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

Melanoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03665597
• Other study ID #: 3475-555
• Secondary ID: MK-3475-555KEYNO
• Status: Completed
• Phase: Phase 1
• Start date: November 19, 2018
• Est. completion date: December 4, 2023

Study information

• Verified date: December 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 138
• Est. completion date: December 4, 2023
• Est. primary completion date: December 4, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Melanoma

Intervention

Biological:
• Pembrolizumab Dose C
SC injection
• Pembrolizumab Dose A
SC injection
• Pembrolizumab Dose B
IV infusion
• Pembrolizumab Dose D
IV infusion once every 6 weeks

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital ( Site 0002)	Adelaide	South Australia
Australia	Ballarat Health Services ( Site 0003)	Ballarat
Australia	Cairns and Hinterland Hospital and Health Service ( Site 0001)	Cairns	Queensland
Australia	Orange Health Services ( Site 0004)	Orange	New South Wales
Australia	MNCCI Port Macquarie Base Hospital ( Site 0005)	Port Macquarie
Australia	Calvary Mater Newcastle ( Site 0006)	Waratah	New South Wales
South Africa	MPOC ( Site 0027)	Groenkloof Pretoria	Gauteng
South Africa	Sandton Oncology Medical Group PTY LTD ( Site 0029)	Johannesburg
South Africa	The Medical Oncology Centre of Rosebank ( Site 0026)	Johannesburg	Gauteng
South Africa	WITS Clinical Research CMJAH Clinical Trial Site ( Site 0030)	Johannesburg	Gauteng
South Africa	Cape Town Oncology Trials Pty Ltd ( Site 0028)	Kraaifontein	Western Cape
Spain	Hospital Clinic i Provincial de Barcelona ( Site 0061)	Barcelona
Spain	Hospital Universitari Vall d Hebron ( Site 0062)	Barcelona
Spain	Onkologikoa - Instituto Oncologico de San Sebastian ( Site 0063)	San Sebastian
Sweden	Karolinska Universitetssjukhuset Solna ( Site 0040)	Solna

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

Australia,  South Africa,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)

External Links

•   Merck Clinical Trials Information