A Phase 1, Open-Label, Single-Dose, Randomized, Three-Period Crossover Study to Evaluate the Relative Bioavailability and Food Effect of GDC-9545 in Healthy Female Subjects of Non-Childbearing Potential
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Apparent Terminal Elimination Rate Constant (λz) of GDC-9545
研究概览
简要总结
This study will be an open-label, randomized, three-period, six-sequence crossover study of GDC-9545 administered to healthy females of non-childbearing potential to determine the relative bioavailability of the Phase 3 capsule formulation to the Phase 1 tablet formulation in the fasted state and the effect of food on the Phase 3 capsule formulation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Females of non-childbearing potential including non-pregnant, non-lactating, and either postmenopausal or surgically sterile for at least 90 days prior to screening, as defined in the protocol
- •Body mass index (BMI) from 18.5 to 30.0 kilograms per square metre of body surface area (kg/m^2) at screening
- •In good health, determined by no clinically significant findings from medical history, 12-lead ECG, or vital signs
- •Clinical laboratory evaluations within the reference range for the test laboratory, unless deemed not clinically significant by the investigator
- •Negative test for selected drugs of abuse at Screening (does not include alcohol) and at Check-in (Day -1) for Period 1 (does include alcohol)
- •Negative hepatitis panel (hepatitis B surface antigen and hepatitis C virus antibody) and negative human immunodeficiency virus (HIV) antibody screens
- •Subject must receive an explanation of the mandatory Research Biosample Repository (RBR) component of the study and be able to comprehend and willing to sign an Informed Consent Form (ICF)
排除标准
- •Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal (GI), neurological, or psychiatric disorder (as determined by the investigator)
- •History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator
- •History of allergy to GDC-9545 or any of its excipients
- •History of stomach or intestinal surgery (including cholecystectomy) or resection that would potentially alter absorption and/or excretion of orally administered drugs (except that appendectomy and hernia repair will be allowed)
- •History or presence of an abnormal ECG that, in the investigator's opinion, is clinically significant including complete left bundle branch block; right bundle branch block; first-, second-, or third-degree heart block; sick sinus syndrome; or evidence of prior myocardial infarction
- •Having a QTc interval greater than (>)470 milliseconds (msec), PR interval >210 msec, or QRS complex >120 msec
- •Confirmed (e.g., 2 consecutive measurements) baseline heart rate ≤50 beats per minute (bpm) prior to enrollment
- •History of alcoholism or drug addiction within 1 year prior to Check-in (Day -1) of Period 1
- •The use of tobacco- or nicotine-containing products within 6 months prior to Check-in (Day -1) of Period 1
- •History of active or latent tuberculosis (TB), regardless of treatment history
- •History of previous use of tamoxifen, aromatase inhibitors, or any other endocrine agent for the treatment of breast cancer
- •The use of hormone replacement therapy or selective ER modulators (SERMs; e.g., raloxifene) within 1 year prior to Check-in (Day -1) of Period 1
- •The use of oral antibiotics within 4 weeks or intravenous antibiotics within 8 weeks prior to Check-in (Day -1) of Period 1
- •The use or intent to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to Check-in (Day -1) of Period 1
- •The participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 5 half-lives or 30 days, whichever is longer, prior to Check-in (Day -1) of Period 1
- •The use of drugs of abuse (including opioids) within 4 weeks of Screening
- •The use of any prescription medications/products within 14 days prior to Check-in (Day -1) of Period 1, unless deemed acceptable by the investigator
- •The use of any over-the-counter, non-prescription preparations (including vitamins; minerals; and phytotherapeutic-, herbal-, and plant-derived preparations) within 7 days prior to Check-in (Day -1) of Period 1, unless deemed acceptable by the investigator
- •The use of poppy seed-containing foods or beverages within 7 days prior to Check-in (Day -1) of Period 1, unless deemed acceptable by the investigator
- •The use of alcohol- or caffeine-containing foods or beverages within 72 hours prior to Check-in (Day -1) of Period 1, unless deemed acceptable by the investigator
- •Not refraining from strenuous exercise from 7 days prior to Check-in (Day -1) of Period 1
- •The need to follow a special diet and unable to consume the high-fat meal
- •Poor peripheral venous access
- •History of malignancy, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer (must be cancer-free for at least 5 years)
- •Donation of blood from 90 days prior to Screening through Follow-up, inclusive, or of plasma from 2 weeks prior to Screening
- •Receipt of blood products within 2 months prior to Check-in (Day -1) of Period 1
- •Any acute or chronic condition that, in the opinion of the investigator, would limit the subject's ability to complete and/or participate in this clinical study
