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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)
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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)
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Secondary ID [1]
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MK-3475-555
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Secondary ID [2]
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3475-555
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Melanoma
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Condition category
Condition code
Cancer
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0
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Malignant melanoma
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Intervention/exposure
Study type
Interventional
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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: Pembrolizumab Sequence 1 - Participants receive a single dose of pembrolizumab (pembro) in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembro Dose A subcutaneously (SC); Cycle 2 Day 1: pembro Dose B intravenously (IV); Cycle 3 Day 1: pembro Dose C SC; Cycle 4 Day 1 and every cycle thereafter (up to a total of 35 cycles) Day 1: pembro Dose B IV.
Experimental: Pembrolizumab Sequence 2 - Participants receive a single dose of pembro in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembro Dose A SC; Cycle 2 Day 1: pembro Dose C SC; Cycle 3 Day 1: pembro Dose B IV; Cycle 4 Day 1 and every cycle thereafter (up to a total of 35 cycles) Day 1: pembro Dose B IV.
Experimental: Pembrolizumab Sequence 3 - Participants receive a single dose of pembro in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembro Dose C SC; Cycle 2 Day 1: pembro Dose A SC; Cycle 3 Day 1: pembro Dose B IV; Cycle 4 Day 1 and every cycle thereafter (up to a total of 35 cycles) Day 1: pembro Dose B IV.
Experimental: Pembrolizumab Sequence 4 - Participants receive a single dose of pembro in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembro Dose C SC; Cycle 2 Day 1: pembro Dose B IV; Cycle 3 Day 1: pembro Dose A SC; Cycle 4 Day 1 and every cycle thereafter (up to a total of 35 cycles) Day 1: pembro Dose B IV.
Experimental: Pembrolizumab Sequence 5 - Participants receive a single dose of pembro in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembro Dose B IV; Cycle 2 Day 1: pembro Dose C SC; Cycle 3 Day 1: pembro Dose A SC: Cycle 4 Day 1 and every cycle thereafter (up to a total of 35 cycles) Day 1: pembro Dose B IV.
Experimental: Pembrolizumab Sequence 6 - Participants receive a single dose of pembro in each 21-day cycle in the following sequence: Cycle 1 Day 1: pembro Dose B IV; Cycle 2 Day 1: pembro Dose A SC; Cycle 3 Day 1: pembro Dose C SC; Cycle 4 Day 1 and every cycle thereafter (up to a total of 35 cycles) Day 1: pembro Dose B IV.
Experimental: Pembrolizumab Dose D - Participants receive a single dose of pembro Dose D 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
SC injection
Treatment: Other: Pembrolizumab Dose A
SC injection
Treatment: Other: Pembrolizumab Dose B
IV infusion
Treatment: Other: Pembrolizumab Dose D
IV infusion once every 6 weeks
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Intervention code [1]
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Treatment: Other
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Pembrolizumab Area Under the Concentration-Time Curve (AUC) - Pembrolizumab Sequence 1-6
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Assessment method [1]
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Blood samples are to be collected at designated time points for the determination of the pembro AUC. (Time points for SC injection: Cycles 1-4: Day 1 Predose, and Days 2, 3, 4, 5, 6, 7, 10 and 15. Time points for IV Infusion: Cycles 1-4: Day 1 Predose; Cycles 1-3: Day 1 End of Infusion \[\~0.5 hours after start of infusion\], and Days 2, 5, 10 and 15.) Each cycle is 21 days.
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Timepoint [1]
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At designated time points (Up to approximately 78 days)
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Primary outcome [2]
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Pembrolizumab Maximum Plasma Concentration (Cmax) - Pembrolizumab Sequence 1-6
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Assessment method [2]
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Blood samples are to be collected at designated time points for the determination of the pembro Cmax. (Time points for SC injection: Cycles 1-4: Day 1 Predose, and Days 2, 3, 4, 5, 6, 7, 10 and 15. Time points for IV Infusion: Cycles 1-4: Day 1 Predose; Cycles 1-3: Day 1 End of Infusion \[\~0.5 hours after start of infusion\], and Days 2, 5, 10 and 15.) Each cycle is 21 days.
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Timepoint [2]
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At designated time points (Up to approximately 78 days)
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Primary outcome [3]
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Pembrolizumab Bioavailability (F)
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Assessment method [3]
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Blood samples are to be collected at designated time points for the determination of the pembro F. (Time points for SC injection: Cycles 1-4: Day 1 Predose, and Days 2, 3, 4, 5, 6, 7, 10 and 15. Time points for IV Infusion: Cycles 1-4: Day 1 Predose; Cycles 1-3: Day 1 End of Infusion \[\~0.5 hours after start of infusion\], and Days 2, 5, 10 and 15.) Each cycle is 21 days.
