Phase 1 Trial of Single Agent MK-4166 and MK-4166 in Combination With Pembrolizumab in Subjects With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 116
- 主要终点
- Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
This is planned to be a 5-part dose-escalation study to determine the safety and tolerability of MK-4166 monotherapy and MK-4166 plus pembrolizumab combination therapy, and to establish the maximum tolerated dose (MTD) or maximum administered dose (MAD) of MK-4166 and MK-4166 plus pembrolizumab by defining dose-limiting toxicities (DLTs) in participants with advanced solid tumors.
详细描述
In Part A, MK-4166 doses will be escalated quickly in successive cohorts and based on safety events may progress to Part B, in which the preliminary MTD will be identified. Based on safety events the study may progress to Part C in which the MTD will be confirmed. In Part D, participants will receive escalating doses of MK-4166 plus a fixed dose of pembrolizumab (MK-3475) 200 mg to determine the MTD for MK-4166 in combination with pembrolizumab. Based on safety events in Part D, the study may progress to Part E in which the MTD for MK-4166 in combination with pembrolizumab will be confirmed.
With Amendments 05/06, the dose confirmation Part C will be removed and the dose confirmation Part E (combination of MK-4166 and pembrolizumab) will be limited to participants with advanced malignant melanoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
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 metastatic solid tumor for which there is no available therapy which may convey clinical benefit. Part E: Has advanced malignant melanoma.
- •Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- •Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
- •Adequate organ function
- •Female participants of childbearing potential must have a negative urine or serum pregnancy test and must be surgically sterile or willing to use 2 methods of birth control or abstain from heterosexual activity for the course of the study through 120 days after last dose of study drug
- •Male participants must agree to use an adequate method of contraception during sexual contact with females of childbearing potential starting with the first dose of study drug through 180 days after the last dose of study drug
- •Submit an evaluable tumor sample for analysis.
排除标准
- •Chemotherapy, radiation, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or who has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the adverse events due to cancer therapeutics administered more than 4 weeks earlier
- •Currently participating or has participated in a study of an investigational agent or using an investigational device within 28 days of administration of MK-4166
- •Expected to require any other form of antineoplastic therapy while on study
- •On chronic systemic steroid therapy in excess of replacement doses, or on any other form of immunosuppressive medication
- •History of a malignancy for which potentially curative treatment has been completed, with no evidence of malignancy for 5 years excepting successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, or in situ cervical cancer
- •Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Severe hypersensitivity reaction to treatment with another monoclonal antibody
- •Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy
- •Active infection requiring therapy
- •Current pneumonitis, or a history of (non-infectious) pneumonitis that required steroids
- •Prior stem cell or bone marrow transplant
- •Positive for human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C
- •Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- •Regular user (including "recreational use") of any illicit drugs or recent history (within the last year) of substance abuse (including alcohol)
- •Symptomatic ascites or pleural effusion
- •Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study
- •Clinically significant heart disease
- •Major surgery in the past 16 weeks
- •Received a live vaccine within 30 days prior to first dose of study drug
研究组 & 干预措施
MK-4166 0.0045 mg
Participant received 0.0045 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 42 mg + Pembro
Participants received 42 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 480 mg
Participants received 480 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 900 mg
Participants received 900 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 120 mg + Pembro
Participants received 120 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 10 mg + Pembro
Participants received 10 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 670 mg + Pembro
Participants received 670 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 59 mg + Pembro
Participants received 59 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 3.3 mg + Pembro
Participants received 3.3 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 1.1 mg
Participant received 1.1 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 59 mg
Participants received 59 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 10 mg + Pembro
Participants received 10 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 42 mg
Participants received 42 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 82 mg + Pembro
Participants received 82 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 170 mg + Pembro
Participants received 170 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 480 mg + Pembro
Participants received 480 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 120 mg + Pembro
Participants received 120 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 240 mg + Pembro
Participants received 240 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 670 mg + Pembro
Participants received 670 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 340 mg + Pembro
Participants received 340 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 3.3 mg
Participant received 3.3 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 670 mg
Participants received 670 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 900 mg + Pembro
Participants received 900 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 82 mg + Pembro
Participants received 82 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 59 mg + Pembro
Participants received 59 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 900 mg + Pembro
Participants received 900 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 480 mg + Pembro
Participants received 480 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 340 mg + Pembro
Participants received 340 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 240 mg + Pembro
Participants received 240 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 170 mg + Pembro
Participants received 170 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 42 mg + Pembro
Participants received 42 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 30 mg + Pembro
Participants received 30 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 30 mg + Pembro
Participants received 30 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 3.3 mg + Pembro
Participants received 3.3 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 1.1 mg + Pembro
Participants received 1.1 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: Pembrolizumab (Biological)
MK-4166 1.1 mg + Pembro
Participants received 1.1 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles.
