An Open-Label, Phase 1/2 Study to Evaluate Safety, Efficacy, and Pharmacokinetics of EU101, an Agonistic Anti-CD137 (4-1BB) Monoclonal Antibody in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 110
- 试验地点
- 6
- 主要终点
- Phase 1: Number of Participants With Adverse Event (AEs) and Serious Adverse Events (SAEs) and Adverse Events Leading to Discontinuation
研究概览
简要总结
Phase 1 (Dose Escalation) of this study will assess the safety, tolerability, dose-limiting toxicity (DLT), and will determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of EU101 in participants with advanced solid tumors. Phase 2 (Dose Expansion) of the study will assess the antitumor effect of EU101 in two indications including colorectal cancer (CRC) and non-small cell lung cancer (NSCLC).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumors for which no standard therapy exists or standard therapy has failed because of disease progression or unacceptable toxicities. Also includes patients who cannot be treated with standard therapy because of underlying/existing medical condition.
- •Cohort 1 (colorectal cancer): a) CRC (including microsatellite instability-high [MSI-H] and microsatellite-stable [MSS]) regardless of RAS mutation. b) Disease progression within 3 months after last administration of approved standard therapies. c) Prior cytotoxic chemotherapy for metastatic disease include all the following agents: fluoropyrimidine, oxaliplatin, and irinotecan
- •Adjuvant chemotherapy-based treatments count as prior therapy, as long as relapse had occurred within 6 months of completion of such therapies, prior anti-epidermal growth factor receptor (EGFR) therapy (cetuximab, panitumumab), anti-angiogenic therapy (bevacizumab, aflibercept, ramucirumab), regorafenib, and TAS-102 are allowed. d) No more than 5 prior therapies for metastatic disease. For participants who had disease recurrence within 6 months of completing adjuvant chemotherapy, the adjuvant regimen can be considered as 1 chemotherapy regimen for metastatic disease
- •Cohort 2 (NSCLC): a) NSCLC without known EGFR, anaplastic lymphoma kinase (ALK), and ROS1 genomic tumor aberrations. b) No standard therapy exists or standard therapy has failed. c) No more than 3 prior therapies for metastatic disease
- •Phase 2: At least 1 measurable lesion per RECIST version 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2
- •Adequate organ and bone marrow function (Hemoglobin >9.0 g/dL, Absolute neutrophil count ≥1,500/μL, Absolute lymphocyte count ≥600 and ≤2,500/μL, Platelet count ≥100,000/μL, Total bilirubin ≤1.5 × upper limit of normal, Alanine aminotransferase and aspartate aminotransferase ≤2.5 × ULN, Serum creatinine ≤1.5 × ULN or creatinine clearance >30 mL/min, Prothrombin time and activated partial thromboplastin time ≤1.5 × ULN)
- •Life expectancy of at least 12 weeks
- •Voluntarily provided a written consent to participate in the study
- •Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within the 7 days before study drug administration
- •WOCBP and sexually active fertile male patients with partners who are WOCBP must agree to use 2 highly effective methods of contraception throughout the course of the study and for 12 weeks after the last dose of study drug.
排除标准
- •Primary central nervous system (CNS) tumor (Phase 1), CNS metastasis, and/or carcinomatous meningitis. Participants with prior brain metastases treated at least 4 weeks before the first dose of EU101 that are clinically stable and do not require chronic corticosteroid treatment are allowed. Untreated but asymptomatic and clinically stable brain metastases per investigator's discretion are allowed
- •Received prior therapy with any anti-CD137 monoclonal antibody (mAb) or agent
- •Major surgery requiring general anesthesia within 3 weeks before first dose of EU101 or still recovering from prior surgery
- •Active infection that is not controlled or requires intravenous antibiotics in the last 2 weeks
- •History of allogeneic tissue or organ transplant
- •Active hepatitis B virus or hepatitis C virus infection
- •History of any noninfectious hepatitis
- •Human immunodeficiency virus (HIV) infection
- •Received or receiving systemic corticosteroid therapy or any other form of systemic immunosuppressive medicaion 1 week before first dose of EU101
- •Known severe (≥Grade 3) hypersensitivity reactions to antibody, or severe reaction to immuno-oncology agents requiring treatment with steroids
- •Konwn or suspected hypersensitivity to EU101 or any component of its formulation
- •Current or history of interstitial lung disease, anaphylaxis, uncontrolled asthma, or pneumonitis that has required systemic corticosteroids
- •Patients with second primary cancer
- •Clinically significant concurrent cardiovascular disease
- •Pregnant women, breasfeeding women, WOCBP, or men with partners who are WOCBP who do not agree to use adequate contraceptive measures
- •Determined as unable to participate in the study per investigator's judgment
- •Other protocol defined Inclusion/Exclusion criteria may apply
研究组 & 干预措施
EU101: Dose Escalation Cohort
Participants with advanced solid tumors will receive EU101 intravenously once every 3 weeks (3 weeks = 1 cycle) with escalating doses starting from 0.05 milligrams per kilogram (mg/kg) to 10 mg/kg until disease progression, unacceptable toxicities or death, withdrawal of consent, end of study, or physician's decision, whichever occurs first.
干预措施: EU101 (Drug)
EU101: Dose Expansion Cohort 1
Participants with CRC will receive EU101 intravenously once every 3 weeks (3 weeks = 1 cycle) with a determined recommended phase 2 dose until disease progression, unacceptable toxicities or death, withdrawal of consent, end of study, or physician's decision, whichever occurs first.