- •In the opinion of the investigator or Sponsor, are unsuitable for inclusion in the study
研究组 & 干预措施
GDC-9545 Treatment Sequence A, B, and C
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence A, B, and C (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Tablet, Fasted: Treatment A (Drug)
GDC-9545 Treatment Sequence A, B, and C
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence A, B, and C (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fasted: Treatment B (Drug)
GDC-9545 Treatment Sequence A, B, and C
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence A, B, and C (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fed: Treatment C (Drug)
GDC-9545 Treatment Sequence B, C, and A
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence B, C, and A (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Tablet, Fasted: Treatment A (Drug)
GDC-9545 Treatment Sequence B, C, and A
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence B, C, and A (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fasted: Treatment B (Drug)
GDC-9545 Treatment Sequence B, C, and A
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence B, C, and A (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fed: Treatment C (Drug)
GDC-9545 Treatment Sequence C, A, and B
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence C, A, and B (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Tablet, Fasted: Treatment A (Drug)
GDC-9545 Treatment Sequence C, A, and B
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence C, A, and B (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fasted: Treatment B (Drug)
GDC-9545 Treatment Sequence C, A, and B
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence C, A, and B (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fed: Treatment C (Drug)
GDC-9545 Treatment Sequence A, C, and B
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence A, C, and B (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Tablet, Fasted: Treatment A (Drug)
GDC-9545 Treatment Sequence A, C, and B
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence A, C, and B (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fasted: Treatment B (Drug)
GDC-9545 Treatment Sequence A, C, and B
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence A, C, and B (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fed: Treatment C (Drug)
GDC-9545 Treatment Sequence B, A, and C
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence B, A, and C (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Tablet, Fasted: Treatment A (Drug)
GDC-9545 Treatment Sequence B, A, and C
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence B, A, and C (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fasted: Treatment B (Drug)
GDC-9545 Treatment Sequence B, A, and C
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence B, A, and C (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fed: Treatment C (Drug)
GDC-9545 Treatment Sequence C, B, and A
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence C, B, and A (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Tablet, Fasted: Treatment A (Drug)
GDC-9545 Treatment Sequence C, B, and A
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence C, B, and A (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fasted: Treatment B (Drug)
GDC-9545 Treatment Sequence C, B, and A
Participants randomized to this arm will receive one dose of GDC-9545 at the start of each of three periods according to the treatment sequence C, B, and A (refer to the intervention descriptions). The washout period between doses will be a minimum of 10 days.
干预措施: GDC-9545 Capsule, Fed: Treatment C (Drug)
结局指标
主要结局
Apparent Terminal Elimination Rate Constant (λz) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin. The apparent terminal elimination rate constant (λz) is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase.
Apparent Terminal Elimination Half-Life (t1/2) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.
Apparent Total Clearance (CL/F) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.
Time to First Quantifiable Plasma Concentration (Tlag) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.
Maximum Observed Plasma Concentration (Cmax) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics (PK) parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin. The PK parameters Cmax, AUC0-t, and AUC0-∞ for GDC-9545 were analyzed to evaluate the relative bioavailability of GDC-9545 as a Phase 3 capsule formulation compared to a Phase 1 tablet formulation under fasted conditions (Treatment B vs. Treatment A) and to assess the food effect on GDC-9545 PK for a Phase 3 capsule formulation (Treatment C vs. Treatment B). The mixed-effect analysis of variance model for three-period crossover design was used for formulation comparison and fasted state and fed state comparison of capsule. The model included sequence, formulation, and period as fixed effects and a random effect for subject within sequence. An unstructured covariance structure was to be used; however, if it failed to converge, an alternative covariance structure may have been applied.
