Relative Bioavailability Study of Subcutaneous Injection Versus Intravenous Infusion of Pembrolizumab (MK-3475) in Participants With Advanced Melanoma (MK-3475-555/KEYNOTE-555)

A Phase 1 Randomized Clinical Study of Pembrolizumab (MK-3475) to Evaluate the Relative Bioavailability of Subcutaneous Injection Versus Intravenous Infusion in Participants With Advanced Melanoma (KEYNOTE-555)

The purpose of this study is to characterize the pharmacokinetic (PK) profile of pembrolizumab (MK-3475) following single subcutaneous (SC) injection of pembrolizumab Dose A versus pembrolizumab Dose C in adults with advanced melanoma. Additionally, the safety and tolerability of pembrolizumab SC injections will be assessed. And, finally, the efficacy of pembrolizumab intravenous (IV) infusion administration will be assessed.

Study Overview

• Status: Completed
• Conditions: Melanoma
• Intervention / Treatment: Biological: Pembrolizumab Dose C; Biological: Pembrolizumab Dose A; Biological: Pembrolizumab Dose B; Biological: Pembrolizumab Dose D

Detailed Description

This study consists of two cohorts. Participants in Cohort A are randomized to one of six treatment sequences which will include 2 cycles of pembrolizumab administered via subcutaneous injection and 1 cycle of intravenous (IV) infusion, followed by up to 32 cycles (up to ~2 years) of pembrolizumab administered via IV infusion (each cycle is 21 days). Participants in Cohort B will receive pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 18 cycles, up to ~ 2 years. Each cycle is 42 days.

• Study Type: Interventional
• Enrollment (Actual): 138
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Ballarat, Australia, 3350
    • Ballarat Health Services ( Site 0003)
  • Port Macquarie, Australia, 2444
    • MNCCI Port Macquarie Base Hospital ( Site 0005)
  • New South Wales
    • Orange, New South Wales, Australia, 2800
      • Orange Health Services ( Site 0004)
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle ( Site 0006)
  • Queensland
    • Cairns, Queensland, Australia, 4870
      • Cairns and Hinterland Hospital and Health Service ( Site 0001)
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital ( Site 0002)
• South Africa
  • Johannesburg, South Africa, 2196
    • Sandton Oncology Medical Group PTY LTD ( Site 0029)
  • Gauteng
    • Groenkloof Pretoria, Gauteng, South Africa, 0181
      • MPOC ( Site 0027)
    • Johannesburg, Gauteng, South Africa, 2193
      • WITS Clinical Research CMJAH Clinical Trial Site ( Site 0030)
    • Johannesburg, Gauteng, South Africa, 2196
      • The Medical Oncology Centre of Rosebank ( Site 0026)
  • Western Cape
    • Kraaifontein, Western Cape, South Africa, 7570
      • Cape Town Oncology Trials Pty Ltd ( Site 0028)
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d Hebron ( Site 0062)
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona ( Site 0061)
  • San Sebastian, Spain, 20014
    • Onkologikoa - Instituto Oncologico de San Sebastian ( Site 0063)
• Sweden
  • Solna, Sweden, 171 64
    • Karolinska Universitetssjukhuset Solna ( Site 0040)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has histologically or cytologically confirmed diagnosis of advanced melanoma.
• Has unresectable Stage III or Stage IV melanoma, as per American Joint Committee on Cancer (AJCC) staging system not amenable to local therapy.
• Has been untreated for advanced or metastatic disease except as follows:
• a. BRAF V600 mutant melanoma may have received standard of care targeted therapy (e.g. BRAF/ mitogen-activated protein kinase kinase enzyme [MEK] inhibitor, alone or in combination) and be eligible for this study.
• b. Prior adjuvant (post-surgery) or neoadjuvant (pre-surgery) melanoma therapy is permitted if it was completed ≥4 weeks before randomization and all related AEs have either returned to baseline or stabilized (resolution of toxic effect[s] of the most recent prior therapy to Grade 1 or less [except alopecia]).
• Female participants must agree to use contraception during the treatment period and for ≥120 days after the last dose of study treatment.
• Has measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Has adequate organ function.

