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

NCT04274075 | Completed Phase 1 Results FDA Drug

• 1 other identifier: GP42006
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Healthy Volunteers

Outcome Measures

Primary Outcomes (11)

• 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-∞ 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)

• 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)

• 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)

• 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)

• 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-∞ 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)

• Area Under the Plasma Concentration-Time Curve From Hour 0 Extrapolated to Infinity (AUC0-∞) 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-∞ 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)

• 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)

• Apparent Terminal Elimination Rate Constant (λz) 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 (λz) 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)

• 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)

• 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)

• 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 Outcomes (9)

• 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)

Study Arms (6)

GDC-9545 Treatment Sequence A, B, and C

EXPERIMENTAL

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.

Drug: GDC-9545 Tablet, Fasted: Treatment A; Drug: GDC-9545 Capsule, Fasted: Treatment B; Drug: GDC-9545 Capsule, Fed: Treatment C

GDC-9545 Treatment Sequence B, C, and A

EXPERIMENTAL

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.

Drug: GDC-9545 Tablet, Fasted: Treatment A; Drug: GDC-9545 Capsule, Fasted: Treatment B; Drug: GDC-9545 Capsule, Fed: Treatment C

GDC-9545 Treatment Sequence C, A, and B

EXPERIMENTAL

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.

Drug: GDC-9545 Tablet, Fasted: Treatment A; Drug: GDC-9545 Capsule, Fasted: Treatment B; Drug: GDC-9545 Capsule, Fed: Treatment C

GDC-9545 Treatment Sequence A, C, and B

EXPERIMENTAL

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.

Drug: GDC-9545 Tablet, Fasted: Treatment A; Drug: GDC-9545 Capsule, Fasted: Treatment B; Drug: GDC-9545 Capsule, Fed: Treatment C

GDC-9545 Treatment Sequence B, A, and C

EXPERIMENTAL

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.

Drug: GDC-9545 Tablet, Fasted: Treatment A; Drug: GDC-9545 Capsule, Fasted: Treatment B; Drug: GDC-9545 Capsule, Fed: Treatment C

GDC-9545 Treatment Sequence C, B, and A

EXPERIMENTAL

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.

Drug: GDC-9545 Tablet, Fasted: Treatment A; Drug: GDC-9545 Capsule, Fasted: Treatment B; Drug: GDC-9545 Capsule, Fed: Treatment C

Interventions

GDC-9545 Tablet, Fasted: Treatment A DRUG

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.

Also known as: Giredestrant, RO7197597, RG6171

GDC-9545 Treatment Sequence A, B, and C; GDC-9545 Treatment Sequence A, C, and B; GDC-9545 Treatment Sequence B, A, and C; GDC-9545 Treatment Sequence B, C, and A; GDC-9545 Treatment Sequence C, A, and B; GDC-9545 Treatment Sequence C, B, and A

GDC-9545 Capsule, Fasted: Treatment B DRUG

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.

Also known as: Giredestrant, RO7197597, RG6171

GDC-9545 Treatment Sequence A, B, and C; GDC-9545 Treatment Sequence A, C, and B; GDC-9545 Treatment Sequence B, A, and C; GDC-9545 Treatment Sequence B, C, and A; GDC-9545 Treatment Sequence C, A, and B; GDC-9545 Treatment Sequence C, B, and A

GDC-9545 Capsule, Fed: Treatment C DRUG

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.

Also known as: Giredestrant, RO7197597, RG6171

GDC-9545 Treatment Sequence A, B, and C; GDC-9545 Treatment Sequence A, C, and B; GDC-9545 Treatment Sequence B, A, and C; GDC-9545 Treatment Sequence B, C, and A; GDC-9545 Treatment Sequence C, A, and B; GDC-9545 Treatment Sequence C, B, and A

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (1)

Covance Research Unit - Daytona

Daytona Beach, Florida, 32117, United States

Location

MeSH Terms

Interventions

giredestrant

Limitations and Caveats

Caution should be used when interpreting results from the statistical analyses conducted in this study because the sample size is not based on power calculations.

Results Point of Contact

• Title: Medical Communications
• Organization: Genentech, Inc.

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Genentech, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 14, 2020
• First Posted: February 18, 2020
• Study Start: March 6, 2020
• Primary Completion: April 16, 2020
• Study Completion: April 16, 2020
• Last Updated: April 28, 2021
• Results First Posted: April 28, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)