Male Male | 289 Participants | 589 Participants | 300 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 17 / 487 | 18 / 489 | 3 / 45 |
| other Total, other adverse events | 417 / 483 | 364 / 486 | 26 / 45 |
| serious Total, serious adverse events | 101 / 483 | 91 / 486 | 6 / 45 |
Outcome results
Primary
Recurrence-free Survival (RFS)
RFS was defined as the time from randomization to any of the following events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or death due to any cause, whichever occurs first. Per protocol, final analysis for this primary outcome measure was performed using the initial pembrolizumab or placebo treatment with a protocol-specified analysis data cut-off date of June-21-2021.
Time frame: Up to ~32.7 months
Population: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Recurrence-free Survival (RFS) | NA Months |
| Placebo | Recurrence-free Survival (RFS) | NA Months |
p-value: 0.0004695% CI: [0.45, 0.82]Log Rank
Secondary
Distant Metastasis-free Survival (DMFS)
DMFS will be defined as the time from randomization to the first diagnosis of a distant metastasis per RECIST 1.1. Distant metastasis will refer to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes. DMFS will be reported for randomized participants.
Time frame: Up to ~9 years
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.
Time frame: Up to ~19.3 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to an AE | 84 Participants |
| Placebo | Number of Participants Who Discontinued Study Treatment Due to an AE | 22 Participants |
95% CI: [9.1, 16.9]
Secondary
Number of Participants Who Experienced at Least One Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.
Time frame: Up to ~19.3 months
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Experienced at Least One Adverse Event (AE) | 461 Participants |
| Placebo | Number of Participants Who Experienced at Least One Adverse Event (AE) | 444 Participants |
95% CI: [1, 7.3]
Secondary
Overall Survival (OS)
OS will be defined as the time from randomization to death due to any cause. OS will be reported for randomized participants.
Time frame: Up to ~15 years