Melanoma
Conditions
Keywords
Melanoma, Metastatic Melanoma
Brief summary
The purpose of the study is to assess the efficacy, safety, and tolerability when combining pembrolizumab with epacadostat or placebo in participants with unresectable or metastatic melanoma
Interventions
DRUGpembrolizumab + epacadostat
* Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1) * Epacadostat will be administered orally daily starting at Day 1 (Week 1)
DRUGpembrolizumab + placebo
* Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1) * Placebo will be administered orally daily starting at Day 1 (Week 1)
Sponsors
Merck Sharp & Dohme LLC
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have histologically or cytologically confirmed melanoma * Have unresectable Stage III or Stage IV melanoma, as per AJCC staging system not amenable to local therapy * A minimum of 1 measurable lesion by CT or MRI * Provide a baseline tumor biopsy * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
Exclusion criteria
* Has received prior systemic treatment for unresectable or metastatic melanoma (except BRAF directed therapy) * Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or IDO1 inhibitor or any other antibody or drug specifically targeting checkpoint pathways other than anti-CTLA-4 which is permitted in the adjuvant setting * Has received prior adjuvant therapy, monoclonal antibody or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) * Has an active infection requiring systemic therapy * Has known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) * Has known history of or is positive for Hepatitis B or Hepatitis C * Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Assessed every 9 weeks for duration of study participation which is estimated to be 24 months | Progression-free survival, defined as the time from date of randomization until the earliest date of disease progression, as determined by independent central review of objective radiographic disease assessments per RECIST 1.1, or death from any cause, whichever comes first. |
| Overall Survival (OS) Rate at 6 Months | Assessed every 9 weeks of study participation which is estimated to be 24 months. The OS rate at Month 6 was calculated. | Defined as time from date of randomization to date of death due to any cause. OS was calculated using product-limit (Kaplan-Meier) method for censored data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Assessed every 9 weeks for duration of study participation which is estimated to be 24 months | Defined as the time from the earliest date of qualifying response until earliest date of disease progression, per RECIST v1.1, or death from any cause, whichever comes first. Includes participants with complete response or partial response. |
| Apparent Oral Clearance (CL/F) of Epacadostat | Through up to 30 days after the end of treatment, up to 25 months | Defined as oral dose clearance. |
| Apparent Volume of Distribution (Vd/F) of Epacadostat | Through up to 30 days after the end of treatment, up to 25 months | Apparent volume of distribution after administration. |
| Objective Response Rate (ORR) | Assessed every 9 weeks for duration of study participation which is estimated to be 24 months | Objective response rate (ORR) is defined as the percentage of the participants in the analysis population who have a confirmed complete response (CR) or partial response (PR) based on RECIST 1.1 by independent central review. |
| Volume of Distribution (V) of Pembrolizumab | Through up to 30 days after the end of treatment, up to 25 months | — |
| Formation of Anti-pembrolizumab Antibodies | Through up to 30 days after the end of treatment, up to 25 months | Evaluate the measurement of anti-drug antibodies (ADA). |
| Clearance (CL) of Pembrolizumab | Through up to 30 days after the end of treatment, up to 25 months | — |
| Safety and Tolerability, as Assessed by Percentage of Participants With Adverse Events | Through up to 90 days after end of treatment, up to 27 months | Safety and tolerability, as assessed by percentage of participants with adverse events and changes in laboratory parameters. |
Countries
Australia, Belgium, Canada, Chile, Denmark, France, Germany, Ireland, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Poland, Russia, South Africa, South Korea, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 135 centers in 23 countries
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Epacadostat Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Epacadostat will be administered orally daily starting at Day 1 (Week 1). | 354 |
| Pembrolizumab + Placebo Pembrolizumab will be administered intravenously every 3 weeks starting at Day 1 (Week 1). Placebo will be administered orally daily starting at Day 1 (Week 1). | 352 |
| Total | 706 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 146 | 129 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Withdrawal by Subject | 9 | 10 |
Baseline characteristics
| Characteristic | Pembrolizumab + Epacadostat | Pembrolizumab + Placebo | Total |
|---|---|---|---|
| Age, Customized < 65 years | 183 Participants | 193 Participants | 376 Participants |
| Age, Customized ≥ 65 years | 171 Participants | 159 Participants | 330 Participants |
| Eastern Cooperative Oncology Group (ECOG) Fully active | 261 Participants | 267 Participants | 528 Participants |
| Eastern Cooperative Oncology Group (ECOG) Restricted in physically strenuous activity | 93 Participants | 85 Participants | 178 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 36 Participants | 27 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 302 Participants | 306 Participants | 608 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 19 Participants | 35 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 40 Participants | 36 Participants | 76 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 311 Participants | 315 Participants | 626 Participants |
| Sex: Female, Male Female | 137 Participants | 146 Participants | 283 Participants |
| Sex: Female, Male Male | 217 Participants | 206 Participants | 423 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 147 / 353 | 136 / 352 |
| other Total, other adverse events | 327 / 353 | 325 / 352 |
| serious Total, serious adverse events | 99 / 353 | 100 / 352 |
Outcome results
Primary
Overall Survival (OS) Rate at 6 Months
Defined as time from date of randomization to date of death due to any cause. OS was calculated using product-limit (Kaplan-Meier) method for censored data.