Exclusion Criteria:

• Has received prior systemic treatment for unresectable or metastatic melanoma (exceptions as noted above in the Inclusion Criteria).
• Has received prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. OX-40 and CD137) or any other antibody or drug specifically targeting checkpoint pathways other than anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) which is permitted in the adjuvant setting.
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
• 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 a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment.
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with 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 are not excluded.
• Has known active central nervous system metastases and/or carcinomatous meningitis.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has ocular melanoma.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
• 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 or known active Hepatitis C virus infection.
• 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.
• Has had an allogenic tissue/solid organ transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A Pembrolizumab Treatment Sequence 1; Participants receive a single dose of pembrolizumab in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembrolizumab 165 mg/mL subcutaneously (SC); Cycle 2 Day 1: pembrolizumab 200 mg intravenously (IV); Cycle 3 Day 1: pembrolizumab 130 mg/mL SC; Cycle 4 Day 1 and every cycle thereafter, up to a total of 35 cycles (up to approximately 2 years), Day 1: pembrolizumab 200 mg IV.	Biological: Pembrolizumab Dose C; 165 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose A; 130 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose B; 200 mg administered via intravenous infusion; Other Names: KEYTRUDA®, MK-3475
Experimental: Cohort A Pembrolizumab Treatment Sequence 2; Participants receive a single dose of pembrolizumab in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembrolizumab 165 mg/mL SC; Cycle 2 Day 1: pembrolizumab 130 mg/mL SC; Cycle 3 Day 1: pembrolizumab 200 mg IV; Cycle 4 Day 1 and every cycle thereafter, up to a total of 35 cycles (up to approximately 2 years), Day 1: pembrolizumab 200 mg IV.	Biological: Pembrolizumab Dose C; 165 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose A; 130 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose B; 200 mg administered via intravenous infusion; Other Names: KEYTRUDA®, MK-3475
Experimental: Cohort A Pembrolizumab Treatment Sequence 3; Participants receive a single dose of pembrolizumab in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembrolizumab 130 mg/mL SC; Cycle 2 Day 1: pembrolizumab 165 mg/mL SC; Cycle 3 Day 1: pembrolizumab 200 mg IV; Cycle 4 Day 1 and every cycle thereafter, up to a total of 35 cycles (up to approximately 2 years), Day 1: pembrolizumab 200 mg IV.	Biological: Pembrolizumab Dose C; 165 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose A; 130 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose B; 200 mg administered via intravenous infusion; Other Names: KEYTRUDA®, MK-3475
Experimental: Cohort A Pembrolizumab Treatment Sequence 4; Participants receive a single dose of pembrolizumab in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembrolizumab 200 mg SC; Cycle 2 Day 1: pembrolizumab 200 mg IV; Cycle 3 Day 1: pembrolizumab 130 mg/mL SC; Cycle 4 Day 1 and every cycle thereafter, up to a total of 35 cycles (up to approximately 2 years), Day 1: pembrolizumab Dose 200 mg IV.	Biological: Pembrolizumab Dose C; 165 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose A; 130 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose B; 200 mg administered via intravenous infusion; Other Names: KEYTRUDA®, MK-3475
Experimental: Cohort A Pembrolizumab Treatment Sequence 5; Participants receive a single dose of pembrolizumab in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembrolizumab 200 mg IV; Cycle 2 Day 1: pembrolizumab 130 mg/mL SC; Cycle 3 Day 1: pembrolizumab 165 mg/mL SC: Cycle 4 Day 1 and every cycle thereafter, up to a total of 35 cycles (up to approximately 2 years), Day 1: pembrolizumab 200 mg IV.	Biological: Pembrolizumab Dose C; 165 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose A; 130 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose B; 200 mg administered via intravenous infusion; Other Names: KEYTRUDA®, MK-3475
Experimental: Cohort A Pembrolizumab Treatment Sequence 6; Participants receive a single dose of pembrolizumab in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembrolizumab 200 mg IV; Cycle 2 Day 1: pembrolizumab 165 mg/mL SC; Cycle 3 Day 1: pembrolizumab 130 mg/mL SC; Cycle 4 Day 1 and every cycle thereafter, up to a total of 35 cycles (up to approximately 2 years), Day 1: pembrolizumab 200 mg IV.	Biological: Pembrolizumab Dose C; 165 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose A; 130 mg/mL administered to a final dose of 285 mg via subcutaneous injection; Other Names: KEYTRUDA®, MK-3475; Biological: Pembrolizumab Dose B; 200 mg administered via intravenous infusion; Other Names: KEYTRUDA®, MK-3475