干预措施: MK-4166 (Biological)
MK-4166 340 mg
Participants received 340 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 240 mg
Participants received 240 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 170 mg
Participants received 170 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 120 mg
Participants received 120 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 82 mg
Participants received 82 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 30 mg
Participants received 30 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 10 mg
Participant received 10 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 0.37 mg
Participant received 0.37 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 0.12 mg
Participant received 0.12 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 0.04 mg
Participant received 0.04 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 0.014 mg
Participant received 0.014 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
MK-4166 0.0015 mg
Participant received 0.0015 mg MK-4166 IV on Day 1 of each 21-day cycle for up to 4 cycles.
干预措施: MK-4166 (Biological)
结局指标
主要结局
Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)
时间窗: Cycle 1 (up to 21 days)
DLT's were assessed during the first cycle (21 days) for each dose level and included the following if assessed by the Investigator to be possibly, probably or definitely related to MK-4166 or MK-4166 plus pembrolizumab combination: Grade 4 non-hematologic toxicity; Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia (Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia if associated with bleeding); Grade 3 non-hematologic toxicity lasting \>3 days despite optimal supportive care; Grade 3 nausea, vomiting or diarrhea if \>3 days despite optimal supportive care; any Grade 3 or Grade 4 non-hematologic laboratory abnormality if medical intervention is required or if leading to hospitalization or if persisting for \>1 week; febrile neutropenia Grade 3 or Grade 4; any drug-related AE which caused participant to discontinue treatment during Cycle 1; Grade 5 toxicity; any treatment-related toxicity which caused a \>2 week delay in initiation of Cycle 2.
Number of Participants Experiencing Adverse Events (AEs)
时间窗: From first dose up to 90 days post last dose (up to 27 months)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Per protocol, the number of participants experiencing an AE was assessed and reported by arm (MK-4166 monotherapy and MK-4166 plus pembrolizumab combination therapy) as well as by dose cohort.
Number of Participants Discontinuing Study Treatment Due to AEs
时间窗: Up to approximately 24 months
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of the Sponsor's product was also an AE. Per protocol, the number of participants discontinuing study treatment due to AEs was assessed and reported by arm (MK-4166 monotherapy and MK-4166 plus pembrolizumab combination therapy) as well as by dose cohort.
次要结局
- Maximum Concentration (Cmax) of MK-4166 Over Time(Cycles 1-4: Day 1 pre-dose, at end of MK-4166 infusion (up to 10 minutes), 2 hours; Days 2, 3, 5 (Cohorts 1-9 only), 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Area Under the Concentration-Time Curve of MK-4166 From Time Zero to The Last Quantifiable Sample (AUC 0-last) Over Time(Cycles 1-4: Day 1 pre-dose, at end of MK-4166 infusion (up to 10 minutes), 2 hours; Days 2, 3, 5 (Cohorts 1-9 only), 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Apparent Clearance (CL) of MK-4166 Over Time(Cycles 1-4: Day 1 pre-dose, at end of MK-4166 infusion (up to 10 minutes), 2 hours; Days 2, 3, 5 (Cohorts 1-9 only), 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Area Under the Concentration-Time Curve of MK-4166 From Time Zero to Infinity (AUC 0-inf) Over Time(Cycles 1-4: Day 1 pre-dose, at end of MK-4166 infusion (up to 10 minutes), 2 hours; Days 2, 3, 5 (Cohorts 1-9 only), 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Time to Maximum Concentration (Tmax) of MK-4166 Over Time(Cycles 1-4: Day 1 pre-dose, at end of MK-4166 infusion (up to 10 minutes), 2 hours; Days 2, 3, 5 (Cohorts 1-9 only), 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Area Under the Concentration-Time Curve of MK-4166 From Time Zero to 21 Hours After Dosing (AUC 0-21) Over Time(Cycles 1-4: Day 1 pre-dose, at end of MK-4166 infusion (up to 10 minutes), 2 hours; Day 2. Each cycle was 21 days. (Up to ~3 months))
- Time to Maximum Concentration (Tmax) of Pembrolizumab Over Time(Cycles 1-4: Day 1 pre-dose, at end of pembro infusion (up to 10 minutes), at end of MK-4166 infusion (up to 10 minutes), ~2 hours after start of MK-4166 infusion, Days 2, 3, 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related Protein (GITR) Receptor Availability Following MK-4166 Administration(Cycle 1 Day 1: at end of infusion (up to 10 minutes), 2 hours post-infusion, Cycle 1 Days 2, 3, 5, 8, 15, Cycle 2 Day 1 pre-dose. Each cycle was 21 days.)
