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

Study Overview
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Brief Summary
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This is a study to assess the pharmacokinetics, safety, and tolerability of pembrolizumab formulated with MK-5180 when administered as a SC injection to participants with advanced solid tumors. Participants will receive SC injections of MK-3475A 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.

Official Title
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A Phase 1 Clinical Study to Evaluate the Bioavailability of Pembrolizumab Via Subcutaneous Injection of MK-3475A, a Formulation of Pembrolizumab With MK-5180, in Participants With Advanced Solid Tumors

Conditions
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Advanced or Metastatic Solid Tumors

Intervention / Treatment
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* Biological: MK-3475A
* Biological: Pembrolizumab
* Drug: Pemetrexed
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Nab-paclitaxel
* Drug: Axitinib
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. Has a known sensitivity to recombinant hyaluronidase or other form of hyaluronidase. Has a history of severe hypersensitivity reaction (eg, generalized rash/erythema, hypotension, bronchospasm, angioedema, or anaphylaxis) to pemetrexed, cisplatin, axitinib, carboplatin, paclitaxel, or nab-paclitaxel. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-3475A (Pembrolizumab Conc1 [dose 1] + MK-5180)<br>Participants receive MK-3475A (pembrolizumab Conc1 [dose 1] + MK-5180) 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: MK-3475A<br>* MK-3475A is a fixed-dose formulation of pembrolizumab (either Conc1 or Conc2) and MK-5180 for SC administration.<br>Biological: Pembrolizumab<br>* Participants will receive pembrolizumab 400 mg IV.<br>* Other names: MK-3475;Drug: Pemetrexed<br>* 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.<br>* Other names: Alimta;Drug: Carboplatin<br>* 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.<br>Drug: Paclitaxel<br>* 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.<br>* Other names: Taxol;Drug: Nab-paclitaxel<br>* 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.<br>* Other names: Albumin-bound paclitaxel;Drug: Axitinib<br>* Participants may receive 5 mg orally twice daily continuously as background SOC treatment during the study, as applicable to their diagnosis.<br>Drug: Cisplatin<br>* 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.<br>* Other names: Platinol-AQ;|
| Experimental: MK-3475A (Pembrolizumab Conc2 [dose 1] + MK-5180)<br>Participants receive MK-3475A (pembrolizumab Conc2 [dose 1] + MK-5180) 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: MK-3475A<br>* MK-3475A is a fixed-dose formulation of pembrolizumab (either Conc1 or Conc2) and MK-5180 for SC administration.<br>Biological: Pembrolizumab<br>* Participants will receive pembrolizumab 400 mg IV.<br>* Other names: MK-3475;Drug: Pemetrexed<br>* 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.<br>* Other names: Alimta;Drug: Carboplatin<br>* 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.<br>Drug: Paclitaxel<br>* 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.<br>* Other names: Taxol;Drug: Nab-paclitaxel<br>* 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.<br>* Other names: Albumin-bound paclitaxel;Drug: Axitinib<br>* Participants may receive 5 mg orally twice daily continuously as background SOC treatment during the study, as applicable to their diagnosis.<br>Drug: Cisplatin<br>* 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.<br>* Other names: Platinol-AQ;|
| Experimental: MK-3475A (Pembrolizumab Conc1 [dose 1] + MK-5180) + SOC Chemotherapy<br>Participants in Japan receive MK-3475A (pembrolizumab Conc1 [dose 1] + MK-5180) 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: MK-3475A<br>* MK-3475A is a fixed-dose formulation of pembrolizumab (either Conc1 or Conc2) and MK-5180 for SC administration.<br>Biological: Pembrolizumab<br>* Participants will receive pembrolizumab 400 mg IV.<br>* Other names: MK-3475;Drug: Pemetrexed<br>* 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.<br>* Other names: Alimta;Drug: Carboplatin<br>* 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.<br>Drug: Paclitaxel<br>* 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.<br>* Other names: Taxol;Drug: Nab-paclitaxel<br>* 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.<br>* Other names: Albumin-bound paclitaxel;Drug: Cisplatin<br>* 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.<br>* Other names: Platinol-AQ;|
| Experimental: MK-3475A (Pembrolizumab Conc1 [dose 2] + MK-5180)<br>Participants receive MK-3475A (pembrolizumab Conc1 [dose 2] + MK-5180) SC on Day 1 of Cycles 1 to 35 without background standard of care (SOC) chemotherapy. A cycle is 21 days. | Biological: MK-3475A<br>* MK-3475A is a fixed-dose formulation of pembrolizumab (either Conc1 or Conc2) and MK-5180 for SC administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arms 1, 2, and 3: Pembrolizumab Trough Concentration (Ctrough) After MK-3475A Treatment | Ctrough is defined as the observed trough concentration measured during the absorption phase, prior to SC injection of MK-3475A. 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 MK-3475A Treatment | Cmax is defined as the maximum plasma concentration measured during the absorption phase, following SC injection of MK-3475A. 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 MK-3475A Treatment | Tmax is defined as the time to maximum plasma concentration measured during the absorption phase, following SC injection of MK-3475A. 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 MK 3475A Treatment | AUC is defined as the area under the curve measured during the absorption phase, following SC injection of MK-3475A. 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 MK-3475A 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 MK-3475A. 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 MK-3475A 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 MK 3475A Treatment | Ctrough is defined as the observed trough concentration measured during the absorption phase, prior to SC injection of MK-3475A. 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 MK 3475A Treatment | Cmax is defined as the maximum plasma concentration measured during the absorption phase, following SC injection of MK-3475A. 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 MK 3475A Treatment | AUC is defined as the area under the curve measured during the absorption phase, following SC injection of MK-3475A. 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Positive for Anti-Pembrolizumab Antibodies After MK-3475A Treatment | Blood samples are to be collected at designated time points for the determination of the presence or absence of anti-pembrolizumab antibodies. The percentage of participants who develop anti-pembrolizumab antibodies will be reported. | 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) | 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 Arms 1, 2, and 4. | Up to approximately 120 weeks | 
| Arms 1, 2, and 4: 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 Arms 1, 2, and 4. | 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 | Approximately 60 minutes post injection of MK-3475A 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 Arms 1 and 2. | 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 | Approximately 60 minutes post injection of MK-3475A on Day 1 of Cycle 1, 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 4. | Cycle 1 Day 1: Up to 60 minutes postdose. Cycle = 21 days | 
| Arm 3 (Japan): Pembrolizumab Bioavailability (F) After MK 3475A 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 MK-3475A. F will be reported for Arm 3. | At designated timepoints in Cycles 1-2 (up to 84 days). Cycle = 42 days | 

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