Time to Maximum Observed Plasma Concentration (Tmax) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics (PK) parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin. The parameter tmax was analyzed nonparametrically using the Wilcoxon signed-rank test. The median difference between the test and reference investigational products (GDC-9545 Phase 3 capsule formulation compared to a Phase 1 tablet formulation under fasted conditions \[Treatment B vs. Treatment A\] and the food effect on GDC-9545 PK for a Phase 3 capsule formulation \[Treatment C vs. Treatment B\]) and the corresponding 90% confidence interval were calculated.
Time of Last Quantifiable Plasma Concentration (Tlast) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.
Area Under the Plasma Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics (PK) parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin. The PK parameters Cmax, AUC0-t, and AUC0-∞ for GDC-9545 were analyzed to evaluate the relative bioavailability of GDC-9545 as a Phase 3 capsule formulation compared to a Phase 1 tablet formulation under fasted conditions (Treatment B vs. Treatment A) and to assess the food effect on GDC-9545 PK for a Phase 3 capsule formulation (Treatment C vs. Treatment B). The mixed-effect analysis of variance model for three-period crossover design was used for formulation comparison and fasted state and fed state comparison of capsule. The model included sequence, formulation, and period as fixed effects and a random effect for subject within sequence. An unstructured covariance structure was to be used; however, if it failed to converge, an alternative covariance structure may have been applied.
Area Under the Plasma Concentration-Time Curve From Hour 0 Extrapolated to Infinity (AUC0-∞) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics (PK) parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin. The PK parameters Cmax, AUC0-t, and AUC0-∞ for GDC-9545 were analyzed to evaluate the relative bioavailability of GDC-9545 as a Phase 3 capsule formulation compared to a Phase 1 tablet formulation under fasted conditions (Treatment B vs. Treatment A) and to assess the food effect on GDC-9545 PK for a Phase 3 capsule formulation (Treatment C vs. Treatment B). The mixed-effect analysis of variance model for three-period crossover design was used for formulation comparison and fasted state and fed state comparison of capsule. The model included sequence, formulation, and period as fixed effects and a random effect for subject within sequence. An unstructured covariance structure was to be used; however, if it failed to converge, an alternative covariance structure may have been applied.
Percentage of Area Under the Plasma Concentration-Time Curve (AUC) That is Due to Extrapolation From Last Measurable Concentration to Infinity (%AUCextrap) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.
Apparent Volume of Distribution During the Terminal Elimination Phase (Vz/F) of GDC-9545
时间窗: Pre-dose (0 hour) and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours on Day 1 and post-dose once a day on Days 2 to 8 of Periods 1-3 (up to 27 days)
The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.
次要结局
- Number of Participants Who Experienced at Least One Adverse Event by Severity, According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI-CTCAE v5.0)(From first dose of study drug until 14 days after the last dose of study drug (up to 41 days))
- Number of Participants With Clinically Significant Abnormalities in Clinical Chemistry, Hematology, and Urinalysis Laboratory Tests(Baseline, Days 2 and 8 of Period 1-3, and 12-14 days after last dose (up to 34 days))
- Change From Baseline in Systolic Blood Pressure Over Time(Baseline and post-dose on Days 1 to 8 of Periods 1-3 (up to 27 days))
- Change From Baseline in Diastolic Blood Pressure Over Time(Baseline and Days 1 to 8 of Periods 1-3 (up to 27 days))
- Change From Baseline in Pulse Rate Over Time(Baseline and Days 1 to 8 of Periods 1-3 (up to 27 days))
- Change From Baseline in Respiratory Rate Over Time(Baseline and Days 1 to 8 of Periods 1-3 (up to 27 days))
- Change From Baseline in Oral Body Temperature Over Time(Baseline and Days 1 to 8 of Periods 1-3 (up to 27 days))
- Change From Baseline in Duration of PR, RR, QRS, QT, QTcB, and QTcF Intervals Over Time, as Measured by Electrocardiogram(Baseline, and pre-dose and 4 hours post-dose on Day 1, and post-dose on Days 2, and 8 of Periods 1-3 (up to 27 days))
- Change From Baseline in Heart Rate Over Time, as Measured by Electrocardiogram(Baseline, and post-dose on Days 1, 2, and 8 of Periods 1-3 (up to 27 days))