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

NCT ID: NCT03665597

Last Updated: 2025-02-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 138 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-19
• Study Completion Date: 2023-12-04

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.

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.

Conditions

Melanoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Pembrolizumab Dose C

Intervention Type: BIOLOGICAL

165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose A

Intervention Type: BIOLOGICAL

130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose B

Intervention Type: BIOLOGICAL

200 mg administered via intravenous infusion

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.

Group Type: EXPERIMENTAL

Pembrolizumab Dose C

Intervention Type: BIOLOGICAL

165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose A

Intervention Type: BIOLOGICAL

130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose B

Intervention Type: BIOLOGICAL

200 mg administered via intravenous infusion

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.

Group Type: EXPERIMENTAL

Pembrolizumab Dose C

Intervention Type: BIOLOGICAL

165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose A

Intervention Type: BIOLOGICAL

130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose B

Intervention Type: BIOLOGICAL

200 mg administered via intravenous infusion

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.

Group Type: EXPERIMENTAL

Pembrolizumab Dose C

Intervention Type: BIOLOGICAL

165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose A

Intervention Type: BIOLOGICAL

130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose B

Intervention Type: BIOLOGICAL

200 mg administered via intravenous infusion

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.

Group Type: EXPERIMENTAL

Pembrolizumab Dose C

Intervention Type: BIOLOGICAL

165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose A

Intervention Type: BIOLOGICAL

130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose B

Intervention Type: BIOLOGICAL

200 mg administered via intravenous infusion

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.

Group Type: EXPERIMENTAL

Pembrolizumab Dose C

Intervention Type: BIOLOGICAL

165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose A

Intervention Type: BIOLOGICAL

130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Pembrolizumab Dose B

Intervention Type: BIOLOGICAL

200 mg administered via intravenous infusion

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).

Group Type: EXPERIMENTAL

Pembrolizumab Dose D

Intervention Type: BIOLOGICAL

400 mg administered via intravenous infusion

Interventions

Pembrolizumab Dose C

165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Intervention Type: BIOLOGICAL

Pembrolizumab Dose A

130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Intervention Type: BIOLOGICAL

Pembrolizumab Dose B

200 mg administered via intravenous infusion

Intervention Type: BIOLOGICAL

Pembrolizumab Dose D

400 mg administered via intravenous infusion

Intervention Type: BIOLOGICAL

Other Intervention Names

KEYTRUDA®, MK-3475; KEYTRUDA®, MK-3475; KEYTRUDA®, MK-3475; KEYTRUDA®, MK-3475

Eligibility Criteria

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.

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

Locations

Orange Health Services ( Site 0004)

Orange, New South Wales, Australia

Calvary Mater Newcastle ( Site 0006)

Waratah, New South Wales, Australia

Cairns and Hinterland Hospital and Health Service ( Site 0001)

Cairns, Queensland, Australia

Royal Adelaide Hospital ( Site 0002)

Adelaide, South Australia, Australia

Ballarat Health Services ( Site 0003)

Ballarat, , Australia

MNCCI Port Macquarie Base Hospital ( Site 0005)

Port Macquarie, , Australia

MPOC ( Site 0027)

Groenkloof Pretoria, Gauteng, South Africa

WITS Clinical Research CMJAH Clinical Trial Site ( Site 0030)

Johannesburg, Gauteng, South Africa

The Medical Oncology Centre of Rosebank ( Site 0026)

Johannesburg, Gauteng, South Africa

Cape Town Oncology Trials Pty Ltd ( Site 0028)

Kraaifontein, Western Cape, South Africa

Sandton Oncology Medical Group PTY LTD ( Site 0029)

Johannesburg, , South Africa

Hospital Universitari Vall d Hebron ( Site 0062)

Barcelona, , Spain

Hospital Clinic i Provincial de Barcelona ( Site 0061)

Barcelona, , Spain

Onkologikoa - Instituto Oncologico de San Sebastian ( Site 0063)

Donostia / San Sebastian, , Spain

Karolinska Universitetssjukhuset Solna ( Site 0040)

Solna, , Sweden

Countries

Australia; South Africa; Spain; Sweden

References

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.

Reference Type: RESULT

PMID: 39531423 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.merckclinicaltrials.com/

Merck Clinical Trials Information

Other Identifiers

MK-3475-555

Identifier Type: OTHER

Identifier Source: secondary_id

KEYNOTE-555

Identifier Type: OTHER

Identifier Source: secondary_id

2019-001052-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

3475-555

Identifier Type: -

Identifier Source: org_study_id