Phase 1 Single Dose Escalation/Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, And Pharmacokinetics of Ascending Doses of a MEK Inhibitor (ATR-002) Given for 7 Days in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Treatment-emergent adverse events (TEAE) - SAD
研究概览
简要总结
This was a combination of a single ascending dose (SAD) study to evaluate the safety, tolerability, and PK of 3 oral doses of a MEK inhibitor and a multiple ascending dose (MAD) study of 3 oral doses of a MEK inhibitor.
Subjects were to be enrolled in 3 different cohorts in the SAD and 3 different cohorts in the MAD and were to be randomly (blinded) allocated to active treatment or placebo (each cohort consisted of 8 subjects receiving active treatment and 2 subjects receiving placebo).
详细描述
Each subject in the SAD cohorts was to receive a single dose of the MEK inhibitor ATR-002 (PD0184264), with a starting dose of 100 mg ATR-002 or placebo:
- Cohort 1: 100 mg ATR-002 or placebo;
- Cohort 2: 100 mg + X mg ATR-002 or placebo;
- Cohort 3: 100 mg + X mg + Y mg ATR-002 or placebo. An additional cohort (Cohort 4) of 10 subjects (4:1 active vs placebo) could have been recruited into the SAD Part, if appropriate.
Effectively, 4 cohorts were treated:
- Cohort 1: 100 mg ATR-002 or placebo;
- Cohort 2: 300 mg ATR-002 or placebo;
- Cohort 3: 600 mg ATR-002 or placebo;
- Cohort 4: 900 mg ATR-002 or placebo. Between each cohort, a blinded interim analysis of PK, safety and tolerability had to be performed. The available data was evaluated by the Investigator and sponsor in a Safety Review Committee (SRC) meeting.
Once a dose level was judged to be safe, the SRC determined the dose level for the next cohort considering a maximal increment of 400 mg compared to the previous cohort, and the next dose level could be administered to the next cohort.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Between each cohort, a blinded interim analysis of PK, safety and tolerability had to be performed. The available data was evaluated by the Investigator and sponsor in a Safety Review Committee (SRC) meeting.
Once a dose level was judged to be safe, the SRC determined the dose level for the next cohort considering a maximal increment of 400 mg compared to the previous cohort, and the next dose level could be administered to the next cohort.
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
- •Male or female, between 18 and 55 years old, extremes included;
- •Weighed at least 50 kg and had a body mass index (BMI) within normal range: 18.0≤ BMI <31.0 kg/m2;
- •In good physical and mental health as determined on the basis of medical history and general physical examination performed at screening;
- •Haematology and chemistry parameters, pulse rate and/or blood pressure, and ECG within the reference range for the population studied, or showing no clinically relevant deviations, as judged by the Investigator;
- •Negative urine test for selected drugs of abuse at screening and upon check-in at the clinical site; Note: Subjects could not consume poppy-seeds within 24h before screening and before each urine drug screening because this could falsify the results of the opiate urine drug test.
- •Negative alcohol breath test at screening and upon check-in at the clinical site;
- •Negative hepatitis panel (including hepatitis B surface antigen [HBsAg] and anti hepatitis C virus [HCV] antibodies) and negative human immunodeficiency virus (HIV) antibody screens;
- •Female subjects had to be of non-childbearing potential, as follows:
- •At least 1 year post-menopausal (amenorrhea >12 months in the absence of an alternative medical cause and follicle-stimulating hormone >30 mIU/mL in women not using hormonal contraception or hormonal replacement therapy) prior to screening;
- •Surgically sterile (bilateral oophorectomy, hysterectomy, bilateral salpingectomy, or bilateral tubal ligation);
- •To protect partners from possible exposure to study medication in semen, male subjects had to use a condom during the study, even if they had a vasectomy or their partner was not of childbearing potential.
- •Note: medically acceptable methods of contraception that could be used by the partner included combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, and etonogestrel implant;
- •Willing to adhere to the prohibitions and restrictions specified in the protocol (see Appendix 16.1.1);
- •Ability to comprehend the nature of the study and any hazards of participating in it. Ability to communicate satisfactorily with the Investigator and to participate in, and comply with the requirements of, the entire study;
- •Informed Consent Form (ICF) signed voluntarily before any study-related procedure was performed, indicating that the subject understood the purpose of and procedures required for the study and was willing to participate in the study.
