Advanced or Metastatic Solid Tumors
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
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.
Interventions
BIOLOGICALPembrolizumab (+) Berahyaluronidase alfa
Pembrolizumab (+) Berahyaluronidase alfa is a fixed-dose formulation of pembrolizumab (either Conc1 or Conc2) and berahyaluronidase alfa for SC administration.
BIOLOGICALPembrolizumab
Participants will receive pembrolizumab 400 mg IV.
DRUGPemetrexed
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.
DRUGCarboplatin
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.
DRUGPaclitaxel
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.
DRUGNab-paclitaxel
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.
DRUGAxitinib
Participants may receive 5 mg orally twice daily continuously as background SOC treatment during the study, as applicable to their diagnosis.
DRUGCisplatin
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
None (Open-label)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Arms 1, 2, and 3: Pembrolizumab Trough Concentration (Ctrough) After pembrolizumab (+) berahyaluronidase alfa Treatment | 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 | 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. |
| Arms 1, 2, and 3: Pembrolizumab Maximum Plasma Concentration (Cmax) After pembrolizumab (+) berahyaluronidase alfa Treatment | 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 | 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. |
| Arms 1, 2, and 3: Pembrolizumab Time of Maximum Plasma Concentration (Tmax) After pembrolizumab (+) berahyaluronidase alfa Treatment | 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 | 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. |
| Arms 1, 2, and 3: Pembrolizumab Area under the Curve (AUC) After pembrolizumab (+) berahyaluronidase alfa Treatment | 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 | 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. |
| Arms 1 and 2: Pembrolizumab Bioavailability (F) After pembrolizumab (+) berahyaluronidase alfa Treatment | At designated timepoints in Cycles 1 to 4 (up to 127 days). Cycle = 42 days | 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. |
| Arm 3 (Japan): Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) | Up to 21 days of Cycle 1 (each cycle is 42 days) | 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. |
| Arm 3 (Japan): Number of Participants with Adverse Events (AEs) | Up to approximately 120 weeks | 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. |
| Arm 3 (Japan): Number of Participants who Discontinue Study Treatment Due to an AE | Up to approximately 108 weeks | 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. |
| Arm 3 (Japan): Number of Participants with Injection Site Signs and Symptoms as Assessed by the Subcutaneous Injection Site Signs and Symptoms Questionnaire | Day 1 of Cycle 1: Up to 60 minutes postdose. Cycle = 42 days | 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. |
| Arm 4: Pembrolizumab Trough Concentration (Ctrough) After pembrolizumab (+) berahyaluronidase alfa Treatment | 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 | 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. |
| Arm 4: Pembrolizumab Maximum Plasma Concentration (Cmax) After pembrolizumab (+) berahyaluronidase alfa Treatment | 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 | 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. |
| Arm 4: Pembrolizumab Area under the Curve (AUC) After pembrolizumab (+) berahyaluronidase alfa Treatment | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
| Arms 1, 2, and 4: Number of Participants with Adverse Events (AEs) | Up to approximately 120 weeks | 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. |
| Arms 1, 2, and 4: Number of Participants who Discontinue Study Treatment Due to an AE | Up to approximately 108 weeks | 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. |
| 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. | 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 Arms 1 and 2. |
| 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 | Approximately 60 minutes post injection of pembrolizumab (+) berahyaluronidase alfa 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. |
| Arm 3 (Japan): Pembrolizumab Bioavailability (F) After pembrolizumab (+) berahyaluronidase alfa Treatment | At designated timepoints in Cycles 1-2 (up to 84 days). Cycle = 42 days | 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 Arm 3. |
Countries
Chile, Hungary, Japan, South Africa, South Korea, Spain
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Outcome results
None listed