Evaluation of the Relative Bioavailability and Food Effect of GDC-9545 in Healthy Females of Non-Childbearing Potential

Healthy Volunteers Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04274075
• Other study ID #: GP42006
• Status: Completed
• Phase: Phase 1
• Start date: March 6, 2020
• Est. completion date: April 16, 2020

Study information

• Verified date: March 2021
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: April 16, 2020
• Est. primary completion date: April 16, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• GDC-9545 Tablet, Fasted: Treatment A
One dose of the GDC-9545 Phase 1 reference tablet formulation (three 10-mg tablets) administered orally with approximately 240 mL room temperature water after at least an 8-hour fast.
• GDC-9545 Capsule, Fasted: Treatment B
One dose of the GDC-9545 Phase 3 capsule formulation (one 30-mg capsule) administered orally with approximately 240 mL room temperature water after at least an 8-hour fast.
• GDC-9545 Capsule, Fed: Treatment C
One dose of the GDC-9545 Phase 3 capsule formulation (one 30-mg capsule) administered orally with approximately 240 mL room temperature water within 30 minutes of eating a high-fat meal.

Locations

Country	Name	City	State
United States	Covance Research Unit - Daytona	Daytona Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Observed Plasma Concentration (Cmax) of GDC-9545	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 AUC0-8 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.	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)
Primary	Time to Maximum Observed Plasma Concentration (Tmax) of GDC-9545	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.	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)
Primary	Time of Last Quantifiable Plasma Concentration (Tlast) of GDC-9545	The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.	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)
Primary	Time to First Quantifiable Plasma Concentration (Tlag) of GDC-9545	The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.	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)
Primary	Area Under the Plasma Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of GDC-9545	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 AUC0-8 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.	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)
Primary	Area Under the Plasma Concentration-Time Curve From Hour 0 Extrapolated to Infinity (AUC0-8) of GDC-9545	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 AUC0-8 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.	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)
Primary	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	The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.	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)
Primary	Apparent Terminal Elimination Rate Constant (?z) of GDC-9545	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 (?z) is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase.	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)
Primary	Apparent Terminal Elimination Half-Life (t1/2) of GDC-9545	The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.	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)
Primary	Apparent Total Clearance (CL/F) of GDC-9545	The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.	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)
Primary	Apparent Volume of Distribution During the Terminal Elimination Phase (Vz/F) of GDC-9545	The pharmacokinetics parameters were determined where possible from the plasma concentrations of GDC-9545 using non-compartmental methods performed using Phoenix WinNonlin.	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)
Secondary	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)	The investigator sought information on adverse events (AEs) at each contact with a participant. All AEs, whether reported by the participant or noted by study personnel, were recorded. All AEs were assigned a severity grade (from 1 to 5) using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0). Severity refers to the intensity of an AE. The following is the severity grading scale used for AEs that are not specifically listed in the NCI-CTCAE: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening; and Grade 5 is death related to an AE.	From first dose of study drug until 14 days after the last dose of study drug (up to 41 days)
Secondary	Number of Participants With Clinically Significant Abnormalities in Clinical Chemistry, Hematology, and Urinalysis Laboratory Tests	Participants provided blood and urine samples at the specified timepoints for laboratory analysis of clinical chemistry, hematology, and urinalysis parameters (please refer to Appendix A of the protocol for a complete list of parameters). Any of the laboratory test results that were outside of the reference range were considered abnormalities. Not every laboratory abnormality qualified as an adverse event (AE). A laboratory test result was reported as an AE if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. All AEs were assigned a severity grade (from 1 to 5) using the NCI-CTCAE v5.0; for AEs not specifically listed in the NCI-CTCAE: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening; and Grade 5 is death related to an AE.	Baseline, Days 2 and 8 of Period 1-3, and 12-14 days after last dose (up to 34 days)
