A Double-Blind, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZE66-0205 in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Incidence of treatment-emergent adverse events (TEAEs)
研究概览
简要总结
This first-in-human study will evaluate ZE66-0205 in healthy adults. The main purpose is to assess the safety and tolerability of single oral doses and, if evaluated, two doses given on Day 1. The study will also assess how ZE66-0205 is absorbed, distributed, and eliminated from the body and how it affects MALT1 levels in blood cells. Participants will be assigned by chance to receive ZE66-0205 or placebo in sequential ascending-dose cohorts.
详细描述
This is a Phase 1, randomised, double-blind, placebo-controlled, first-in-human study in healthy male and female adult volunteers. The study will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ZE66-0205, a novel orally administered small-molecule degrader of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).
Up to 32 participants are planned to be enrolled in four sequential dose-escalation cohorts. Each cohort will include 8 participants, with 6 participants randomised to ZE66-0205 and 2 participants randomised to matching placebo. The starting dose is 50 mg. The nominal dose levels for Cohorts 2, 3, and 4 are 100 mg, 200 mg, and 300 mg, respectively; however, the dose level for each subsequent cohort may be adjusted by the Safety Review Committee (SRC) after review of blinded safety and available PK and PD data. Sequential dose escalation will generally not exceed a 2-fold increase, except that escalation from Cohort 1 to Cohort 2 may be up to 4-fold based on emerging PK data.
Dosing within each cohort will begin with 2 sentinel participants, with 1 sentinel assigned to ZE66-0205 and 1 assigned to placebo. Sentinel safety and tolerability data through Day 3 will be reviewed before the remaining participants in the cohort are dosed. The SRC will review all available blinded safety data through the End-of-Study visit and available blinded PK data before recommending escalation, dose adjustment, repetition of a dose level, evaluation of fed conditions or twice-daily dosing, addition of another cohort, or termination of enrolment. Additional higher-dose, food-effect, or twice-daily cohorts may be added as permitted by the protocol. Evaluation of CYP3A4 interaction or the effect of a proton pump inhibitor would require a protocol amendment before implementation.
Participants will be screened from Day -28 to Day -2, admitted to the clinical facility on Day -1, dosed on Day 1, and remain confined through Day 4. A follow-up telephone call will occur between Days 5 and 7, and the End-of-Study visit will occur on Day 8 (plus or minus 1 day). Safety assessments include adverse-event monitoring, physical examinations, body weight, vital signs, 12-lead electrocardiograms, and clinical laboratory testing. Blood samples for PK and PD assessments will be collected through approximately 168 hours after dosing.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- Single (Participant)
盲法说明
Participants, the Sponsor, the Principal Investigator, and clinical study personnel involved in participant care or clinical evaluations will be blinded to treatment assignment. The randomisation statistician, designated unblinded pharmacy staff, unblinded study monitor, bioanalytical laboratory, and unblinded pharmacokineticist performing interim PK analyses will be unblinded. Data provided to the Safety Review Committee will be blinded.
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Written informed consent provided before any study-related activities; able to understand the nature, purpose, risks, and possible adverse effects of the study.
- •Male or female, 18 to 55 years of age, inclusive, at Screening.
- •Body mass index 18.0 to 32.0 kg/m², inclusive, and body weight no more than 100 kg at Screening.
- •Medically healthy in the opinion of the Investigator or delegate based on medical history and absence of clinically significant abnormalities, including: no clinically relevant physical-examination findings; systolic blood pressure 90 to 160 mmHg and diastolic blood pressure 50 to 95 mmHg after at least 5 minutes of rest; pulse rate 40 to 100 beats/minute after at least 5 minutes of rest; tympanic body temperature 35.5°C to 37.7°C; and electrocardiogram without clinically significant abnormalities, including QTcF less than 450 msec for males and less than 470 msec for females.
- •Female participants must be of non-childbearing potential (surgically sterilised at least 6 weeks before Screening or postmenopausal with confirmatory follicle-stimulating hormone level) or, if of childbearing potential, must have negative pregnancy tests at Screening and Day -1, agree not to become pregnant or donate ova until at least 30 days after the last dose, and use protocol-defined adequate contraception during this period unless exclusively in a same-sex relationship or abstinent as a committed lifestyle.