Experimental: Cohort B Pembrolizumab 400 mg IV; Participants receive a single dose of pembrolizumab 400 mg IV on Day 1 of each 42-day cycle (every 6 weeks; Q6W) for up to 18 cycles (up to approximately 2 years).	Biological: Pembrolizumab Dose D; 400 mg administered via intravenous infusion; Other Names: KEYTRUDA®, MK-3475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-Time Curve (AUC) of Pembrolizumab - Cohort A	AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time. Blood samples were collected at designated time points and a pharmacokinetic (PK) model based on historical intravenous pembrolizumab PK data were used for the determination of the AUC of pembrolizumab. Geometric least-square mean (GM) and 95% confidence intervals were derived from mixed-effects model performed on natural log-transformed values. Data were reported by treatment received.	Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.
Maximum Plasma Concentration (Cmax) of Pembrolizumab - Cohort A	Cmax was defined as the maximum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points and a PK model based on historical intravenous pembrolizumab PK data were used for the determination of the AUC of pembrolizumab. GM and 95% confidence intervals were derived from mixed-effects model performed on natural log-transformed values. Data were reported by treatment received.	Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.
Bioavailability (F) of Pembrolizumab - Cohort A	Blood samples were collected at designated time points and a population PK model based on historical intravenous pembrolizumab PK data was used for the determination of the F of pembrolizumab. Per protocol, an integrated population PK analysis was performed and combined data for Cohort A was reported.	Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.
Absorption Rate Constant (Ka) of Pembrolizumab - Cohort A	Blood samples were collected at designated time points and a population PK model based on historical intravenous pembrolizumab PK data was used for the determination of the Ka of pembrolizumab. Per protocol, an integrated population PK analysis was performed and combined data for Cohort A was reported. Participants in Cohort B weren't analyzed, per protocol.	Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.
Time of Maximum Plasma Concentration (Tmax) of Pembrolizumab - Cohort A	Blood samples were collected at designated time points for the determination of the Tmax of pembrolizumab.	Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.
Clearance (CL) of Pembrolizumab - Cohort A	Blood samples were collected at designated time points and a population PK model based on historical intravenous pembrolizumab PK data was used for the determination of the CL of pembrolizumab. Per protocol, an integrated population PK analysis was performed and combined data for Cohort A was reported.	Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.
Central Volume of Distribution (Vc) of Pembrolizumab - Cohort A	Blood samples were collected at designated time points and a population PK model based on historical intravenous pembrolizumab PK data was used for the determination of the Vc of pembrolizumab. Per protocol, an integrated population PK analysis was performed and combined data for Cohort A was reported.	Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Cohort B	ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions). Responses were based upon blinded independent central review (BICR) per RECIST 1.1. ORR was reported for participants in Cohort B.	Up to approximately 54 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Positive for Pembrolizumab Anti-Drug Antibody (ADA) Formation - Cohort A	Blood samples were collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The number of participants who develop anti-pembrolizumab antibodies were assessed in Cycles 1 through Cycle 4. Per ADA immunogenicity analysis report, data from participants in Cohort A were reported combined across treatment cycles 1-4.	Cycles 1-4 Day 1: Predose. Each cycle is 21 days. (Up to approximately 64 days)
Number of Participants Who Experienced One or More Adverse Event (AEs) - Cohort A	An AE was 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. The number of participants who experienced one or more AEs in Cohort A was reported. Per protocol, data were reported by treatment received and AEs from Cycles 4-35 were reported separately.	Up to approximately 27 months
Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort A	An AE was 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. The number of participants who discontinued due to an AE in Cohort A were reported. Per protocol, data were reported by treatment received and data from Cycles 4-35 were reported separately.	Up to approximately 23 months
Number of Participants With One or More Injection Site Signs and Symptoms After Subcutaneous Pembrolizumab Injection in Cycles 1-3 - Cohort A	Participants completed the Injection Site Signs and Symptoms Questionnaire, within 60 minutes after each pembrolizumab SC injection during Cycles 1-3. Participants rated any pain, itching, swelling and redness they experienced at the pembrolizumab SC injection site from "None" to "Severe". The number of participants who experienced an injection site sign or symptom was reported.	Cycles 1-3 Day 1: Up to 60 minutes postdose. Each cycle is 21 days. (Up to approximately 43 days)
Duration of Response (DOR) Per RECIST 1.1 - Cohort B	For participants who demonstrated a CR (disappearance of all target lesions) or PR (At least a 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. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR was calculated for RECIST 1.1 based on BICR. DOR for Cohort B was reported.	Up to approximately 54 months
