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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT03665597
Ethics application status
Date submitted
23/08/2018
Date registered
11/09/2018
Date last updated
27/02/2020

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
Other interventions - Pembrolizumab Dose C
Other interventions - Pembrolizumab Dose A
Other interventions - Pembrolizumab Dose B
Other interventions - 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).


Other interventions: Pembrolizumab Dose C
SC injection

Other interventions: Pembrolizumab Dose A
SC injection

Other interventions: Pembrolizumab Dose B
IV infusion

Other interventions: Pembrolizumab Dose D
IV infusion once every 6 weeks

Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Pembrolizumab Area Under the Concentration-Time Curve (AUC) - 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.
Timepoint [1] 0 0
At designated time points (Up to approximately 78 days)
Primary outcome [2] 0 0
Pembrolizumab Maximum Plasma Concentration (Cmax) - 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.
Timepoint [2] 0 0
At designated time points (Up to approximately 78 days)
Primary outcome [3] 0 0
Pembrolizumab Bioavailability (F) - 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.
Timepoint [3] 0 0
At designated time points (Up to approximately 78 days)
Primary outcome [4] 0 0
Pembrolizumab Absorption Rate (Ka) - 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.
Timepoint [4] 0 0
At designated time points (Up to approximately 78 days)
Primary outcome [5] 0 0
Pembrolizumab Time of Maximum Plasma Concentration (Tmax) - 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.
Timepoint [5] 0 0
At designated time points (Up to approximately 78 days)
Primary outcome [6] 0 0
Pembrolizumab Clearance (CL) - 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.
Timepoint [6] 0 0
At designated time points (Up to approximately 78 days)
Primary outcome [7] 0 0
Pembrolizumab Central Volume of Distribution (Vc) - 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.
Timepoint [7] 0 0
At designated time points (Up to approximately 78 days)
Primary outcome [8] 0 0
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab Dose D Only - 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.
Timepoint [8] 0 0
Up to approximately 2 years
Secondary outcome [1] 0 0
Pembrolizumab Anti-drug Antibody Levels: Cycles 1-4 of Pembrolizumab SC Treatment - SC Injections Only - 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.
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
Adverse Events (AEs): Cycles 1-3 - 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.
Timepoint [2] 0 0
AEs: 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)
Secondary outcome [3] 0 0
Study Treatment Discontinuations Due to an AE: Cycles 1-3 - The percentage of participants who discontinue study treatment due to an AE during Cycles 1-3 will be presented.
Timepoint [3] 0 0
Through Cycle 3 Day 1. Each cycle is 21 days. (Up to approximately 43 days)
Secondary outcome [4] 0 0
Injection Site Signs and Symptoms: Cycles 1-3 of Pembrolizumab - SC Injection Only - 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.
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 - Pembrolizumab Dose D Only - 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.
Timepoint [5] 0 0
Up to approximately 2 years
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 - Pembrolizumab Dose D Only - 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.
Timepoint [6] 0 0
Up to approximately 2 years
Secondary outcome [7] 0 0
Overall Survival (OS) - Pembrolizumab Dose D Only - 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.
Timepoint [7] 0 0
Up to approximately 2 years
Secondary outcome [8] 0 0
Pembrolizumab Minimum Plasma Concentration (Cmin) - Pembrolizumab Dose D Only - Blood samples are to be collected at designated time points for the determination of the pembro Cmin in participants receiving Pembrolizumab Dose D only.
Timepoint [8] 0 0
At designated time points (Up to approximately 7 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
Gender
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
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
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 Corp.
Address
Country

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/show/NCT03665597
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
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

Summary results
Other publications