A Study of Giredestrant (GDC-9545) in Postmenopausal Women With Stage I-III Operable, Estrogen Receptor-Positive Breast Cancer

• ClinicalTrials.gov Identifier: NCT03916744
• Recruitment Status: Completed
• First Posted: April 16, 2019
• Results First Posted: March 10, 2023
• Last Update Posted: March 10, 2023
• Sponsor: Genentech, Inc.
• Information provided by (Responsible Party): Genentech, Inc.

Study Description

Brief Summary:

This study will evaluate the pharmacodynamics, pharmacokinetics, safety, and biologic activity of giredestrant in participants with Stage I-III operable estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, untreated breast cancer.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Giredestrant; Procedure: Surgery	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 75 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Phase I, Multicenter, Open-Label Preoperative, Short-Term Window Study of GDC-9545 in Postmenopausal Women With Stage I-III Operable, Estrogen Receptor-Positive Breast Cancer
• Actual Study Start Date: July 26, 2019
• Actual Primary Completion Date: May 25, 2021
• Actual Study Completion Date: May 25, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Giredestrant 10 mg	Drug: Giredestrant; Giredestrant will be administered orally once daily (QD) starting on Day 1 up to and including the day of surgery (if allowed per local process) on Day 15 (+/-2 days).; Other Names: GDC-9545; RO7197597; RG6171; Procedure: Surgery; Breast cancer surgery will take place on Day 15 (+/-2 days).
Experimental: Giredestrant 30 mg	Drug: Giredestrant; Giredestrant will be administered orally once daily (QD) starting on Day 1 up to and including the day of surgery (if allowed per local process) on Day 15 (+/-2 days).; Other Names: GDC-9545; RO7197597; RG6171; Procedure: Surgery; Breast cancer surgery will take place on Day 15 (+/-2 days).
Experimental: Giredestrant 100 mg	Drug: Giredestrant; Giredestrant will be administered orally once daily (QD) starting on Day 1 up to and including the day of surgery (if allowed per local process) on Day 15 (+/-2 days).; Other Names: GDC-9545; RO7197597; RG6171; Procedure: Surgery; Breast cancer surgery will take place on Day 15 (+/-2 days).

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Tumor Cell Proliferation, as Measured by the Proportion of Nuclei Staining Ki67-Positive at Surgery Relative to Baseline in Pre- and Post-Treatment Tumor Biopsy Samples [ Time Frame: Baseline and Surgery (Day 15) ]
   The biological response to the study treatment was assessed by measuring changes in cell proliferation (Ki67 expression) using formalin-fixed paraffin-embedded histopathology sections of the tumor biopsy specimens taken at baseline and at day of surgery. Baseline was defined as a sample taken prior to initiation of study drug. The results show the proportion of nuclei staining Ki67-positive (Ki67+) in the tumor biopsy sample taken post-treatment (at surgery) relative to that in the pre-treatment sample (at baseline).
2. Change From Baseline in Tumor Cell Proliferation, as Measured by the Difference in the Percentage of Nuclei Staining Ki67-Positive at Surgery Compared With Baseline in Pre- and Post-Treatment Tumor Biopsy Samples [ Time Frame: Baseline and Surgery (Day 15) ]
   The biological response to the study treatment was assessed by measuring changes in cell proliferation (Ki67 expression) using formalin-fixed paraffin-embedded histopathology sections of the tumor biopsy specimens taken at baseline and at day of surgery. Baseline was defined as a sample taken prior to initiation of study drug. The results show the percentage of nuclei staining Ki67-positive (Ki67+) in the pre- and post-treatment tumor biopsy samples (taken at baseline and surgery, respectively) and the absolute difference in the percentage of Ki67+ nuclei between the two samples (calculated as surgery minus baseline).

Secondary Outcome Measures :