Progression-free Survival (PFS) Per to RECIST v1.1 Modified to Follow a Maximum of 10 Target Lesions and a Maximum of 5 Target Lesions Per Organ - Cohort B	PFS was defined as the time from the first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Although RECIST 1.1 was modified to allow for a maximum of 10 target lesions in total and 5 per organ. Per protocol, PFS as assessed by BICR for participants in Cohort B was reported.	Up to approximately 54 months
Overall Survival (OS) - Cohort B	OS was defined as the time from the first dose of study treatment to death due to any cause. Per protocol, OS for participants in Cohort B was reported.	Up to approximately 54 months
Early Cycle AUC of Pembrolizumab - Cohort B	AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time. Blood samples were collected at designated time points for the determination of the pembrolizumab AUC in participants in Cohort B during Cycle 1 (early cycle). Blood samples were also collected predose on Day 1 of Cycle 2 just prior to the next dose as the last sample (trough concentration) of Cycle 1. A cycle was 42 days.	Cycle 1: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 2: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)
Steady State AUC of Pembrolizumab - Cohort B	AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time. Blood samples were collected at designated time points for the determination of the pembrolizumab AUC in participants in Cohort B during Cycle 4 (steady state). Blood samples were also collected predose on Day 1 of Cycle 5 just prior to the next dose as the last samples (trough concentration) of Cycle 4. Each cycle was 42 days.	Cycle 4: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 5: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)
Early Cycle Cmax of Pembrolizumab - Cohort B	Cmax was defined as the maximum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points for the determination of the pembrolizumab Cmax in participants in Cohort B during Cycle 1 (early cycle). Blood samples were also collected predose on Day 1 of Cycle 2 just prior to the next dose as the last sample (trough concentration) of Cycle 1. Each cycle was 42 days.	Cycle 1: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 2: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)
Steady State Cmax of Pembrolizumab - Cohort B	Cmax was defined as the maximum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points for the determination of the pembrolizumab Cmax in participants in Cohort B during Cycle 4 (steady state). Blood samples were also collected predose on Day 1 of Cycle 5 just prior to the next dose as the last sample (trough concentration) of Cycle 4. Each cycle was 42 days.	Cycle 4: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 5: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)
Early Cycle Minimum Plasma Concentration (Cmin) of Pembrolizumab - Cohort B	Cmin was defined as the minimum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points for the determination of the pembrolizumab Cmin in participants in Cohort B during Cycle 1 (early cycle). Blood samples were also collected predose on Day 1 of Cycle 2 just prior to the next dose as the last sample (trough concentration) of Cycle 1. Each cycle was 42 days.	Cycle 1: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 2: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)
Steady State Cmin of Pembrolizumab - Cohort B	Cmin was defined as the minimum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points for the determination of the pembrolizumab Cmin in participants in Cohort B during Cycle 4 (steady state). Blood samples were also collected predose on Day 1 of Cycle 5 just prior to the next dose as the last sample (trough concentration) of Cycle 4. Each cycle was 42 days.	Cycle 4: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 5: Predose. Each Cycle was 42 days. (Up to approximately 6 weeks)
Number of Participants Who Experienced One or More AEs - Cohort B	An AE was 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. The number of participants who experienced one or more AEs in Cohort B was reported.	Up to approximately 54 months
Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort B	An AE was 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. The number of participants who discontinued due to an AE in Cohort B were reported.	Up to approximately 26 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Cohen G, Rapoport B, Chan SW, Ruff P, Arance A, Mujika Eizmendi K, Houghton B, Brown MP, Zielinski RM, Munoz Couselo E, Lyle M, Anderson JR, Jain L, de Alwis D, Lala M, Akala O, Chartash E, Jacobs C. Pembrolizumab 400 mg every 6 weeks as first-line therapy for advanced melanoma (KEYNOTE-555): Results from cohort B of an open-label, phase 1 study. PLoS One. 2024 Nov 12;19(11):e0309778. doi: 10.1371/journal.pone.0309778. eCollection 2024.

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2018
• Primary Completion (Actual): December 4, 2023
• Study Completion (Actual): December 4, 2023

Study Registration Dates

• First Submitted: August 23, 2018
• First Submitted That Met QC Criteria: September 7, 2018
• First Posted (Actual): September 11, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 3, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: PD-1; PD-L1; Programmed Cell Death 1; PD1; PDL1; Programmed Cell Death-Ligand 1
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pembrolizumab
• Other Study ID Numbers: 3475-555; MK-3475-555 (Other Identifier: MSD); KEYNOTE-555 (Other Identifier: MSD); 2019-001052-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No