- Terminal Half-Life (t ½) of MK-4166 Over Time(Cycles 1-4: Day 1 pre-dose, at end of MK-4166 infusion (up to 10 minutes), 2 hours; Days 2, 3, 5 (Cohorts 1-9 only), 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Apparent Volume of Distribution (V) of MK-4166 Over Time(Cycles 1-4: Day 1 pre-dose, at end of MK-4166 infusion (up to 10 minutes), 2 hours; Days 2, 3, 5 (Cohorts 1-9 only), 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Maximum Concentration (Cmax) of Pembrolizumab Over Time(Cycles 1-4: Day 1 pre-dose, at end of pembro infusion (up to 10 minutes), at end of MK-4166 infusion (up to 10 minutes), ~2 hours after start of MK-4166 infusion, Days 2, 3, 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Terminal Half-Life (t ½) of Pembrolizumab Over Time(Cycles 1-4: Day 1 pre-dose, at end of pembro infusion (up to 10 minutes), at end of MK-4166 infusion (up to 10 minutes), ~2 hours after start of MK-4166 infusion, Days 2, 3, 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Area Under the Concentration-Time Curve of Pembrolizumab From Time Zero to Infinity (AUC 0-inf) Over Time(Cycles 1-4: Day 1 pre-dose, at end of pembro infusion (up to 10 minutes), at end of MK-4166 infusion (up to 10 minutes), ~2 hours after start of MK-4166 infusion, Days 2, 3, 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Apparent Volume of Distribution (V) of Pembrolizumab Over Time(Cycles 1-4: Day 1 pre-dose, at end of pembro infusion (up to 10 minutes), at end of MK-4166 infusion (up to 10 minutes), ~2 hours after start of MK-4166 infusion, Days 2, 3, 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Area Under the Concentration-Time Curve of Pembrolizumab From Time Zero to 21 Hours After Dosing (AUC 0-21) Over Time(Cycles 1-4: Day 1 pre-dose, at end of pembro infusion (up to 10 minutes), at end of MK-4166 infusion (up to 10 minutes), ~2 hours after start of MK-4166 infusion, Day 2. Each cycle was 21 days. (Up to ~3 months))
- Area Under the Concentration-Time Curve of Pembrolizumab From Time Zero to The Last Quantifiable Sample (AUC 0-last) Over Time(Cycles 1-4: Day 1 pre-dose, at end of pembro infusion (up to 10 minutes), at end of MK-4166 infusion (up to 10 minutes), ~2 hours after start of MK-4166 infusion, Days 2, 3, 8, 15. Each cycle was 21 days. (Up to ~3 months))
- Apparent Clearance (CL) of Pembrolizumab Over Time(Cycles 1-4: Day 1 pre-dose, at end of pembro infusion (up to 10 minutes), at end of MK-4166 infusion (up to 10 minutes), ~2 hours after start of MK-4166 infusion, Days 2, 3, 8, 15. Each cycle was 21 days. (Up to ~3 months))