Secondary	Change From Baseline in Systolic Blood Pressure Over Time	Vital signs (including oral temperature, respiratory rate, and supine blood pressure and pulse rate) were obtained at the specified timepoints. Supine blood pressure was obtained after the participant had been supine for at least 5 minutes. When vital signs were scheduled at the same time as blood draws, the blood draws were obtained at the scheduled timepoint, and the vital signs were obtained as close to the scheduled blood draw as possible, but prior to the blood draw. The baseline value was defined as the last value recorded prior to the first dose in each treatment period. The normal reference range for supine systolic blood pressure was 90-140 millimetres of mercury (mmHg).	Baseline and post-dose on Days 1 to 8 of Periods 1-3 (up to 27 days)
Secondary	Change From Baseline in Diastolic Blood Pressure Over Time	Vital signs (including oral temperature, respiratory rate, and supine blood pressure and pulse rate) were obtained at the specified timepoints. Supine blood pressure was obtained after the participant had been supine for at least 5 minutes. When vital signs were scheduled at the same time as blood draws, the blood draws were obtained at the scheduled timepoint, and the vital signs were obtained as close to the scheduled blood draw as possible, but prior to the blood draw. The baseline value was defined as the last value recorded prior to the first dose in each treatment period. The normal reference range for supine diastolic blood pressure was 50-90 mmHg.	Baseline and Days 1 to 8 of Periods 1-3 (up to 27 days)
Secondary	Change From Baseline in Pulse Rate Over Time	Vital signs (including oral temperature, respiratory rate, and supine blood pressure and pulse rate) were obtained at the specified timepoints. Supine pulse rate was obtained after the participant had been supine for at least 5 minutes. When vital signs were scheduled at the same time as blood draws, the blood draws were obtained at the scheduled timepoint, and the vital signs were obtained as close to the scheduled blood draw as possible, but prior to the blood draw. The baseline value was defined as the last value recorded prior to the first dose in each treatment period. The normal reference range for supine pulse rate was 40-100 beats per minute.	Baseline and Days 1 to 8 of Periods 1-3 (up to 27 days)
Secondary	Change From Baseline in Respiratory Rate Over Time	Vital signs (including oral temperature, respiratory rate, and supine blood pressure and pulse rate) were obtained at the specified timepoints. When vital signs were scheduled at the same time as blood draws, the blood draws were obtained at the scheduled timepoint, and the vital signs were obtained as close to the scheduled blood draw as possible, but prior to the blood draw. The baseline value was defined as the last value recorded prior to the first dose in each treatment period. The normal reference range for respiratory rate was 10-24 breaths per minute.	Baseline and Days 1 to 8 of Periods 1-3 (up to 27 days)
Secondary	Change From Baseline in Oral Body Temperature Over Time	Vital signs (including oral temperature, respiratory rate, and supine blood pressure and pulse rate) were obtained at the specified timepoints. When vital signs were scheduled at the same time as blood draws, the blood draws were obtained at the scheduled timepoint, and the vital signs were obtained as close to the scheduled blood draw as possible, but prior to the blood draw. The baseline value was defined as the last value recorded prior to the first dose in each treatment period. The normal reference range for oral body temperature was 35.5-37.8 degrees Celsius (C).	Baseline and Days 1 to 8 of Periods 1-3 (up to 27 days)
Secondary	Change From Baseline in Duration of PR, RR, QRS, QT, QTcB, and QTcF Intervals Over Time, as Measured by Electrocardiogram	A single 12-lead electrocardiogram (ECG) was obtained at the specified timepoints. To minimize variability in autonomic tone and heart rate, participants rested quietly and in a supine position for at least 5 minutes prior to recording the ECG. Blood draws, other procedures, activity, and environmental distractions (e.g., television, radio, conversation) were to be avoided during the pre-ECG resting period and between ECG recordings to minimize variability due to the effects of activity and stress on cardiac electrophysiology. Whenever possible, ECG tracings for each participant were to be obtained from the same type of machine throughout the study. The baseline value was defined as the last value recorded prior to the first dose in each treatment period. The following are the normal reference ranges for ECG interval durations in milliseconds (msec): PR [120-210 msec]; QRS [upper limit: <120 msec]; QT, QTcB, and QTcF [upper limit: <470 msec].	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)
Secondary	Change From Baseline in Heart Rate Over Time, as Measured by Electrocardiogram	A single 12-lead electrocardiogram (ECG) was obtained at the specified timepoints. To minimize variability in autonomic tone and heart rate, participants rested quietly and in a supine position for at least 5 minutes prior to recording the ECG. Blood draws, other procedures, activity, and environmental distractions (e.g., television, radio, conversation) were to be avoided during the pre-ECG resting period and between ECG recordings to minimize variability due to the effects of activity and stress on cardiac electrophysiology. Whenever possible, ECG tracings for each participant were to be obtained from the same type of machine throughout the study. The baseline value was defined as the last value recorded prior to the first dose in each treatment period. The normal reference range for heart rate was 50-100 beats per minute.	Baseline, and post-dose on Days 1, 2, and 8 of Periods 1-3 (up to 27 days)