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Timepoint [3]
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At designated time points (Up to approximately 78 days)
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Primary outcome [4]
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Pembrolizumab Absorption Rate (Ka)
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Assessment method [4]
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Blood samples are to be collected at designated time points for the determination of the pembro Ka. (Time points for SC injection: Cycles 1-4: Day 1 Predose, and Days 2, 3, 4, 5, 6, 7, 10 and 15. Time points for IV Infusion: Cycles 1-4: Day 1 Predose; Cycles 1-3: Day 1 End of Infusion \[\~0.5 hours after start of infusion\], and Days 2, 5, 10 and 15.) Each cycle is 21 days.
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Timepoint [4]
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At designated time points (Up to approximately 78 days)
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Primary outcome [5]
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Pembrolizumab Time of Maximum Plasma Concentration (Tmax)
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Assessment method [5]
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Blood samples are to be collected at designated time points for the determination of the pembro Tmax. (Time points for SC injection: Cycles 1-4: Day 1 Predose, and Days 2, 3, 4, 5, 6, 7, 10 and 15. Time points for IV Infusion: Cycles 1-4: Day 1 Predose; Cycles 1-3: Day 1 End of Infusion \[\~0.5 hours after start of infusion\], and Days 2, 5, 10 and 15.) Each cycle is 21 days.
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Timepoint [5]
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At designated time points (Up to approximately 78 days)
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Primary outcome [6]
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Pembrolizumab Clearance (CL)
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Assessment method [6]
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Blood samples are to be collected at designated time points for the determination of the pembro CL. (Time points for SC injection: Cycles 1-4: Day 1 Predose, and Days 2, 3, 4, 5, 6, 7, 10 and 15. Time points for IV Infusion: Cycles 1-4: Day 1 Predose; Cycles 1-3: Day 1 End of Infusion \[\~0.5 hours after start of infusion\], and Days 2, 5, 10 and 15.) Each cycle is 21 days.
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Timepoint [6]
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At designated time points (Up to approximately 78 days)
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Primary outcome [7]
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Pembrolizumab Central Volume of Distribution (Vc)
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Assessment method [7]
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Blood samples are to be collected at designated time points for the determination of the pembro Vc. (Time points for SC injection: Cycles 1-4: Day 1 Predose, and Days 2, 3, 4, 5, 6, 7, 10 and 15. Time points for IV Infusion: Cycles 1-4: Day 1 Predose; Cycles 1-3: Day 1 End of Infusion \[\~0.5 hours after start of infusion\], and Days 2, 5, 10 and 15.) Each cycle is 21 days.
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Timepoint [7]
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At designated time points (Up to approximately 78 days)
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Primary outcome [8]
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Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab Dose D Only
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Assessment method [8]
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ORR is defined as the percentage of participants in the analysis population who have 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 are based upon blinded independent central review (BICR) per RECIST 1.1. ORR will be presented.
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Timepoint [8]
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Up to approximately 2 years
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Secondary outcome [1]
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Pembrolizumab Anti-drug Antibody Levels: Cycles 1-4 of Pembrolizumab SC Treatment - SC Injections Only
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Assessment method [1]
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Blood samples are to be collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The percentage of participants who develop anti-pembrolizumab antibodies will be presented.
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Timepoint [1]
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Cycles 1-4 Day 1: Predose. Each cycle is 21 days. (Up to approximately 64 days)
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Secondary outcome [2]
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Adverse Events (AEs): Cycles 1-3
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Assessment method [2]
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An AE is 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 percentage of participants who experience an AE during Cycles 1-3 will be presented.
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Timepoint [2]
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Through Cycle 3 Day 21; Serious AEs: Through 90 days after end of treatment on Cycle 3 Day 1. Each cycle is 21 days. (Up to approximately 133 days)
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Secondary outcome [3]
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Study Treatment Discontinuations Due to an AE: Cycles 1-3
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Assessment method [3]
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The percentage of participants who discontinue study treatment due to an AE during Cycles 1-3 will be presented.
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Timepoint [3]
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Through Cycle 3 Day 1. Each cycle is 21 days. (Up to approximately 43 days)
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Secondary outcome [4]
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Injection Site Signs and Symptoms: Cycles 1-3 of Pembrolizumab - SC Injection Only
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Assessment method [4]
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Within 60 minutes after each pembrolizumab SC injection during Cycles 1-3, participants are to complete the Injection Site Signs and Symptoms Questionnaire. Participants are asked to rate any pain, itching, swelling and redness they experience at the pembrolizumab SC injection site from "None" to "Severe". The percentage of participants who experience an injection site sign or symptom will be presented.
