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NCT Number: NCT03665597

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

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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Key information

Conditions

Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Orange Health Services ( Site 0004), Orange, New South Wales, Australia

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About this study

This study consists of two cohorts. Participants in Cohort A are randomized to one of six treatment sequences which will include 2 cycles of pembrolizumab administered via subcutaneous injection and 1 cycle of intravenous (IV) infusion, followed by up to 32 cycles (up to ~2 years) of pembrolizumab administered via IV infusion (each cycle is 21 days). Participants in Cohort B will receive pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 18 cycles, up to ~ 2 years. Each cycle is 42 days.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Pembrolizumab Dose C

Biological

165 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Other names: KEYTRUDA®, MK-3475

Pembrolizumab Dose A

Biological

130 mg/mL administered to a final dose of 285 mg via subcutaneous injection

Other names: KEYTRUDA®, MK-3475

Pembrolizumab Dose B

Biological

200 mg administered via intravenous infusion

Other names: KEYTRUDA®, MK-3475

Pembrolizumab Dose D

Biological

400 mg administered via intravenous infusion

Other names: KEYTRUDA®, MK-3475

Primary outcomes

  1. Area Under the Concentration-Time Curve (AUC) of Pembrolizumab - Cohort A

    Time frame: Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.

    AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time. Blood samples were collected at designated time points and a pharmacokinetic (PK) model based on historical intravenous pembrolizumab PK data were used for the determination of the AUC of pembrolizumab. Geometric least-square mean (GM) and 95% confidence intervals were derived from mixed-effects model performed on natural log-transformed values. Data were reported by treatment received.

  2. Maximum Plasma Concentration (Cmax) of Pembrolizumab - Cohort A

    Time frame: Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.

    Cmax was defined as the maximum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points and a PK model based on historical intravenous pembrolizumab PK data were used for the determination of the AUC of pembrolizumab. GM and 95% confidence intervals were derived from mixed-effects model performed on natural log-transformed values. Data were reported by treatment received.

  3. Bioavailability (F) of Pembrolizumab - Cohort A

    Time frame: Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.

    Blood samples were collected at designated time points and a population PK model based on historical intravenous pembrolizumab PK data was used for the determination of the F of pembrolizumab. Per protocol, an integrated population PK analysis was performed and combined data for Cohort A was reported.

  4. Absorption Rate Constant (Ka) of Pembrolizumab - Cohort A

    Time frame: Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.

    Blood samples were collected at designated time points and a population PK model based on historical intravenous pembrolizumab PK data was used for the determination of the Ka of pembrolizumab. Per protocol, an integrated population PK analysis was performed and combined data for Cohort A was reported. Participants in Cohort B weren't analyzed, per protocol.

  5. Time of Maximum Plasma Concentration (Tmax) of Pembrolizumab - Cohort A

    Time frame: Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.

    Blood samples were collected at designated time points for the determination of the Tmax of pembrolizumab.

  6. Clearance (CL) of Pembrolizumab - Cohort A

    Time frame: Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.

    Blood samples were collected at designated time points and a population PK model based on historical intravenous pembrolizumab PK data was used for the determination of the CL of pembrolizumab. Per protocol, an integrated population PK analysis was performed and combined data for Cohort A was reported.

  7. Central Volume of Distribution (Vc) of Pembrolizumab - Cohort A

    Time frame: Cycles 1-3: Day 1 Predose and Days 2, 5, 10 and 15; Cycle 4: Day 1 Predose. Samples were also collected after IV infusion on Cycles 1-3: Day 1 ~0.5 hours after infusion and after SC injection on Days 3, 4, 6, and 7. Each cycle was 21 days.

    Blood samples were collected at designated time points and a population PK model based on historical intravenous pembrolizumab PK data was used for the determination of the Vc of pembrolizumab. Per protocol, an integrated population PK analysis was performed and combined data for Cohort A was reported.

  8. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - Cohort B

    Time frame: Up to approximately 54 months

    ORR was defined as the percentage of participants in the analysis population who had 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 were based upon blinded independent central review (BICR) per RECIST 1.1. ORR was reported for participants in Cohort B.

Secondary outcomes

  1. Number of Participants Positive for Pembrolizumab Anti-Drug Antibody (ADA) Formation - Cohort A

    Time frame: Cycles 1-4 Day 1: Predose. Each cycle is 21 days. (Up to approximately 64 days)

    Blood samples were collected at designated time points for the determination of the presence or absence of pembrolizumab anti-drug antibodies. The number of participants who develop anti-pembrolizumab antibodies were assessed in Cycles 1 through Cycle 4. Per ADA immunogenicity analysis report, data from participants in Cohort A were reported combined across treatment cycles 1-4.

  2. Number of Participants Who Experienced One or More Adverse Event (AEs) - Cohort A

    Time frame: Up to approximately 27 months

    An AE was 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 number of participants who experienced one or more AEs in Cohort A was reported. Per protocol, data were reported by treatment received and AEs from Cycles 4-35 were reported separately.

  3. Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort A

    Time frame: Up to approximately 23 months

    An AE was 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 number of participants who discontinued due to an AE in Cohort A were reported. Per protocol, data were reported by treatment received and data from Cycles 4-35 were reported separately.