- •Male participants must agree not to donate sperm until at least 90 days after the last dose. When engaging in sexual intercourse with a female partner who could become pregnant, the participant must use a condom together with a protocol-defined highly effective method of contraception until at least 90 days after the last dose. When engaging in sexual intercourse with a female partner who is not of childbearing potential or with a same-sex partner, the participant must use a condom until at least 5 days after the last dose.
- •Suitable venous access for blood sampling.
- •Willing and able to comply with all study assessments, schedule requirements, and restrictions.
排除标准
- •History of anaphylaxis or another significant allergy that, in the opinion of the Investigator or delegate, could interfere with study participation.
- •History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, psychiatric, or neurological disease or disorder, including any clinically relevant acute illness within the previous 3 months.
- •Surgery or hospitalization within 3 months before Screening, or planned surgery during the study.
- •History of malignant disease within the previous 10 years, except surgically resected squamous-cell or basal-cell skin carcinoma with histopathologically confirmed clear margins.
- •Clinically relevant immunosuppression, including immunodeficiency conditions such as common variable hypogammaglobulinemia.
- •History of risk factors for torsade de pointes, including family history of long QT syndrome or sudden cardiac death, or a known arrhythmia.
- •Gastrointestinal, hepatic (including Gilbert syndrome), renal, or other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- •Gamma-glutamyl transferase, total bilirubin, alkaline phosphatase, aspartate aminotransferase, or alanine aminotransferase greater than 1.5 times the upper limit of normal, unless an isolated elevation is considered a normal variant by the Investigator or delegate and is not accompanied by clinical signs.
- •Estimated creatinine clearance below 60 mL/min using the Cockcroft-Gault formula or serum creatinine greater than 1.5 times the upper limit of normal.
- •History of or positive Screening test for human immunodeficiency virus, hepatitis B surface antigen, or hepatitis C virus antibodies.
- •Positive urine drug-of-abuse test, carbon monoxide breath test, or alcohol breath test at Screening or Day -
- •Regular smoking of more than 5 cigarettes per week or equivalent, including tobacco, nicotine replacement therapy, e-cigarettes, or marijuana. Casual smokers may be eligible only if all protocol requirements are met.
- •Pregnant or breastfeeding female, or female planning to breastfeed from Screening until 3 months after the last dose or 5 half-lives, whichever is longer.
- •Unable to swallow oral medication.
- •Use of prescription medication, including oral contraceptives, within 14 days or 5 half-lives, whichever is longer, before the first dose; or use of over-the-counter medication within 7 days or 5 half-lives, whichever is longer, before the first dose, except protocol-permitted paracetamol.
- •Current infection requiring a systemically absorbed antibiotic, antifungal, antiparasitic, or antiviral medication within 10 days before the first dose.
- •Receipt of an inactivated vaccination within 14 days or a live vaccination within 30 days before the first dose, or planned vaccination during the study.
- •Use of systemic immunosuppressive or immunomodulating medication within 28 days or 5 half-lives, whichever is longer, before dosing or during the study.
- •Blood or plasma donation within 30 days before the first dose; loss of more than 500 mL of whole blood within 30 days before the first dose; or receipt of a blood transfusion within 1 year before the first dose.
- •Participation in a clinical study of an investigational drug or device within 30 days or 5 half-lives of the investigational drug, whichever is longer, before Screening.
- •Any other condition or prior therapy that, in the opinion of the Investigator or delegate, makes the participant unsuitable for the study, including inability to cooperate fully or likely noncompliance with study requirements.
研究组 & 干预措施
Experimental: Cohort 4
ZE66-0205 nominal 300 mg. Six participants will receive the SRC-confirmed oral dose on Day 1. The nominal dose is 300 mg; the actual dose may be adjusted based on emerging safety, PK, and PD data. Fed conditions or twice-daily dosing may be evaluated if selected by the SRC.
干预措施: ZE66-0205 (Drug)
Experimental: Cohort 3
ZE66-0205 nominal 200 mg. Six participants will receive the SRC-confirmed oral dose on Day 1. The nominal dose is 200 mg; the actual dose may be adjusted based on emerging safety, PK, and PD data. Fed conditions or twice-daily dosing may be evaluated if selected by the SRC.