Time frame: Assessed every 9 weeks of study participation which is estimated to be 24 months. The OS rate at Month 6 was calculated.
Population: Intent to Treat (ITT) population: consists of all randomized participants. OS was analyzed at the time of primary analysis at 6 months. An overall OS was not conducted after the primary analysis since all participants were unblinded, transitioned to monotherapy pembrolizumab and survival follow-up was discontinued.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Epacadostat | Overall Survival (OS) Rate at 6 Months | 84.1 percent probability |
| Pembrolizumab + Placebo | Overall Survival (OS) Rate at 6 Months | 87.2 percent probability |
p-value: 0.8066695% CI: [0.86, 1.49]Log Rank
Primary
Progression-free Survival
Progression-free survival, defined as the time from date of randomization until the earliest date of disease progression, as determined by independent central review of objective radiographic disease assessments per RECIST 1.1, or death from any cause, whichever comes first.
Time frame: Assessed every 9 weeks for duration of study participation which is estimated to be 24 months
Population: Intent to Treat (ITT) population: consists of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Epacadostat | Progression-free Survival | 4.7 months |
| Pembrolizumab + Placebo | Progression-free Survival | 4.9 months |
p-value: 0.5171195% CI: [0.83, 1.21]Log Rank
Secondary
Apparent Oral Clearance (CL/F) of Epacadostat
Defined as oral dose clearance.
Time frame: Through up to 30 days after the end of treatment, up to 25 months
Population: All randomized participants enrolled in the Epacadostat arm currently with melanoma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pembrolizumab + Epacadostat | Apparent Oral Clearance (CL/F) of Epacadostat | 59.8 Liter/hour (L/h) | Standard Deviation 17.5 |
Secondary
Apparent Volume of Distribution (Vd/F) of Epacadostat
Apparent volume of distribution after administration.
Time frame: Through up to 30 days after the end of treatment, up to 25 months
Population: All randomized participants enrolled in the Epacadostat arm currently with melanoma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pembrolizumab + Epacadostat | Apparent Volume of Distribution (Vd/F) of Epacadostat | 139 Liter | Standard Deviation 22.5 |
Secondary
Clearance (CL) of Pembrolizumab
Time frame: Through up to 30 days after the end of treatment, up to 25 months
Population: The data was not available nor was the analysis completed for pembrolizumab CL, because participants were unblinded and sample collections and the planned analysis for pembrolizumab CL were discontinued after the interim analysis.
Secondary
Duration of Response (DOR)
Defined as the time from the earliest date of qualifying response until earliest date of disease progression, per RECIST v1.1, or death from any cause, whichever comes first. Includes participants with complete response or partial response.
Time frame: Assessed every 9 weeks for duration of study participation which is estimated to be 24 months
Population: Intent to Treat (ITT) population: consists of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Epacadostat | Duration of Response (DOR) | NA months |
| Pembrolizumab + Placebo | Duration of Response (DOR) | NA months |
Secondary
Formation of Anti-pembrolizumab Antibodies
Evaluate the measurement of anti-drug antibodies (ADA).
Time frame: Through up to 30 days after the end of treatment, up to 25 months
Population: Data was not available nor the analysis completed for the incidence of ADA to pembrolizumab, because all participants were unblinded; sample collections and the planned analysis for ADA were discontinued after the interim analysis.
Secondary
Objective Response Rate (ORR)
Objective response rate (ORR) is defined as the percentage of the participants in the analysis population who have a confirmed complete response (CR) or partial response (PR) based on RECIST 1.1 by independent central review.
Time frame: Assessed every 9 weeks for duration of study participation which is estimated to be 24 months
Population: Intent to Treat (ITT) population: consists of all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Epacadostat | Objective Response Rate (ORR) | 121 Participants |
| Pembrolizumab + Placebo | Objective Response Rate (ORR) | 111 Participants |
Secondary
Safety and Tolerability, as Assessed by Percentage of Participants With Adverse Events
Safety and tolerability, as assessed by percentage of participants with adverse events and changes in laboratory parameters.
Time frame: Through up to 90 days after end of treatment, up to 27 months
Population: All Subjects as Treated (ASaT): All participants who were enrolled and took at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab + Epacadostat | Safety and Tolerability, as Assessed by Percentage of Participants With Adverse Events | With one or more adverse events | 346 Participants |
| Pembrolizumab + Epacadostat | Safety and Tolerability, as Assessed by Percentage of Participants With Adverse Events | Serious adverse events | 99 Participants |
| Pembrolizumab + Placebo | Safety and Tolerability, as Assessed by Percentage of Participants With Adverse Events | With one or more adverse events | 345 Participants |
| Pembrolizumab + Placebo | Safety and Tolerability, as Assessed by Percentage of Participants With Adverse Events | Serious adverse events | 100 Participants |
Secondary
Volume of Distribution (V) of Pembrolizumab
Time frame: Through up to 30 days after the end of treatment, up to 25 months
Population: The data was not available nor was the analysis completed for pembrolizumab V, because participants were unblinded and sample collections and the planned analysis for pembrolizumab V were discontinued after the interim analysis.