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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03665597




Registration number
NCT03665597
Ethics application status
Date submitted
23/08/2018
Date registered
11/09/2018

Titles & IDs
Public title
Relative Bioavailability Study of Subcutaneous Injection Versus Intravenous Infusion of Pembrolizumab (MK-3475) in Participants With Advanced Melanoma (MK-3475-555/KEYNOTE-555)
Scientific 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)
Secondary ID [1] 0 0
MK-3475-555
Secondary ID [2] 0 0
3475-555
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Pembrolizumab Dose C
Treatment: Other - Pembrolizumab Dose A
Treatment: Other - Pembrolizumab Dose B
Treatment: Other - Pembrolizumab Dose D

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.

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.

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.

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.

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.

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.

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).


Treatment: Other: Pembrolizumab Dose C
165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Treatment: Other: Pembrolizumab Dose A
130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Treatment: Other: Pembrolizumab Dose B
200 mg administered via intravenous infusion

Treatment: Other: Pembrolizumab Dose D
400 mg administered via intravenous infusion
Intervention code [1] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Area Under the Concentration-Time Curve (AUC) of Pembrolizumab - Cohort A
Timepoint [1] 0 0
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.
Primary outcome [2] 0 0
Maximum Plasma Concentration (Cmax) of Pembrolizumab - Cohort A
Timepoint [2] 0 0
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.
Primary outcome [3] 0 0
Bioavailability (F) of Pembrolizumab - Cohort A
Timepoint [3] 0 0
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.
Primary outcome [4] 0 0
Absorption Rate Constant (Ka) of Pembrolizumab - Cohort A
Timepoint [4] 0 0
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.
Primary outcome [5] 0 0
Time of Maximum Plasma Concentration (Tmax) of Pembrolizumab - Cohort A
Timepoint [5] 0 0
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.
Primary outcome [6] 0 0
Clearance (CL) of Pembrolizumab - Cohort A
Timepoint [6] 0 0
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.
Primary outcome [7] 0 0
Central Volume of Distribution (Vc) of Pembrolizumab - Cohort A
Timepoint [7] 0 0
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.
Primary outcome [8] 0 0
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Cohort B
Timepoint [8] 0 0
Up to approximately 54 months
Secondary outcome [1] 0 0
Number of Participants Positive for Pembrolizumab Anti-Drug Antibody (ADA) Formation - Cohort A
Timepoint [1] 0 0
Cycles 1-4 Day 1: Predose. Each cycle is 21 days. (Up to approximately 64 days)
Secondary outcome [2] 0 0
Number of Participants Who Experienced One or More Adverse Event (AEs) - Cohort A
Timepoint [2] 0 0
Up to approximately 27 months
Secondary outcome [3] 0 0
Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort A
Timepoint [3] 0 0
Up to approximately 23 months
Secondary outcome [4] 0 0
Number of Participants With One or More Injection Site Signs and Symptoms After Subcutaneous Pembrolizumab Injection in Cycles 1-3 - Cohort A
Timepoint [4] 0 0
Cycles 1-3 Day 1: Up to 60 minutes postdose. Each cycle is 21 days. (Up to approximately 43 days)
Secondary outcome [5] 0 0
Duration of Response (DOR) Per RECIST 1.1 - Cohort B
Timepoint [5] 0 0
Up to approximately 54 months
Secondary outcome [6] 0 0
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
Timepoint [6] 0 0
Up to approximately 54 months
Secondary outcome [7] 0 0
Overall Survival (OS) - Cohort B
Timepoint [7] 0 0
Up to approximately 54 months
Secondary outcome [8] 0 0
Early Cycle AUC of Pembrolizumab - Cohort B
Timepoint [8] 0 0
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)
Secondary outcome [9] 0 0
Steady State AUC of Pembrolizumab - Cohort B
Timepoint [9] 0 0
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)
Secondary outcome [10] 0 0
Early Cycle Cmax of Pembrolizumab - Cohort B
Timepoint [10] 0 0
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)
Secondary outcome [11] 0 0
Steady State Cmax of Pembrolizumab - Cohort B
Timepoint [11] 0 0
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)
Secondary outcome [12] 0 0
Early Cycle Minimum Plasma Concentration (Cmin) of Pembrolizumab - Cohort B
Timepoint [12] 0 0
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)
Secondary outcome [13] 0 0
Steady State Cmin of Pembrolizumab - Cohort B
Timepoint [13] 0 0
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)
Secondary outcome [14] 0 0
Number of Participants Who Experienced One or More AEs - Cohort B
Timepoint [14] 0 0
Up to approximately 54 months
Secondary outcome [15] 0 0
Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort B
Timepoint [15] 0 0
Up to approximately 26 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
19/11/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
4/12/2023
Sample size
Target
Accrual to date
Final
138
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA
Recruitment hospital [1] 0 0
Orange Health Services ( Site 0004) - Orange
Recruitment hospital [2] 0 0
Calvary Mater Newcastle ( Site 0006) - Waratah
Recruitment hospital [3] 0 0
Cairns and Hinterland Hospital and Health Service ( Site 0001) - Cairns
Recruitment hospital [4] 0 0
Royal Adelaide Hospital ( Site 0002) - Adelaide
Recruitment hospital [5] 0 0
Ballarat Health Services ( Site 0003) - Ballarat
Recruitment hospital [6] 0 0
MNCCI Port Macquarie Base Hospital ( Site 0005) - Port Macquarie
Recruitment postcode(s) [1] 0 0
2800 - Orange
Recruitment postcode(s) [2] 0 0
2298 - Waratah
Recruitment postcode(s) [3] 0 0
4870 - Cairns
Recruitment postcode(s) [4] 0 0
5000 - Adelaide
Recruitment postcode(s) [5] 0 0
3350 - Ballarat
Recruitment postcode(s) [6] 0 0
2444 - Port Macquarie
Recruitment outside Australia
Country [1] 0 0
South Africa
State/province [1] 0 0
Gauteng
Country [2] 0 0
South Africa
State/province [2] 0 0
Western Cape
Country [3] 0 0
South Africa
State/province [3] 0 0
Johannesburg
Country [4] 0 0
Spain
State/province [4] 0 0
Barcelona
Country [5] 0 0
Spain
State/province [5] 0 0
San Sebastian
Country [6] 0 0
Sweden
State/province [6] 0 0
Solna

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?

TypeOther DetailsAttachment
Study protocol Study Protocol and Statistical Analysis Plan
Statistical analysis plan Study Protocol and Statistical Analysis Plan



Results publications and other study-related documents

TypeCitations or Other Details
Journal Cohen G, Rapoport B, Chan SW, Ruff P, Arance A, Mu... [More Details]


Results are available at https://clinicaltrials.gov/study/NCT03665597