1. Number of Participants With at Least One Adverse Event and by Severity, Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI-CTCAE v5.0) [ Time Frame: From Baseline to Day 43 ]
   All adverse events (AEs) were recorded and the investigator independently assessed the seriousness and severity of each AE. AE severity was graded on a scale from 1 to 5 using the NCI-CTCAE v5.0; any events not specifically listed in the scale were defined as: 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. Investigators used their knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether an AE was considered to be related to the study drug.
2. Percentage of Participants With Abnormal Vital Signs During Treatment [ Time Frame: Baseline, Days 1, 8, and 15 ]
   Vital signs, which included diastolic and systolic blood pressure, pulse rate, and body temperature, were measured while the participant was sitting and according to institutional practices. Any of the vital signs that were outside of the normal reference range (in the specified direction - low or high) were considered abnormalities. Not every abnormality qualified as an adverse event (AE). A vital sign result had to be 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.
3. Change From Baseline in Pulse Rate [ Time Frame: Baseline, Day 8, Surgery (Day 15), and Post-Surgery (Day 43) ]
   Pulse rate was measured while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The post-baseline minimum and maximum change from baseline values are, respectively, the smallest and largest value changes obtained after baseline through the last study visit. Baseline was defined as the participant's last value prior to initiation of study drug.
4. Change From Baseline in Systolic Blood Pressure [ Time Frame: Baseline, Day 8, Surgery (Day 15), and Post-Surgery (Day 43) ]
   Systolic blood pressure was measured while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The post-baseline minimum and maximum change from baseline values are, respectively, the smallest and largest value changes obtained after baseline through the last study visit. Baseline was defined as the participant's last value prior to initiation of study drug.
5. Change From Baseline in Diastolic Blood Pressure [ Time Frame: Baseline, Day 8, Surgery (Day 15), and Post-Surgery (Day 43) ]
   Diastolic blood pressure was measured while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The post-baseline minimum and maximum change from baseline values are, respectively, the smallest and largest value changes obtained after baseline through the last study visit. Baseline was defined as the participant's last value prior to initiation of study drug.
6. Change From Baseline in Body Temperature [ Time Frame: Baseline, Day 8, Surgery (Day 15), and Post-Surgery (Day 43) ]
   Body temperature was measured according to institutional practice. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The post-baseline minimum and maximum change from baseline values are, respectively, the smallest and largest value changes obtained after baseline through the last study visit. Baseline was defined as the participant's last value prior to initiation of study drug.
7. Percentage of Participants With Laboratory Abnormalities in Hematology Tests During Treatment, Among Participants Without the Abnormality at Baseline [ Time Frame: Baseline, Days 1, 8, and 15 ]
   Laboratory parameters for hematology will be measured and compared with a standard reference range. Any of the laboratory test results that were outside of a parameter's normal reference range (in the specified direction - low or high) 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.
8. Percentage of Participants With Laboratory Abnormalities in Blood Chemistry and Coagulation Tests During Treatment, Among Participants Without the Abnormality at Baseline [ Time Frame: Baseline, Days 1, 8, and 15 ]
   Laboratory parameters for blood chemistry and coagulation were measured and compared with a standard reference range. Any of the laboratory test results that were outside of a parameter's normal reference range (in the specified direction - low or high) 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. SGPT/ALT = alanine aminotransferase; SGOT/AST = aspartate aminotransferase
9. Percentage of Participants With Abnormal Electrocardiogram Parameters During Treatment [ Time Frame: Baseline, Days 1, 8, and 15 ]
   Electrocardiogram (ECG) recordings were performed after the participant had been resting in a supine position for at least 10 minutes. ECG parameters included heart rate, PR and QRS durations, and QT and QTcF intervals. Per the protocol, ECG readings post-treatment were limited to those for whom it was clinically indicated. Any of the ECG parameters that were outside of the normal reference range (in the specified direction - low or high) were considered abnormalities. Not every abnormality qualified as an adverse event (AE). An ECG 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.
10. Plasma Concentration of Giredestrant at Steady State by Dose Level [ Time Frame: Predose on day of surgery (Day 15), or prior to biopsy (Day 14) ]
    Plasma samples were obtained on the day of surgery (Day 15), or prior to biopsy on Day 14.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Ability to comply with the study protocol, in the investigator's judgment
• Histologically confirmed invasive breast carcinoma, with all of the following characteristics: Primary tumor greater than or equal to (≥)1.5 centimeters (cm) in largest diameter by ultrasound; Stage I-III operable breast cancer; Documentation confirming the absence of distant metastasis (M0) as determined by institutional practice.
• ER-positive tumor and HER2-negative breast cancer as per local laboratory testing
• Postmenopausal status
• Breast cancer eligible for primary surgery
• Submission of a representative tumor tissue specimen
• Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to (≤)1
• Adequate organ function

Exclusion Criteria:

• Diagnosis of inflammatory breast cancer
• Diagnosis of bilateral breast cancer
• Concurrent use of hormone replacement therapies
• Previous systemic or local treatment for the primary breast cancer currently under investigation
• Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study entry
• Current treatment with any systemic anti-cancer therapies
• Major surgery within 4 weeks prior to enrollment
• Radiation therapy within 2 weeks prior to enrollment
• Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
• Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or upper gastrointestinal surgery including gastric resection
• Known HIV infection
• Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
• History of allergy to giredestrant or any of its excipients
• Any condition requiring anti-coagulants, such as warfarin, heparin, or thrombolytic drugs
• History of documented hemorrhagic diathesis or coagulopathy
• History or presence of symptomatic bradycardia or sick sinus syndrome
• Baseline heart rate ≤55 beats per minute (bpm) prior to enrollment
• History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, or evidence of prior myocardial infarction
• QT interval corrected through use of Fridericia's formula (QTcF) >470 milliseconds demonstrated by at least two ECGs >30 minutes apart
• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome
• Current treatment with medications that are well known to prolong the QT interval
• History or presence of uncontrolled hypothyroidism
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications

Contacts and Locations

Locations

United States, Colorado

University of Colorado

Aurora, Colorado, United States, 80045-2517

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

Australia, New South Wales

St Vincent's Hospital Sydney

Darlinghurst, New South Wales, Australia, 2010

Australia, Victoria

Sunshine Hospital

St Albans, Victoria, Australia, 3021

Belgium

Clinique Edith Cavell; Pharmacie

Auderghem, Belgium, 1160

UZ Antwerpen

Edegem, Belgium, 2650

Clinique Sainte-Elisabeth; Oncologie

Namur, Belgium, 5000

Spain

Onkologikoa - Instituto Oncológico de Donostia

San Sebastian, Guipuzcoa, Spain, 20014

Hospital Universitari Vall d'Hebron

Barcelona, Spain, 08035

Hospital Ruber Internacional;Servicio de Oncologia

Madrid, Spain, 28034

HM Sanchinarro ? CIOCC

Madrid, Spain, 28050

Hospital Clinico Universitario de Valencia

Valencia, Spain, 46010

United Kingdom

Barts Health NHS Trust; William Harvey Heart Centre, QMUL School of Medicine & Dentistry

London, United Kingdom, EC1M 6BQ

Royal Cornwall Hospital

Truro, United Kingdom, TR1 3LQ

Sponsors and Collaborators

Genentech, Inc.

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

  Study Documents (Full-Text)

Documents provided by Genentech, Inc.:

Study Protocol and Statistical Analysis Plan  [PDF] April 7, 2020

More Information

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT03916744
• Other Study ID Numbers: GO40987; 2018-003798-85 ( EudraCT Number )
• First Posted: April 16, 2019
• Results First Posted: March 10, 2023
• Last Update Posted: March 10, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Plan Description

Qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).

For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases