Clinical trial NCT03665597: Relative Bioavailability Study of Subcutaneous Injection Versus Intravenous Infusion of Pembrolizumab (MK-3475) in Participants With Advanced Melanoma (MK-3475-555/KEYNOTE-555)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Melanoma
Keywords: Programmed Cell Death 1
PD1
PD-1
Programmed Cell Death-Ligand 1
PDL1
PD-L1
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2018-09-11
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Area Under the Concentration-Time Curve (AUC) of Pembrolizumab - Cohort A
timeFrame: 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.
measure: Maximum Plasma Concentration (Cmax) of Pembrolizumab - Cohort A
timeFrame: 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.
measure: Bioavailability (F) of Pembrolizumab - Cohort A
timeFrame: 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.
measure: Absorption Rate Constant (Ka) of Pembrolizumab - Cohort A
timeFrame: 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.
measure: Time of Maximum Plasma Concentration (Tmax) of Pembrolizumab - Cohort A
timeFrame: 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.
measure: Clearance (CL) of Pembrolizumab - Cohort A
timeFrame: 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.
measure: Central Volume of Distribution (Vc) of Pembrolizumab - Cohort A
timeFrame: 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.
measure: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Cohort B
timeFrame: Up to approximately 54 months
Secondary outcomes:
measure: Number of Participants Positive for Pembrolizumab Anti-Drug Antibody (ADA) Formation - Cohort A
timeFrame: Cycles 1-4 Day 1: Predose. Each cycle is 21 days. (Up to approximately 64 days)
measure: Number of Participants Who Experienced One or More Adverse Event (AEs) - Cohort A
timeFrame: Up to approximately 27 months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort A
timeFrame: Up to approximately 23 months
measure: Number of Participants With One or More Injection Site Signs and Symptoms After Subcutaneous Pembrolizumab Injection in Cycles 1-3 - Cohort A
timeFrame: Cycles 1-3 Day 1: Up to 60 minutes postdose. Each cycle is 21 days. (Up to approximately 43 days)
measure: Duration of Response (DOR) Per RECIST 1.1 - Cohort B
timeFrame: Up to approximately 54 months
measure: 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
timeFrame: Up to approximately 54 months
measure: Overall Survival (OS) - Cohort B
timeFrame: Up to approximately 54 months
measure: Early Cycle AUC of Pembrolizumab - Cohort B
timeFrame: 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)
measure: Steady State AUC of Pembrolizumab - Cohort B
timeFrame: 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)
measure: Early Cycle Cmax of Pembrolizumab - Cohort B
timeFrame: 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)
measure: Steady State Cmax of Pembrolizumab - Cohort B
timeFrame: 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)
measure: Early Cycle Minimum Plasma Concentration (Cmin) of Pembrolizumab - Cohort B
timeFrame: 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)
measure: Steady State Cmin of Pembrolizumab - Cohort B
timeFrame: 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)
measure: Number of Participants Who Experienced One or More AEs - Cohort B
timeFrame: Up to approximately 54 months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort B
timeFrame: Up to approximately 26 months
Other outcomes:
Locations:
city: Orange
country: Australia
facility: Orange Health Services ( Site 0004)
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle ( Site 0006)
state: New South Wales
city: Cairns
country: Australia
facility: Cairns and Hinterland Hospital and Health Service ( Site 0001)
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital ( Site 0002)
state: South Australia
city: Ballarat
country: Australia
facility: Ballarat Health Services ( Site 0003)
city: Port Macquarie
country: Australia
facility: MNCCI Port Macquarie Base Hospital ( Site 0005)
city: Groenkloof Pretoria
country: South Africa
facility: MPOC ( Site 0027)
state: Gauteng
city: Johannesburg
country: South Africa
facility: WITS Clinical Research CMJAH Clinical Trial Site ( Site 0030)
state: Gauteng
city: Johannesburg
country: South Africa
facility: The Medical Oncology Centre of Rosebank ( Site 0026)
state: Gauteng
city: Kraaifontein
country: South Africa
facility: Cape Town Oncology Trials Pty Ltd ( Site 0028)
state: Western Cape
city: Johannesburg
country: South Africa
facility: Sandton Oncology Medical Group PTY LTD ( Site 0029)
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d Hebron ( Site 0062)
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona ( Site 0061)
city: San Sebastian
country: Spain
facility: Onkologikoa - Instituto Oncologico de San Sebastian ( Site 0063)
city: Solna
country: Sweden
facility: Karolinska Universitetssjukhuset Solna ( Site 0040)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.