干预措施: EU101 (Drug)
EU101: Dose Expansion Cohort 2
Participants with NSCLC will receive EU101 intravenously once every 3 weeks (3 weeks = 1 cycle) with a determined recommended phase 2 dose until disease progression, unacceptable toxicities or death, withdrawal of consent, end of study, or physician's decision, whichever occurs first.
干预措施: EU101 (Drug)
结局指标
主要结局
Phase 1: Number of Participants With Adverse Event (AEs) and Serious Adverse Events (SAEs) and Adverse Events Leading to Discontinuation
时间窗: Baseline up to 30 months
Phase 1: Number of Participants With Dose Limiting Toxicity (DLT)
时间窗: At the end of Cycle 1 (Each cycle is of 21 Days)
Phase 1: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters
时间窗: Baseline up to 24 months
Laboratory assessments include hematology, serum chemistry, other blood tests, coagulation, and urine analysis. Number of participants with clinically significant abnormalities will be reported.
Phase 1: Number of Participants With Clinically Significant Abnormalities in Vital Signs
时间窗: Baseline up to 24 months
Vital signs will include body temperature, pulse rate, and systolic and diastolic blood pressure measurements. Number of participants with clinically significant abnormalities will be reported.
Phase 1: Number of Participants With Clinically Significant Abnormalities in Physical Examination
时间窗: Baseline up to 24 months
Physical examination will include head, eyes, ears, nose and throat; heart; lungs; abdomen; skin; cervical and axillary lymph nodes; and neurological and musculoskeletal systems. Number of participants with clinically significant abnormalities will be reported.
Phase 1: Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG)
时间窗: Baseline up to 24 months
ECG parameters included heart rhythm, pulse rate intervals, QRS, QT intervals, RR intervals and corrected QT(QTc) intervals. Number of participants with clinically significant abnormalities will be reported.
Phase 2: Objective Response Rate (ORR)
时间窗: Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 24 months)
Objective response rate (ORR), defined as the percentage of participants with a best overall response (BOR) of either a complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for solid tumors by investigators.
次要结局
- Phase 1 and 2: Trough Serum Concentration (Ctrough) of EU101(Cycle 1: Pre-dose up to 336 hours post-dose; Cycle 2: 504 hours post-dose; Cycle 3: Pre-dose (Each cycle is of 21 days)])
- Phase 1 and 2: Apparent Oral Clearance of (CL/F) of EU101(Baseline (Day 1))
- Phase 1: Objective Response Rate (ORR)(Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 24 months))
- Phase 1 and 2: Duration of Response (DOR)(Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 56 months))
- Phase 1 and 2: Time to Response (TTR)(Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 56 months))
- Phase 1 and 2: Durable Clinical Benefit (DCB)(Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 56 months))
- Phase 1 and 2: Disease Control Rate (DCR)(Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 56 months))
- Phase 1 and 2: Time to Progression (TTP)(Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 56 months))
- Phase 1 and 2: Apparent Volume of Distribution (Vd/F) of EU101(Baseline (Day 1))
- Phase 1 and 2: Mean Residence Time (MRT) of EU101(Baseline (Day 1))
- Phase 1 and 2: Renal clearance (CLr) of EU101(Baseline (Day 1))
- Phase 1 and 2: Progression-Free Survival (PFS)(Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 56 months))
- Phase 1 and 2: Overall survival (OS)(Time from first dose of study treatment assessed until disease progression, death, withdrawal of consent, physician's decision, start of new anticancer therapy, or end of study, whichever occurs first (approximately for 56 months))
- Phase 1 and 2: Maximum Observed Serum Concentration (Cmax) of EU101(Cycle 1: Pre-dose up to 336 hours post-dose; Cycle 2: 504 hours post-dose; Cycle 3: Pre-dose (Each cycle is of 21 days)])
- Phase 1 and 2: Area Under the Serum Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of EU101(Cycle 1: Pre-dose up to 336 hours post-dose; Cycle 2: 504 hours post-dose; Cycle 3: Pre-dose (Each cycle is of 21 days)])
- Phase 1 and 2: Elimination Half-Life Time (T1/2) of EU101(Cycle 1: Pre-dose up to 336 hours post-dose; Cycle 2: 504 hours post-dose; Cycle 3: Pre-dose (Each cycle is of 21 days)])
- Phase 2: Number of Participants With AEs and SAEs by Common Terminology Criteria for Adverse Events (CTCAE) v5.0(Time from first dose of study treatment up to 30 months)
- Phase 1 and 2: Time to Reach Maximum Observed Serum Concentration (Tmax) of EU101(Cycle 1: Pre-dose up to 336 hours post-dose; Cycle 2: 504 hours post-dose; Cycle 3: Pre-dose (Each cycle is of 21 days)])
- Phase 1 and 2: Area Under the Serum Concentration-Time Curve From Time Zero to 24 Hours Post-dose (AUC0-24) of EU101(Cycle 1: Pre-dose up to 336 hours post-dose; Cycle 2: 504 hours post-dose; Cycle 3: Pre-dose (Each cycle is of 21 days)])
- Phase 1 and 2: Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of EU101(Cycle 1: Pre-dose up to 336 hours post-dose; Cycle 2: 504 hours post-dose; Cycle 3: Pre-dose (Each cycle is of 21 days)])
- Phase 1 and 2: Number of Participants with Positive Antidrug Antibodies (ADA)(Baseline up to 56 months)