排除标准
- •Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-study screening assessment that could interfere with the objectives of the study or the safety of the subject;
- •Presence of acute or chronic illness or history of chronic illness sufficient to invalidate the subject's participation in the study or make it unnecessarily hazardous;
- •A condition that, in the opinion of the Investigator, could compromise the well being of the subject or course of the study, or prevent the subject from meeting or performing any study requirements;
- •Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes mellitus, coronary heart disease, cancer, or history of any psychotic mental illness;
- •Respiratory tract infection within 4 weeks before the screening visit;
- •History of surgery or medical intervention, or planned surgery or medical intervention, that could interfere with the objectives of the study or the safety of the subject;
- •Presence or history of severe adverse reaction to any drug, or sensitivity to components of the study medication;
- •Use of a prescription or over-the-counter medicine, with the exception of acetaminophen (paracetamol), during the 7 days (or 5 half-lives, whichever is longer) before the first dose of study medication;
- •Participation in another clinical study of a new chemical entity, new device, or a prescription medicine within the 3 months before dosing, or participation within 5 half-lives of receiving an experimental drug (whichever is longer);
- •Presence or history of drug or alcohol abuse, or intake of more than 21 units (14 units for women) of alcohol weekly;
- •Use of a prohibited therapy;
- •Current smoker; or ex-smokers who (a) gave up less than 1 year ago, or (b) who had a history of more than 10 pack-years; Pack-years = cigarettes per day x number of years smoked/20
- •Blood pressure and heart rate at the screening examination outside the ranges 90 150 mmHg systolic, 40-90 mmHg diastolic; heart rate 40-100 bpm;
- •Loss of more than 400 mL blood, e.g. as a blood donor, or donation of blood products, during the 3 months before the study;
- •History of tuberculosis infection;
- •Receipt of a living vaccine within the 3 months before dosing;
- •Active or latent parasitic infection, visit to a country with a high prevalence of parasitic infections within 3 months before receiving study medication;
- •Positive faecal blood test at screening;
- •Employee of the Investigator or the Sponsor, who was directly involved in the study, or a first-degree relative of such person;
研究组 & 干预措施
ATR-002 100 mg (SAD)
100 mg ATR-002 once (morning)
干预措施: ATR-002 MEK Inhibitor (Drug)
ATR-002 300 mg (SAD)
300 mg ATR-002 once (morning)
干预措施: ATR-002 MEK Inhibitor (Drug)
ATR-002 600 mg (SAD)
600 mg ATR-002 once (morning)
干预措施: ATR-002 MEK Inhibitor (Drug)
ATR-002 900 mg (SAD)
900 mg ATR-002 once (morning)
干预措施: ATR-002 MEK Inhibitor (Drug)
Placebo (SAD)
Placebo once (morning)
干预措施: Placebo oral tablet (Drug)
ATR-002 100 mg (MAD)
100 mg ATR-002 once daily (morning) for 7 days
干预措施: ATR-002 MEK Inhibitor (Drug)
ATR-002 300 mg (MAD)
300 mg ATR-002 once daily (morning) for 7 days
干预措施: ATR-002 MEK Inhibitor (Drug)
ATR-002 600 mg (MAD)
600 mg ATR-002 once daily (morning) for 7 days
干预措施: ATR-002 MEK Inhibitor (Drug)
Placebo (MAD)
Placebo once daily (morning) for 7 days
干预措施: Placebo oral tablet (Drug)
结局指标
主要结局
Treatment-emergent adverse events (TEAE) - SAD
时间窗: Day 1- Day 5
TEAEs in SAD groups
Treatment-emergent adverse events (TEAE) - MAD
时间窗: Day 1 - Day 11
TEAEs in MAD groups
次要结局
- Area under plasma concentration AUC0-t (SAD)(Day 1- Day 5)
- Area under plasma concentration AUC0-inf (SAD)(Day 1- Day 5)
- Maximum plasma concentration - Cmax (SAD)(Day 1- Day 5)
- Time to maximum plasma concentration tmax (SAD)(Day 1- Day 5)
- Maximum plasma concentration - Cmax (MAD)(Day 1 - Day 11)
- Elimination half-life t1/2 (SAD)(Day 1- Day 5)
- Area under plasma concentration AUC0-t (MAD)(Day 1 - Day 11)
- Area under plasma concentration AUC0-tau (MAD)(Day 1 - Day 11)
- Minimum plasma concentration Ctrough (MAD)(Day 1 - Day 11)
- Area under plasma concentration AUC0-inf (MAD)(Day 1 - Day 11)
- Elimination half-life t1/2 (MAD)(Day 1 - Day 11)
- Accumulation ratio Cmax (MAD)(Day 1 - Day 11)
- Accumulation ratio AUC0-tau (MAD)(Day 1 - Day 11)
- Accumulation ratio Ctrough (MAD)(Day 1 - Day 11)
- Time to maximum plasma concentration tmax (MAD)(Day 1 - Day 11)