  4. Number of Participants With One or More Injection Site Signs and Symptoms After Subcutaneous Pembrolizumab Injection in Cycles 1-3 - Cohort A

    Time frame: Cycles 1-3 Day 1: Up to 60 minutes postdose. Each cycle is 21 days. (Up to approximately 43 days)

    Participants completed the Injection Site Signs and Symptoms Questionnaire, within 60 minutes after each pembrolizumab SC injection during Cycles 1-3. Participants rated any pain, itching, swelling and redness they experienced at the pembrolizumab SC injection site from "None" to "Severe". The number of participants who experienced an injection site sign or symptom was reported.

  5. Duration of Response (DOR) Per RECIST 1.1 - Cohort B

    Time frame: Up to approximately 54 months

    For participants who demonstrated a CR (disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR was calculated for RECIST 1.1 based on BICR. DOR for Cohort B was reported.

  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 - Cohort B

    Time frame: Up to approximately 54 months

    PFS was defined as the time from the first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Although RECIST 1.1 was modified to allow for a maximum of 10 target lesions in total and 5 per organ. Per protocol, PFS as assessed by BICR for participants in Cohort B was reported.

  7. Overall Survival (OS) - Cohort B

    Time frame: Up to approximately 54 months

    OS was defined as the time from the first dose of study treatment to death due to any cause. Per protocol, OS for participants in Cohort B was reported.

  8. Early Cycle AUC of Pembrolizumab - Cohort B

    Time frame: Cycle 1: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 2: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)

    AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time. Blood samples were collected at designated time points for the determination of the pembrolizumab AUC in participants in Cohort B during Cycle 1 (early cycle). Blood samples were also collected predose on Day 1 of Cycle 2 just prior to the next dose as the last sample (trough concentration) of Cycle 1. A cycle was 42 days.

  9. Steady State AUC of Pembrolizumab - Cohort B

    Time frame: Cycle 4: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 5: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)

    AUC was defined as a measure of pembrolizumab exposure that was calculated as the product of plasma drug concentration and time. Blood samples were collected at designated time points for the determination of the pembrolizumab AUC in participants in Cohort B during Cycle 4 (steady state). Blood samples were also collected predose on Day 1 of Cycle 5 just prior to the next dose as the last samples (trough concentration) of Cycle 4. Each cycle was 42 days.

  10. Early Cycle Cmax of Pembrolizumab - Cohort B

    Time frame: Cycle 1: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 2: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)

    Cmax was defined as the maximum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points for the determination of the pembrolizumab Cmax in participants in Cohort B during Cycle 1 (early cycle). Blood samples were also collected predose on Day 1 of Cycle 2 just prior to the next dose as the last sample (trough concentration) of Cycle 1. Each cycle was 42 days.

  11. Steady State Cmax of Pembrolizumab - Cohort B

    Time frame: Cycle 4: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 5: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)

    Cmax was defined as the maximum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points for the determination of the pembrolizumab Cmax in participants in Cohort B during Cycle 4 (steady state). Blood samples were also collected predose on Day 1 of Cycle 5 just prior to the next dose as the last sample (trough concentration) of Cycle 4. Each cycle was 42 days.

  12. Early Cycle Minimum Plasma Concentration (Cmin) of Pembrolizumab - Cohort B

    Time frame: Cycle 1: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 2: Predose. A Cycle was 42 days. (Up to approximately 6 weeks)

    Cmin was defined as the minimum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points for the determination of the pembrolizumab Cmin in participants in Cohort B during Cycle 1 (early cycle). Blood samples were also collected predose on Day 1 of Cycle 2 just prior to the next dose as the last sample (trough concentration) of Cycle 1. Each cycle was 42 days.

  13. Steady State Cmin of Pembrolizumab - Cohort B

    Time frame: Cycle 4: Day 1 Predose and ~5 minutes post infusion and Day 22; Cycle 5: Predose. Each Cycle was 42 days. (Up to approximately 6 weeks)

    Cmin was defined as the minimum concentration of pembrolizumab observed in plasma following a single dose. Blood samples were collected at designated time points for the determination of the pembrolizumab Cmin in participants in Cohort B during Cycle 4 (steady state). Blood samples were also collected predose on Day 1 of Cycle 5 just prior to the next dose as the last sample (trough concentration) of Cycle 4. Each cycle was 42 days.

  14. Number of Participants Who Experienced One or More AEs - Cohort B

    Time frame: Up to approximately 54 months

    An AE was 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 number of participants who experienced one or more AEs in Cohort B was reported.

  15. Number of Participants Who Discontinued Study Treatment Due to an AE - Cohort B

    Time frame: Up to approximately 26 months

    An AE was 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 number of participants who discontinued due to an AE in Cohort B were reported.

Sponsors and collaborators

Lead sponsor

Merck Sharp & Dohme LLC

Industry

Registry information

Official study 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)

Important dates

Study start
2018
Primary completion
2023
Study completion
2023
First posted
Sep 11, 2018
Registry last updated
Feb 10, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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