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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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ClinicalTrials.gov Identifier: NCT03665597
Recruitment Status : Recruiting
First Posted : September 11, 2018
Last Update Posted : October 11, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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.

Condition or disease Intervention/treatment Phase
Melanoma Biological: Pembrolizumab Dose C Biological: Pembrolizumab Dose A Biological: Pembrolizumab Dose B Biological: Pembrolizumab Dose D Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 136 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : November 19, 2018
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : December 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
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.
Biological: Pembrolizumab Dose C
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose A
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose B
IV infusion
Other Name: MK-3475

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.
Biological: Pembrolizumab Dose C
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose A
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose B
IV infusion
Other Name: MK-3475

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.
Biological: Pembrolizumab Dose C
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose A
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose B
IV infusion
Other Name: MK-3475

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.
Biological: Pembrolizumab Dose C
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose A
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose B
IV infusion
Other Name: MK-3475

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.
Biological: Pembrolizumab Dose C
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose A
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose B
IV infusion
Other Name: MK-3475

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.
Biological: Pembrolizumab Dose C
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose A
SC injection
Other Name: MK-3475

Biological: Pembrolizumab Dose B
IV infusion
Other Name: MK-3475

Experimental: Pembrolizumab Dose D
Participants receive a single dose of pembro Dose D IV at designated time points for up to approximately 2 years.
Biological: Pembrolizumab Dose D
IV infusion
Other Name: MK-3475




Primary Outcome Measures :
  1. Pembrolizumab Area Under the Concentration-Time Curve (AUC) [ Time Frame: At designated time points (Up to approximately 78 days) ]
    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.

  2. Pembrolizumab Maximum Plasma Concentration (Cmax) [ Time Frame: At designated time points (Up to approximately 78 days) ]
    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.

  3. Pembrolizumab Bioavailability (F) [ Time Frame: At designated time points (Up to approximately 78 days) ]
    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.

  4. Pembrolizumab Absorption Rate (Ka) [ Time Frame: At designated time points (Up to approximately 78 days) ]
    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.

  5. Pembrolizumab Time of Maximum Plasma Concentration (Tmax) [ Time Frame: At designated time points (Up to approximately 78 days) ]
    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.

  6. Pembrolizumab Clearance (CL) [ Time Frame: At designated time points (Up to approximately 78 days) ]
    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.

  7. Pembrolizumab Central Volume of Distribution (Vc) [ Time Frame: At designated time points (Up to approximately 78 days) ]
    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.

  8. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab Dose D Only [ Time Frame: Up to approximately 2 years ]
    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.


Secondary Outcome Measures :
  1. Pembrolizumab Anti-drug Antibody Levels: Cycles 1-4 of Pembrolizumab SC Treatment - SC Injections Only [ Time Frame: Cycles 1-4 Day 1: Predose. Each cycle is 21 days. (Up to approximately 64 days) ]
    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.

  2. Adverse Events (AEs): Cycles 1-3 [ Time Frame: 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) ]
    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.

  3. Study Treatment Discontinuations Due to an AE: Cycles 1-3 [ Time Frame: Through Cycle 3 Day 1. Each cycle is 21 days. (Up to approximately 43 days) ]
    The percentage of participants who discontinue study treatment due to an AE during Cycles 1-3 will be presented.

  4. Injection Site Signs and Symptoms: Cycles 1-3 of Pembrolizumab - SC Injection Only [ Time Frame: Cycles 1-3 Day 1: Up to 60 minutes postdose. Each cycle is 21 days. (Up to approximately 43 days) ]
    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.

  5. Duration of Response (DOR) Per RECIST 1.1 - Pembrolizumab Dose D Only [ Time Frame: Up to approximately 2 years ]
    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.

  6. 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 [ Time Frame: Up to approximately 2 years ]
    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.

  7. Overall Survival (OS) - Pembrolizumab Dose D Only [ Time Frame: Up to approximately 2 years ]
    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.

  8. Pembrolizumab Minimum Plasma Concentration (Cmin) - Pembrolizumab Dose D Only [ Time Frame: At designated time points (Up to approximately 7 months) ]
    Blood samples are to be collected at designated time points for the determination of the pembro Cmin in participants receiving Pembrolizumab Dose D only.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03665597


Contacts
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Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
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Australia, New South Wales
Orange Health Services ( Site 0004) Recruiting
Orange, New South Wales, Australia, 2800
Contact: Study Coordinator    +61263693380      
Calvary Mater Newcastle ( Site 0006) Recruiting
Waratah, New South Wales, Australia, 2298
Contact: Study Coordinator    +61240143288      
Australia, Queensland
Cairns and Hinterland Hospital and Health Service ( Site 0001) Recruiting
Cairns, Queensland, Australia, 4870
Contact: Study Coordinator    +61499200998      
Australia, South Australia
Royal Adelaide Hospital ( Site 0002) Recruiting
Adelaide, South Australia, Australia, 5000
Contact: Study Coordinator    +61870742342      
Australia
Ballarat Health Services ( Site 0003) Recruiting
Ballarat, Australia, 3350
Contact: Study Coordinator    +61353204735      
MNCCI Port Macquarie Base Hospital ( Site 0005) Recruiting
Port Macquarie, Australia, 2444
Contact: Study Coordinator    +61265801818      
South Africa
MPOC ( Site 0027) Recruiting
Groenkloof Pretoria, Gauteng, South Africa, 0181
Contact: Study Coordinator    +27123466701      
WITS Clinical Research CMJAH Clinical Trial Site ( Site 0030) Recruiting
Johannesburg, Gauteng, South Africa, 2193
Contact: Study Coordinator    +27113390600      
The Medical Oncology Centre of Rosebank ( Site 0026) Recruiting
Johannesburg, Gauteng, South Africa, 2196
Contact: Study Coordinator    +27118804222      
Cape Town Oncology Trials Pty Ltd ( Site 0028) Recruiting
Kraaifontein, Western Cape, South Africa, 7570
Contact: Study Coordinator    +27219443800      
Sandton Oncology Medical Group PTY LTD ( Site 0029) Recruiting
Johannesburg, South Africa, 2196
Contact: Study Coordinator    +27118830900      
Spain
Hospital Universitari Vall d Hebron ( Site 0062) Recruiting
Barcelona, Spain, 08035
Contact: Study Coordinator    +349327460004350      
Hospital Clinic i Provincial de Barcelona ( Site 0061) Recruiting
Barcelona, Spain, 08036
Contact: Study Coordinator    +34932275402      
Onkologikoa - Instituto Oncologico de San Sebastian ( Site 0063) Recruiting
San Sebastian, Spain, 20014
Contact: Study Coordinator    +34943328315      
Sweden
Karolinska Universitetssjukhuset Solna ( Site 0040) Recruiting
Solna, Sweden, 171 64
Contact: Study Coordinator    +46851770000      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03665597     History of Changes
Other Study ID Numbers: 3475-555
MK-3475-555 ( Other Identifier: Merck Protocol Number )
KEYNOTE-555 ( Other Identifier: Merck )
First Posted: September 11, 2018    Key Record Dates
Last Update Posted: October 11, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Merck Sharp & Dohme Corp.:
Programmed Cell Death 1
PD1
PD-1
Programmed Cell Death-Ligand 1
PDL1
PD-L1
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents