A Study to Evaluate the Bioavailability of Pembrolizumab (MK-3475) Via Subcutaneous (SC) Injection of Pembrolizumab Formulated With Berahyaluronidase Alfa (MK-5180) [MK-3475A] In Advanced Solid Tumors (MK-3475A-C18)

NCT05017012 | Active Not Recruiting Phase 1

• 6 other identifiers: 3475A-C18MK-3475A-C18jRCT20312205072023-505340-19-00U1111-1291-52322021-001569-18
• Study Type: interventional
• Target: 72
• Locations: 6 countries
• Sites: 22

Brief Summary

This is a study to assess the pharmacokinetics, safety, and tolerability of pembrolizumab formulated with berahyaluronidase when administered as a SC injection to participants with advanced solid tumors. Participants will receive SC injections of pembrolizumab (+) berahyaluronidase alfa containing one of 2 different concentrations (Conc) of pembrolizumab, Conc1 and Conc2, corresponding to a pembrolizumab dose level of dose 1 for Arms 1, 2, and 3 and dose 2 for Arm 4.

Conditions

Advanced or Metastatic Solid Tumors

Keywords

Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)

Outcome Measures

Primary Outcomes (12)

• Arms 1, 2, and 3: Pembrolizumab Trough Concentration (Ctrough) After pembrolizumab (+) berahyaluronidase alfa Treatment

  Ctrough is defined as the observed trough concentration measured during the absorption phase, prior to SC injection of pembrolizumab (+) berahyaluronidase alfa. Ctrough will be reported for Arms 1, 2, and 3.

  Predose (0-3 hours) and postdose (0-10 minutes) on Cycle 1 Day 1; any time on Cycle 1 Days 2, 3, 4, 5, 6, 8, 10, 15, 22, 29, and 36. Cycle = 42 days

• Arms 1, 2, and 3: Pembrolizumab Maximum Plasma Concentration (Cmax) After pembrolizumab (+) berahyaluronidase alfa Treatment

  Cmax is defined as the maximum plasma concentration measured during the absorption phase, following SC injection of pembrolizumab (+) berahyaluronidase alfa. Cmax will be reported for Arms 1, 2, and 3.

  Predose (0-3 hours) and postdose (0-10 minutes) on Cycle 1 Day 1; any time on Cycle 1 Days 2, 3, 4, 5, 6, 8, 10, 15, 22, 29, and 36. Cycle = 42 days

• Arms 1, 2, and 3: Pembrolizumab Time of Maximum Plasma Concentration (Tmax) After pembrolizumab (+) berahyaluronidase alfa Treatment

  Tmax is defined as the time to maximum plasma concentration measured during the absorption phase, following SC injection of pembrolizumab (+) berahyaluronidase alfa. Tmax will be reported for Arms 1, 2, and 3.

  Predose (0-3 hours) and postdose (0-10 minutes) on Cycle 1 Day 1; any time on Cycle 1 Days 2, 3, 4, 5, 6, 8, 10, 15, 22, 29, and 36. Cycle = 42 days

• Arms 1, 2, and 3: Pembrolizumab Area under the Curve (AUC) After pembrolizumab (+) berahyaluronidase alfa Treatment

  AUC is defined as the area under the curve measured during the absorption phase, following SC injection of pembrolizumab (+) berahyaluronidase alfa. AUC will be reported for Arms 1, 2, and 3.

  Predose (0-3 hours) and postdose (0-10 minutes) on Cycle 1 Day 1; any time on Cycle 1 Days 2, 3, 4, 5, 6, 8, 10, 15, 22, 29, and 36. Cycle = 42 days

• Arms 1 and 2: Pembrolizumab Bioavailability (F) After pembrolizumab (+) berahyaluronidase alfa Treatment

  Bioavailability (F) is defined as the percentage (or the fraction F) of an administered SC dose that reaches the systemic circulation unaltered during the absorption phase, following SC injection of pembrolizumab (+) berahyaluronidase alfa. F will be reported for Arms 1 and 2.

  At designated timepoints in Cycles 1 to 4 (up to 127 days). Cycle = 42 days

• Arm 3 (Japan): Number of Participants Who Experience a Dose-Limiting Toxicity (DLT)

  DLT is defined as any of the following toxicities, if assessed by the investigator to be related to study treatment: Grade (Gr) 4 nonhematologic toxicity (not laboratory); Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia: Gr 4 thrombocytopenia of any duration; Gr 3 thrombocytopenia associated with clinically significant bleeding; thrombocytopenia requiring platelet transfusion; anemia requiring red blood cell transfusion; Nonhematologic AE Gr ≥3 in severity, with exceptions; Any Gr 3 or 4 nonhematologic laboratory abnormality if: clinically significant medical intervention is required, or if abnormality leads to hospitalization, persists for \>1 week or results in drug-induced liver injury with exceptions; Gr 3 or Gr 4 febrile neutropenia; Prolonged delay (\>2 weeks) during Cycle 1 Days 1 to 21 due to treatment-related toxicity; Treatment-related toxicity resulting in participant study treatment discontinuation during Cycle 1 Days 1 to 21; Gr 5 toxicity.

  Up to 21 days of Cycle 1 (each cycle is 42 days)

• Arm 3 (Japan): Number of Participants with Adverse Events (AEs)

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with an AE will be reported for Arm 3.

  Up to approximately 120 weeks

• Arm 3 (Japan): Number of Participants who Discontinue Study Treatment Due to an AE

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinue study treatment due to an AE will be reported for Arm 3.

  Up to approximately 108 weeks

• Arm 3 (Japan): Number of Participants with Injection Site Signs and Symptoms as Assessed by the Subcutaneous Injection Site Signs and Symptoms Questionnaire

  Approximately 60 minutes post injection of pembrolizumab (+) berahyaluronidase alfa on Day 1 of Cycles 1 and 3, participants are to complete the Subcutaneous 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 number of participants who experience an injection site sign or symptom will be reported for Arm 3.

  Day 1 of Cycle 1: Up to 60 minutes postdose. Cycle = 42 days

• Arm 4: Pembrolizumab Trough Concentration (Ctrough) After pembrolizumab (+) berahyaluronidase alfa Treatment

  Ctrough is defined as the observed trough concentration measured during the absorption phase, prior to SC injection of pembrolizumab (+) berahyaluronidase alfa. Ctrough will be reported for Arm 4.

  Predose (0-3 hours) on Day 1 of Cycles 1 and 6; any time on Days 2, 4, 6, 10, and 15 of Cycles 1 and 6. Cycle = 21 days

• Arm 4: Pembrolizumab Maximum Plasma Concentration (Cmax) After pembrolizumab (+) berahyaluronidase alfa Treatment

  Cmax is defined as the maximum plasma concentration measured during the absorption phase, following SC injection of pembrolizumab (+) berahyaluronidase alfa. Cmax will be reported for Arm 4.

  Predose (0-3 hours) on Day 1 of Cycles 1 and 6; any time on Days 2, 4, 6, 10, and 15 of Cycles 1 and 6. Cycle = 21 days

• Arm 4: Pembrolizumab Area under the Curve (AUC) After pembrolizumab (+) berahyaluronidase alfa Treatment

  AUC is defined as the area under the curve measured during the absorption phase, following SC injection of pembrolizumab (+) berahyaluronidase alfa. AUC will be reported for Arm 4.

  Predose (0-3 hours) on Day 1 of Cycles 1 and 6; any time on Days 2, 4, 6, 10, and 15 of Cycles 1 and 6. Cycle = 21 days

Secondary Outcomes (6)

• Number of Participants Positive for Anti-Pembrolizumab Antibodies After pembrolizumab (+) berahyaluronidase alfa Treatment

  Predose (0-3 hours) on Day 1 of Cycles 1 and 3. Cycle = 42 days.

• Arms 1, 2, and 4: Number of Participants with Adverse Events (AEs)

  Up to approximately 120 weeks

• Arms 1, 2, and 4: Number of Participants who Discontinue Study Treatment Due to an AE

  Up to approximately 108 weeks

• Arms 1 and 2: Number of Participants with Injection Site Signs and Symptoms as Assessed by the Subcutaneous Injection Site Signs and Symptoms Questionnaire

  Day 1 of Cycles 1 and 3: Up to 60 minutes postdose. Cycle = 42 days.

• Arm 4: Number of Participants with Injection Site Signs and Symptoms as Assessed by the Subcutaneous Injection Site Signs and Symptoms Questionnaire

  Cycle 1 Day 1: Up to 60 minutes postdose. Cycle = 21 days

Study Arms (4)

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa

EXPERIMENTAL

Participants receive pembrolizumab (+) berahyaluronidase alfa (pembrolizumab Conc1 \[dose 1\] + berahyaluronidase alfa) SC on Day 1 of Cycles 1 and 3 plus 400 mg pembrolizumab intravenously (IV) on Day 1 of Cycles 2 and 4 to 18, with or without background standard of care (SOC) chemotherapy as appropriate for the indication. A cycle is 42 days.

Biological: Pembrolizumab (+) Berahyaluronidase alfa; Biological: Pembrolizumab; Drug: Pemetrexed; Drug: Carboplatin; Drug: Paclitaxel; Drug: Nab-paclitaxel; Drug: Axitinib; Drug: Cisplatin

Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

EXPERIMENTAL

Participants receive pembrolizumab (+) berahyaluronidase alfa (pembrolizumab Conc2 \[dose 1\] + Berahyaluronidase alfa) SC on Day 1 of Cycles 1 and 3 plus 400 mg pembrolizumab IV on Day 1 of Cycles 2 and 4 to 18, with or without background SOC chemotherapy as appropriate for the indication. A cycle is 42 days.

Biological: Pembrolizumab (+) Berahyaluronidase alfa; Biological: Pembrolizumab; Drug: Pemetrexed; Drug: Carboplatin; Drug: Paclitaxel; Drug: Nab-paclitaxel; Drug: Axitinib; Drug: Cisplatin

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy

EXPERIMENTAL

Participants in Japan receive pembrolizumab (+) berahyaluronidase alfa (pembrolizumab Conc1 \[dose 1\] + berahyaluronidase alfa) SC on Day 1 of Cycle 1, with background SOC chemotherapy, and then receive 400 mg pembrolizumab IV on Day 1 of Cycles 2 to 18, with background SOC chemotherapy. A cycle is 42 days.

Biological: Pembrolizumab (+) Berahyaluronidase alfa; Biological: Pembrolizumab; Drug: Pemetrexed; Drug: Carboplatin; Drug: Paclitaxel; Drug: Nab-paclitaxel; Drug: Cisplatin

Pembrolizumab Conc1 [dose 2]/Berahyaluronidase alfa

EXPERIMENTAL

Participants receive pembrolizumab (+) berahyaluronidase alfa (pembrolizumab Conc1 \[dose 2\] + berahyaluronidase alfa) SC on Day 1 of Cycles 1 to 35 without background standard of care (SOC) chemotherapy. A cycle is 21 days.

Biological: Pembrolizumab (+) Berahyaluronidase alfa

Interventions

Carboplatin DRUG

Participants may receive 5 mg/mL/min IV (nonsquamous) or 6 mg/mL/min IV (squamous) on Day 1 of each 21-day cycle for 4 cycles as background SOC treatment during the study, as applicable to their diagnosis.

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa; Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy; Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

Paclitaxel DRUG

Participants may receive 200 mg/m\^2 IV on Day 1 of each 21-day cycle for 4 cycles as background SOC treatment during the study, as applicable to their diagnosis.

Also known as: Taxol

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa; Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy; Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

Nab-paclitaxel DRUG

Participants may receive 100 mg/m2 IV on Day 1, 8, and 15 of each 21-day cycle for 4 cycles as background SOC treatment during the study, as applicable to their diagnosis.

Also known as: Albumin-bound paclitaxel

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa; Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy; Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

Axitinib DRUG

Participants may receive 5 mg orally twice daily continuously as background SOC treatment during the study, as applicable to their diagnosis.

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa; Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

Cisplatin DRUG

Participants may receive 75 mg/m\^2 IV on Day 1 of each 21-day cycle for 4 cycles as background SOC treatment during the study, as applicable to their diagnosis.

Also known as: Platinol-AQ

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa; Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy; Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

Pembrolizumab BIOLOGICAL

Participants will receive pembrolizumab 400 mg IV.

Also known as: Keytruda, MK-3475

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa; Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy; Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

Pembrolizumab (+) Berahyaluronidase alfa BIOLOGICAL

Pembrolizumab (+) Berahyaluronidase alfa is a fixed-dose formulation of pembrolizumab (either Conc1 or Conc2) and berahyaluronidase alfa for SC administration.

Also known as: MK-3475A

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa; Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy; Pembrolizumab Conc1 [dose 2]/Berahyaluronidase alfa; Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

Pemetrexed DRUG

Participants may receive 500 mg/m\^2 IV every 3 weeks (Q3W) Day 1 and Day 22 of Cycles 1 to 18 as background SOC treatment during the study, as applicable to their diagnosis.

Also known as: Alimta

Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa; Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy; Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor.
• Can provide archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
• Has a measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group Performance Scale.
• Demonstrates adequate organ function.

You may not qualify if:

• 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 to the first dose of study medication.
• Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) before the first dose of study intervention, or has not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from any adverse events (AEs) that were due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immune-related AEs).
• Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
• Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has an active infection requiring therapy.
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years.
• Has known hepatitis B or C infections or known to be positive for hepatitis B surface antigen (HBsAg)/hepatitis B virus deoxyribonucleic acid (DNA) or hepatitis C antibody and ribonucleic acid (RNA)
• Human immunodeficiency virus (HIV)-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study.
• Has not fully recovered from any effects of major surgery without significant detectable infection.
• Has symptomatic ascites or pleural effusion.
• Has preexisting peripheral neuropathy that is \>Grade 2 by latest NCI CTCAE version 5.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (22)

FALP-UIDO ( Site 0101)

Santiago, Region M. de Santiago, 7500921, Chile

Location

Bradfordhill ( Site 0100)

Santiago, Region M. de Santiago, 8420383, Chile

Location

James Lind Centro de Investigación del Cáncer ( Site 0102)

Temuco, Región de la Araucanía, 4800827, Chile

Location

Országos Onkológiai Intézet-Urogenital Tumors Department and Clinical Pharmacology ( Site 0021)

Budapest, Pest County, 1122, Hungary

Location

Magyar Honvedseg Egeszsegugyi Kozpont-Onkologiai Osztaly ( Site 0020)

Budapest, 1062, Hungary

Location

Kansai Medical University Hospital ( Site 0112)

Hirakata, Osaka, 573-1191, Japan

Location

Saitama Prefectural Cancer Center ( Site 0110)

Ina-machi, Saitama, 362-0806, Japan

Location

Shizuoka Cancer Center ( Site 0111)

Nagaizumi-cho,Sunto-gun, Shizuoka, 411-8777, Japan

Location

National Hospital Organization Kyushu Cancer Center ( Site 0114)

Fukuoka, 811-1395, Japan

Location

Osaka International Cancer Institute ( Site 0113)

Osaka, 541-8567, Japan

Location

CANCERCARE LANGENHOVEN DRIVE ONCOLOGY CENTRE ( Site 0051)

Port Elizabeth, Eastern Cape, 6055, South Africa

Location

Medical Oncology Centre of Rosebank ( Site 0058)

Johannesburg, Gauteng, 2196, South Africa

Location

Steve Biko Academic Hospital-Medical Oncology ( Site 0057)

Pretoria, Gauteng, 0001, South Africa

Location

LIFE GROENKLOOF-Mary Potter Cancer Centre ( Site 0052)

Pretoria, Gauteng, 0181, South Africa

Location

Sandton Oncology Medical Group (Pty) Ltd-Research ( Site 0053)

Sandton, Gauteng, 2196, South Africa

Location

Cape Town Oncology Trials ( Site 0050)

Cape Town, Western Cape, 7570, South Africa

Location

Cancercare Rondebosch Oncology-Clinical trials ( Site 0055)

Rondebosch, Western Cape, 7700, South Africa

Location

Severance Hospital, Yonsei University Health System ( Site 0062)

Seoul, 03722, South Korea

Location

Samsung Medical Center ( Site 0063)

Seoul, 06351, South Korea

Location

Hospital Universitario Virgen de la Victoria-Phase I Trials Unit ( Site 0042)

Málaga, Andalusia, 29010, Spain

Location

HOSPITAL CLÍNIC DE BARCELONA-Department of Medical Oncology ( Site 0043)

Barcelona, Catalonia, 08036, Spain

Location

HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON-ONCOLOGY ( Site 0040)

Madrid, Madrid, Comunidad de, 28009, Spain

Location

Related Publications (1)

• Cohen GL, Coetzee C, Walton CA, Reig Torras O, Chul Cho B, McAdam G, Rojas CI, Medina Rodriguez L, Papai Z, Chan SW, Rapoport BL, Caglevic C, Yanez Weber P, Takahashi T, Kurata T, Song G, Cohen JW, Akala OO, Khanyile R. Pharmacokinetics and bioavailability of pembrolizumab with berahyaluronidase alfa for subcutaneous administration in participants with advanced or metastatic solid tumors: The phase 1 study 3475A-C18. Eur J Cancer. 2025 Nov 17;230:115709. doi: 10.1016/j.ejca.2025.115709. Epub 2025 Aug 9.

  PMID: 40957773 DERIVED

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab; Pemetrexed; Carboplatin; Paclitaxel; 130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel; Axitinib; Cisplatin

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Coordination Complexes; Organic Chemicals; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Albumins; Proteins; Benzamides; Amides; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: None (Open-label)
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2021
• First Posted: August 23, 2021
• Study Start: September 21, 2021
• Primary Completion (Estimated): May 19, 2026
• Study Completion (Estimated): May 19, 2026
• Last Updated: March 27, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

KR (2); ES (3); HU (2); JP (5); CL (3); ZA (7)