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Timepoint [4]
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Cycles 1-3 Day 1: Up to 60 minutes postdose. Each cycle is 21 days. (Up to approximately 43 days)
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Secondary outcome [5]
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Duration of Response (DOR) Per RECIST 1.1 - Pembrolizumab Dose D Only
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Assessment method [5]
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For participants who demonstrate a CR or PR, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. DOR will be calculated for RECIST 1.1 based on BICR. DOR for Pembrolizumab Dose D only will be presented.
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Timepoint [5]
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Up to approximately 2 years
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Secondary outcome [6]
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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 - Pembrolizumab Dose D Only
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Assessment method [6]
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PFS is defined as the time from the first dose of study treatment to the first documented disease progression per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol allows for a maximum of 10 target lesions in total and 5 per organ. PFS for Pembrolizumab Dose D only will be presented.
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Timepoint [6]
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Up to approximately 2 years
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Secondary outcome [7]
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Overall Survival (OS) - Pembrolizumab Dose D Only
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Assessment method [7]
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OS is defined as the time from the first dose of study treatment to death due to any cause. OS for Pembrolizumab Dose D only will be presented.
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Timepoint [7]
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Up to approximately 2 years
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Secondary outcome [8]
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Pembrolizumab AUC - Pembrolizumab Dose D Only
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Assessment method [8]
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Blood samples are to be collected at designated time points for the determination of the pembrolizumab AUC in participants receiving Pembrolizumab Dose D only.
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Timepoint [8]
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At designated time points (Up to approximately 7 months)
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Secondary outcome [9]
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Pembrolizumab Cmax - Pembrolizumab Dose D Only
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Assessment method [9]
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Blood samples are to be collected at designated time points for the determination of the pembrolizumab Cmax in participants receiving Pembrolizumab Dose D only.
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Timepoint [9]
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At designated time points (Up to approximately 7 months)
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Secondary outcome [10]
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Pembrolizumab Minimum Plasma Concentration (Cmin) - Pembrolizumab Dose D Only
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Assessment method [10]
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Blood samples are to be collected at designated time points for the determination of the pembrolizumab Cmin in participants receiving Pembrolizumab Dose D only.
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Timepoint [10]
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At designated time points (Up to approximately 7 months)
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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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Crossover
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
19/11/2018
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
4/12/2023
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Sample size
Target
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Accrual to date
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Final
138
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA
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Recruitment hospital [1]
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Orange Health Services ( Site 0004) - Orange
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Recruitment hospital [2]
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0
Calvary Mater Newcastle ( Site 0006) - Waratah
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Recruitment hospital [3]
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0
Cairns and Hinterland Hospital and Health Service ( Site 0001) - Cairns
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Recruitment hospital [4]
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0
Royal Adelaide Hospital ( Site 0002) - Adelaide
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Recruitment hospital [5]
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0
Ballarat Health Services ( Site 0003) - Ballarat
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Recruitment hospital [6]
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MNCCI Port Macquarie Base Hospital ( Site 0005) - Port Macquarie
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Recruitment postcode(s) [1]
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0
2800 - Orange
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Recruitment postcode(s) [2]
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0
2298 - Waratah
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Recruitment postcode(s) [3]
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0
4870 - Cairns
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Recruitment postcode(s) [4]
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0
5000 - Adelaide
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Recruitment postcode(s) [5]
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0
3350 - Ballarat
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Recruitment postcode(s) [6]
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0
2444 - Port Macquarie
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Recruitment outside Australia
Country [1]
0
0
South Africa
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State/province [1]
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0
Gauteng
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Country [2]
0
0
South Africa
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State/province [2]
0
0
Western Cape
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Country [3]
0
0
South Africa
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State/province [3]
0
0
Johannesburg
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Country [4]
0
0
Spain
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State/province [4]
0
0
Barcelona
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Country [5]
0
0
Spain
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State/province [5]
0
0
San Sebastian
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Country [6]
0
0
Sweden
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State/province [6]
0
0
Solna
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Merck Sharp & Dohme LLC
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Address
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Country
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/study/NCT03665597
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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0
Medical Director
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Address
0
0
Merck Sharp & Dohme LLC
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Country
0
0
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Phone
0
0
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Fax
0
0
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Email
0
0
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Contact person for public queries
Name
0
0
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Address
0
0
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Country
0
0
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Phone
0
0
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Fax
0
0
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Email
0
0
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
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When will data be available (start and end dates)?
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Available to whom?
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Available for what types of analyses?
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How or where can data be obtained?
IPD available at link: http://engagezone.msd.com/ds_documentation.php
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/study/NCT03665597