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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Pembrolizumab Dose C
* Biological: Pembrolizumab Dose A
* Biological: Pembrolizumab Dose B
* Biological: Pembrolizumab Dose D


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab Sequence 1<br>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. | Biological: Pembrolizumab Dose C<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose A<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose B<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: Pembrolizumab Sequence 2<br>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. | Biological: Pembrolizumab Dose C<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose A<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose B<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: Pembrolizumab Sequence 3<br>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. | Biological: Pembrolizumab Dose C<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose A<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose B<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: Pembrolizumab Sequence 4<br>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. | Biological: Pembrolizumab Dose C<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose A<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose B<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: Pembrolizumab Sequence 5<br>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. | Biological: Pembrolizumab Dose C<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose A<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose B<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: Pembrolizumab Sequence 6<br>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. | Biological: Pembrolizumab Dose C<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose A<br>* SC injection<br>* Other names: MK-3475;Biological: Pembrolizumab Dose B<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: Pembrolizumab Dose D<br>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). | Biological: Pembrolizumab Dose D<br>* IV infusion once every 6 weeks<br>* Other names: MK-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pembrolizumab Area Under the Concentration-Time Curve (AUC) - Pembrolizumab Sequence 1-6 | 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. | At designated time points (Up to approximately 78 days) | 
| Pembrolizumab Maximum Plasma Concentration (Cmax) - Pembrolizumab Sequence 1-6 | 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. | At designated time points (Up to approximately 78 days) | 
| 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. | At designated time points (Up to approximately 78 days) | 
| 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. | At designated time points (Up to approximately 78 days) | 
| 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. | At designated time points (Up to approximately 78 days) | 
| 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. | At designated time points (Up to approximately 78 days) | 
| 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. | At designated time points (Up to approximately 78 days) | 
| 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. | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycles 1-4 Day 1: Predose. Each cycle is 21 days. (Up to approximately 64 days) | 
| 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. | 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) | 
| 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. | Through Cycle 3 Day 1. Each cycle is 21 days. (Up to approximately 43 days) | 
| 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. | Cycles 1-3 Day 1: Up to 60 minutes postdose. Each cycle is 21 days. (Up to approximately 43 days) | 
| 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. | Up to approximately 2 years | 
| 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. | Up to approximately 2 years | 
| 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. | Up to approximately 2 years | 
| Pembrolizumab AUC - Pembrolizumab Dose D Only | Blood samples are to be collected at designated time points for the determination of the pembrolizumab AUC in participants receiving Pembrolizumab Dose D only. | At designated time points (Up to approximately 7 months) | 
| Pembrolizumab Cmax - Pembrolizumab Dose D Only | Blood samples are to be collected at designated time points for the determination of the pembrolizumab Cmax in participants receiving Pembrolizumab Dose D only. | At designated time points (Up to approximately 7 months) | 
| Pembrolizumab Minimum Plasma Concentration (Cmin) - Pembrolizumab Dose D Only | Blood samples are to be collected at designated time points for the determination of the pembrolizumab Cmin in participants receiving Pembrolizumab Dose D only. | At designated time points (Up to approximately 7 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-L1, Programmed Cell Death 1, PD1, PD-1, Programmed Cell Death-Ligand 1, PDL1