干预措施: ZE66-0205 (Drug)
Experimental: Cohort 2
ZE66-0205 nominal 100 mg. Six participants will receive the SRC-confirmed oral dose on Day 1. The nominal dose is 100 mg; the actual dose may be adjusted based on emerging safety, PK, and PD data. Fed conditions or twice-daily dosing may be evaluated if selected by the SRC.
干预措施: ZE66-0205 (Drug)
Placebo
Matching placebo. Two participants in each planned cohort will receive placebo capsules that match ZE66-0205 in appearance. Placebo will be administered orally under the same dosing and meal conditions as the corresponding active cohort. If twice-daily dosing is evaluated, placebo participants will receive a second dose approximately 12 hours after the first dose.
干预措施: Placebo (Drug)
Experimental: Cohort 1
ZE66-0205 50 mg. Six participants will receive a single oral 50 mg dose on Day 1 under fasted conditions.
干预措施: ZE66-0205 (Drug)
结局指标
主要结局
Incidence of treatment-emergent adverse events (TEAEs)
时间窗: From the first dose on Day 1 through the End-of-Study visit on Day 8 (±1 day)
Number and percentage of participants with one or more TEAEs. Events will be summarised by severity and relationship to study drug; adverse events leading to withdrawal will also be reported.
Incidence of serious adverse events (SAEs)
时间窗: From the first dose on Day 1 through the End-of-Study visit on Day 8 (±1 day)
Number and percentage of participants with one or more SAEs, including severity and relationship to study drug.
Change from Baseline in body weight
时间窗: Baseline to Day 8 (±1 day)
Observed body weight and change from the Day 1 pre-dose Baseline, measured in kilograms.
Change from Baseline in systolic and diastolic blood pressure
时间窗: Baseline through Day 8 (±1 day)
Observed values and changes from the Day 1 pre-dose Baseline in systolic and diastolic blood pressure, measured in mmHg.
Change from Baseline in pulse rate
时间窗: Baseline through Day 8 (±1 day)
Observed pulse rate and change from the Day 1 pre-dose Baseline, measured in beats per minute.
Change from Baseline in respiratory rate
时间窗: Baseline through Day 8 (±1 day)
Observed respiratory rate and change from the Day 1 pre-dose Baseline, measured in breaths per minute.
Change from Baseline in body temperature
时间窗: Baseline through Day 8 (±1 day)
Observed body temperature and change from the Day 1 pre-dose Baseline, measured in degrees Celsius.
Change from Baseline in electrocardiogram parameters
时间窗: Baseline through Day 8 (±1 day)
Observed values and changes from the Day 1 pre-dose Baseline in ventricular heart rate, PR interval, QRS duration, QT interval, and QT interval corrected using Fridericia's formula (QTcF).
Participants with clinically significant post-Baseline clinical laboratory abnormalities
时间窗: Baseline through Day 8 (±1 day)
Number and percentage of participants with clinically significant abnormalities in haematology, clinical chemistry, coagulation, or urinalysis. Observed values and changes from the Day 1 pre-dose Baseline will also be summarised.
次要结局
- Maximum observed plasma concentration (Cmax) of ZE66-0205(Pre-dose through 168 hours post-dose)
- Time to maximum observed plasma concentration (Tmax) of ZE66-0205(Pre-dose through 168 hours post-dose)
- Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last)(Pre-dose through 168 hours post-dose)
- Area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24)(Pre-dose through 24 hours post-dose)
- Area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-inf)(Pre-dose through 168 hours post-dose)
- Apparent terminal elimination half-life (t1/2) of ZE66-0205(Pre-dose through 168 hours post-dose)
- Terminal elimination rate constant (lambda z) of ZE66-0205(Pre-dose through 168 hours post-dose)
- Total apparent body clearance after oral administration (CL/F) of ZE66-0205(Pre-dose through 168 hours post-dose)
- Apparent volume of distribution after oral administration (Vz/F) of ZE66-0205(Pre-dose through 168 hours post-dose)