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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 142
- 试验地点
- 42
- 主要终点
- Arms 1, 2, and 3: Pembrolizumab Area under the Curve (AUC) After pembrolizumab (+) berahyaluronidase alfa Treatment
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
None (Open-label)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group Performance Scale.
- •Demonstrates adequate organ function.
排除标准
- •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
- •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.
研究组 & 干预措施
Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Carboplatin (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Pembrolizumab (+) Berahyaluronidase alfa (Biological)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Pembrolizumab (Biological)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Pemetrexed (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Carboplatin (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Paclitaxel (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Nab-paclitaxel (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Axitinib (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Cisplatin (Drug)
Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Pembrolizumab (+) Berahyaluronidase alfa (Biological)
Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Pembrolizumab (Biological)
Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Pemetrexed (Drug)
Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Paclitaxel (Drug)
Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Nab-paclitaxel (Drug)
Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Axitinib (Drug)
Pembrolizumab Conc2 [dose 1]/Berahyaluronidase alfa
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.
干预措施: Cisplatin (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy
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.
干预措施: Pembrolizumab (+) Berahyaluronidase alfa (Biological)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy
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.
干预措施: Pembrolizumab (Biological)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy
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.
干预措施: Pemetrexed (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy
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.
干预措施: Carboplatin (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy
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.
干预措施: Paclitaxel (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy
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.
干预措施: Nab-paclitaxel (Drug)
Pembrolizumab Conc1 [dose 1]/Berahyaluronidase alfa + SOC Chemotherapy
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.
干预措施: Cisplatin (Drug)
Pembrolizumab Conc1 [dose 2]/Berahyaluronidase alfa
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.
干预措施: Pembrolizumab (+) Berahyaluronidase alfa (Biological)
结局指标
主要结局
Arms 1, 2, and 3: Pembrolizumab Area under the Curve (AUC) After pembrolizumab (+) berahyaluronidase alfa Treatment
时间窗: 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
时间窗: 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.
Arms 1, 2, and 3: Pembrolizumab Trough Concentration (Ctrough) After pembrolizumab (+) berahyaluronidase alfa Treatment
时间窗: 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
时间窗: 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
时间窗: 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.
Arm 3 (Japan): Number of Participants Who Experience a Dose-Limiting Toxicity (DLT)
时间窗: 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)
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- 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)
- 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)