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)
4 other identifiers
interventional
138
4 countries
15
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Nov 2018
Longer than P75 for phase_1
15 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 23, 2018
CompletedFirst Posted
Study publicly available on registry
September 11, 2018
CompletedStudy Start
First participant enrolled
November 19, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 4, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
December 4, 2023
CompletedResults Posted
Study results publicly available
February 10, 2025
CompletedFebruary 10, 2025
January 1, 2025
5 years
August 23, 2018
November 21, 2024
February 3, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (8)
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 Outcomes (15)
Number of Participants Positive for Pembrolizumab Anti-Drug Antibody (ADA) Formation - Cohort A
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
Up to approximately 27 months
Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort A
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
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
Up to approximately 54 months
- +10 more secondary outcomes
Study Arms (7)
Cohort A Pembrolizumab Treatment Sequence 1
EXPERIMENTALParticipants 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.
Cohort A Pembrolizumab Treatment Sequence 2
EXPERIMENTALParticipants 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.
Cohort A Pembrolizumab Treatment Sequence 3
EXPERIMENTALParticipants 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.
Cohort A Pembrolizumab Treatment Sequence 4
EXPERIMENTALParticipants 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.
Cohort A Pembrolizumab Treatment Sequence 5
EXPERIMENTALParticipants 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.
Cohort A Pembrolizumab Treatment Sequence 6
EXPERIMENTALParticipants 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.
Cohort B Pembrolizumab 400 mg IV
EXPERIMENTALParticipants 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).
Interventions
165 mg/mL administered to a final dose of 285 mg via subcutaneous injection
130 mg/mL administered to a final dose of 285 mg via subcutaneous injection
200 mg administered via intravenous infusion
400 mg administered via intravenous infusion
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
- +1 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (15)
Orange Health Services ( Site 0004)
Orange, New South Wales, 2800, Australia
Calvary Mater Newcastle ( Site 0006)
Waratah, New South Wales, 2298, Australia
Cairns and Hinterland Hospital and Health Service ( Site 0001)
Cairns, Queensland, 4870, Australia
Royal Adelaide Hospital ( Site 0002)
Adelaide, South Australia, 5000, Australia
Ballarat Health Services ( Site 0003)
Ballarat, 3350, Australia
MNCCI Port Macquarie Base Hospital ( Site 0005)
Port Macquarie, 2444, Australia
MPOC ( Site 0027)
Groenkloof Pretoria, Gauteng, 0181, South Africa
WITS Clinical Research CMJAH Clinical Trial Site ( Site 0030)
Johannesburg, Gauteng, 2193, South Africa
The Medical Oncology Centre of Rosebank ( Site 0026)
Johannesburg, Gauteng, 2196, South Africa
Cape Town Oncology Trials Pty Ltd ( Site 0028)
Kraaifontein, Western Cape, 7570, South Africa
Sandton Oncology Medical Group PTY LTD ( Site 0029)
Johannesburg, 2196, South Africa
Hospital Universitari Vall d Hebron ( Site 0062)
Barcelona, 08035, Spain
Hospital Clinic i Provincial de Barcelona ( Site 0061)
Barcelona, 08036, Spain
Onkologikoa - Instituto Oncologico de San Sebastian ( Site 0063)
Donostia / San Sebastian, 20014, Spain
Karolinska Universitetssjukhuset Solna ( Site 0040)
Solna, 171 64, Sweden
Related Publications (1)
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.
PMID: 39531423RESULT
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Results Point of Contact
- Title
- Senior Vice President, Global Clinical Development
- Organization
- Merck Sharp & Dohme LLC
Study Officials
- STUDY DIRECTOR
Medical Director
Merck Sharp & Dohme LLC
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- CROSSOVER
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 23, 2018
First Posted
September 11, 2018
Study Start
November 19, 2018
Primary Completion
December 4, 2023
Study Completion
December 4, 2023
Last Updated
February 10, 2025
Results First Posted
February 10, 2025
Record last verified: 2025-01
Data Sharing
- IPD Sharing
- Will share
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf