A Study of GDC-9545 Alone or in Combination With Palbociclib and/or Luteinizing Hormone-Releasing Hormone (LHRH) Agonist in Locally Advanced or Metastatic Estrogen Receptor-Positive Breast Cancer

NCT03332797 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: GO399322017-002083-412023-506700-12-00
• Study Type: interventional
• Target: 181
• Locations: 5 countries
• Sites: 23

Brief Summary

This study will evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GDC-9545 as a single agent and in combination with palbociclib and/or luteinizing hormone-releasing hormone (LHRH) agonist in participants with advanced or metastatic estrogen receptor (ER)-positive (human epidermal growth factor receptor 2 \[HER2\]-negative) breast cancer.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (17)

• Number of Participants with Adverse Events by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0)

  From Baseline until 28 days after the last dose of study treatment (up to 84 months)

• Dose Escalation: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of GDC-9545 When Administered as a Single Agent or in Combination with Palbociclib

  Days -7 to 28 of Cycle 1

• Dose Escalation: Number of Participants with Dose-Limiting Toxicities When GDC-9545 is Administered as a Single Agent or in Combination with Palbociclib

  Days -7 to 28 of Cycle 1

• Change from Baseline in Systolic Blood Pressure Over Time

  Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment

• Change from Baseline in Diastolic Blood Pressure Over Time

  Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment

• Change from Baseline in Body Temperature Over Time

  Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment

• Change from Baseline in Pulse Rate Over Time

  Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment

• Change from Baseline in Respiration Rate Over Time

  Baseline and at each treatment cycle (1 cycle is 28 days) through to 28 days after the last dose of study treatment

• Change from Baseline in Electrocardiogram (ECG) Results Over Time: Heart Rate

  Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment

• Change from Baseline in ECG Results Over Time: PR Duration

  Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment

• Change from Baseline in ECG Results Over Time: QRS Duration

  Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment

• Change from Baseline in ECG Results Over Time: QT Duration

  Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment

• Change from Baseline in ECG Results Over Time: QTcF Duration

  Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment

• Change from Baseline in ECG Results Over Time: RR Duration

  Baseline and at predefined intervals from Cycle 1 and at each subsequent cycle (1 cycle is 28 days) through to the last dose of study treatment

• Number of Participants with Clinical Laboratory Abnormalities in Hematology Tests by Highest Grade According to NCI-CTCAE v4.0

  Laboratory parameters for hematology will be measured and compared with a standard reference range. Values outside of the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment, a medical intervention, or a change in concomitant therapy; or is clinically significant in the investigator's judgment.

  Baseline, Cycle 1, and at each subsequent cycle (1 cycle is 28 days) or at every other cycle starting from Cycle 3 (Cohort X only), up to 28 days after the last dose of study treatment

• Number of Participants with Clinical Laboratory Abnormalities in Blood Chemistry Tests by Highest Grade According to NCI-CTCAE v4.0

  Laboratory parameters for blood chemistry will be measured and compared with a standard reference range. Values outside of the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment, a medical intervention, or a change in concomitant therapy; or is clinically significant in the investigator's judgment.

  Baseline, Cycle 1, and at each subsequent cycle (1 cycle is 28 days) or at every other cycle starting from Cycle 3 (Cohort X only), up to 28 days after the last dose of study treatment

• Number of Participants with Clinical Laboratory Abnormalities in Urinalysis Tests by Highest Grade According to NCI-CTCAE v4.0

  Laboratory parameters for urinalysis will be measured and compared with a standard reference range. Values outside of the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment, a medical intervention, or a change in concomitant therapy; or is clinically significant in the investigator's judgment.

  Baseline, Cycle 3, and at every other cycle (1 cycle is 28 days) up to 28 days after the last dose of study treatment

Secondary Outcomes (6)

• Plasma Concentration of GDC-9545 Over Time

  At predefined intervals from Cycle 1, Day -7 (Single-Agent Dose Escalation and A1-A5 only) or Cycle 1, Day 1 (B0, B1, and B2) to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion; Cycle 1, Days -7 or 8 (C1 only); Cycle 1, Day 8 (C2 only)

• Plasma Concentration of Palbociclib Over Time

  At predefined intervals from Cycle 1, Day 1 to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion (B0, B1, and B2 only); Cycle 1, Day 8 (C2 only)

• Plasma Concentration of LHRH Over Time

  At predefined intervals from Cycle 1, Day 1 to Cycle 4, Day 1 (1 cycle is 28 days) and at study completion (B2 only)

• Percentage of Participants with Objective Response

  For all cohorts, except for Cohort X: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 84 months)

• Clinical Benefit Rate

  For all cohorts, except for Cohort X: Baseline and every 8 weeks from Cycle 1, Day 1 until end of study treatment (up to 84 months)

Study Arms (12)

Dose Escalation: GDC-9545

EXPERIMENTAL

During dose escalation, postmenopausal participants will be assigned sequentially to escalating doses of GDC-9545, up to the maximum tolerated dose (MTD) or maximum administered dose (MAD).

Drug: GDC-9545

Dose Escalation: Cohort B0: GDC-9545 + Palbociclib

EXPERIMENTAL

GDC-9545 will be administered to postmenopausal participants, at a dose lower than the MTD or MAD determined in single-agent dose escalation, in combination with the label-recommended dose of palbociclib.

Drug: GDC-9545; Drug: Palbociclib

Dose Expansion: Cohort A1: GDC-9545 Dose 1

EXPERIMENTAL

GDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 1).

Drug: GDC-9545

Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH

EXPERIMENTAL

GDC-9545 will be administered to pre- or perimenopausal participants at a dose that is less than or equal to the MTD/MAD (Dose 1) in combination with an approved LHRH agonist.

Drug: GDC-9545; Drug: LHRH Agonist

Dose Expansion: Cohort A3: GDC-9545 Dose 2

EXPERIMENTAL

GDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 2).

Drug: GDC-9545

Dose Expansion: Cohort A4: GDC-9545 Dose 2 + LHRH

EXPERIMENTAL

GDC-9545 will be administered to pre- or perimenopausal participants at a dose that is less than or equal to the MTD/MAD (Dose 2) in combination with an LHRH agonist.

Drug: GDC-9545; Drug: LHRH Agonist

Dose Expansion: Cohort A5: GDC-9545 Dose 3

EXPERIMENTAL

GDC-9545 will be administered to postmenopausal participants as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 3).

Drug: GDC-9545

Dose Expansion: Cohort B1: GDC-9545 + Palbociclib

EXPERIMENTAL

GDC-9545 will be administered to postmenopausal participants, at a dose that is less than or equal to the MTD/MAD, in combination with the label-recommended dose of palbociclib.

Drug: GDC-9545; Drug: Palbociclib

Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH

EXPERIMENTAL

GDC-9545 will be administered to pre- or perimenopausal participants, at a dose that is less than or equal to the MTD/MAD, in combination with the label-recommended dose of palbociclib and an approved LHRH agonist.

Drug: GDC-9545; Drug: Palbociclib; Drug: LHRH Agonist

Dose Expansion: Cohort C1: GDC-9545 Dose 2 +/- Palbociclib

EXPERIMENTAL

GDC-9545 will be administered to postmenopausal participants at a pre-defined dose level (Dose 2) as a single agent for 14 days, followed by treatment with either GDC-9545 (Dose 2) plus palbociclib or GDC-9545 (Dose 2) alone for the duration of the study, as determined by the investigator.

Drug: GDC-9545; Drug: Palbociclib

Dose Expansion: Cohort C2: GDC-9545 Dose 2 + Palbociclib

EXPERIMENTAL

GDC-9545 will be administered to postmenopausal participants at a pre-defined dose level (Dose 2), in combination with the label-recommended dose of palbociclib.

Drug: GDC-9545; Drug: Palbociclib

Dose Expansion: Cohort X: GDC-9545 Dose 3

EXPERIMENTAL

GDC-9545 will be administered at a pre-defined dose level (Dose 3) to postmenopausal participants currently receiving clinical benefit with GDC-0927 or GDC-0810 on Studies GO29656 (NCT02316509) or GO29642 (NCT01823835), respectively, upon completion of their studies.

Drug: GDC-9545

Interventions

GDC-9545 DRUG

GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Also known as: Giredestrant, RO7197597, RG6171

Dose Escalation: Cohort B0: GDC-9545 + Palbociclib; Dose Escalation: GDC-9545; Dose Expansion: Cohort A1: GDC-9545 Dose 1; Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH; Dose Expansion: Cohort A3: GDC-9545 Dose 2; Dose Expansion: Cohort A4: GDC-9545 Dose 2 + LHRH; Dose Expansion: Cohort A5: GDC-9545 Dose 3; Dose Expansion: Cohort B1: GDC-9545 + Palbociclib; Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH; Dose Expansion: Cohort C1: GDC-9545 Dose 2 +/- Palbociclib; Dose Expansion: Cohort C2: GDC-9545 Dose 2 + Palbociclib; Dose Expansion: Cohort X: GDC-9545 Dose 3

Palbociclib DRUG

Palbociclib will be administered orally, once daily, at the label-recommended dose of 125 mg on Days 1-21 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Dose Escalation: Cohort B0: GDC-9545 + Palbociclib; Dose Expansion: Cohort B1: GDC-9545 + Palbociclib; Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH; Dose Expansion: Cohort C1: GDC-9545 Dose 2 +/- Palbociclib; Dose Expansion: Cohort C2: GDC-9545 Dose 2 + Palbociclib

LHRH Agonist DRUG

The LHRH agonist (leuprolide acetate, goserelin acetate, or triptorelin pamoate) will be administered by injection once every 4 weeks on Day 1 of each 28-day cycle, according to the label. The investigator will choose the appropriate LHRH agonist approved for use in breast cancer.

Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH; Dose Expansion: Cohort A4: GDC-9545 Dose 2 + LHRH; Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of either locally recurrent disease not amenable to resection or radiation therapy with curative intent or with metastatic disease
• Estrogen receptor (ER)-positive tumor
• Human epidermal growth factor receptor 2 (HER2)-negative breast cancer as per local laboratory testing
• Measurable disease, or evaluable bone disease; that is, bone lesions that are lytic or mixed (lytic + sclerotic) in the absence of measurable lesion
• Required paired pre- and on-treatment tumor biopsies for participants with metastases that are safely accessible as determined by the investigator
• Advanced or metastatic ER-positive/HER2-negative breast cancer that has recurred or progressed while being treated with adjuvant endocrine therapy for a duration of at least 24 months and/or endocrine therapy in the incurable, locally advanced, or metastatic setting and derived a clinical benefit from therapy (i.e., tumor response or stable disease for at least 6 months)
• No more than 2 prior lines of treatment for advanced or metastatic breast cancer
• Greater than or equal to (≥)2 weeks must have elapsed from the use of any other endocrine, targeted therapy or chemotherapy
• Single-Agent Cohorts (only applies to Dose Escalation): Advanced or metastatic disease that is either refractory to or intolerant of existing standard therapy or for which no effective standard therapy that confers clinical benefit is available
• Cohort B0: No prior treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitor
• For participants undergoing 18F-fluoroestradiol-positron emission tomography (FES-PET) imaging additional restrictions on prior therapy include: ≥2 months must have elapsed from the use of tamoxifen; ≥6 months must have elapsed from the use of fulvestrant
• Postmenopausal status
• Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to (≤)1
• Resolution of all acute toxic effects of prior therapy or surgical procedures to baseline or Grade ≤1 (except alopecia or other toxicities not considered to be a safety risk for the patient)
• Life expectancy of ≥12 weeks

You may not qualify if:

• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms
• Current treatment with any systemic anti-cancer therapies for advanced disease (not applicable to Cohort X participants currently receiving GDC-0810 or GDC-0927)
• Concurrent treatment with warfarin or phenytoin
• 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, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection
• Known human immunodeficiency virus (HIV) infection
• Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis
• Major surgery within 4 weeks prior to enrollment
• Radiation therapy within 2 weeks prior to enrollment
• 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
• Inability or unwillingness to swallow tablets or capsules (only applies to Dose Escalation)
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study (only applies to Dose Escalation)
• 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 using Fridericia's formula (QTcF) greater than (\>)470 milliseconds (ms) 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (23)

University of Colorado

Aurora, Colorado, 80045, United States

Location

Massachusetts General Hospital.

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37204, United States

Location

St Vincent's Hospital Sydney

Darlinghurst, New South Wales, 2010, Australia

Location

Peter Maccallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

National Cancer Center

Gyeonggi-do, 410-769, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Severance Hospital, Yonsei University Health System

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

ICO L'Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Hospital Quiron Barcelona

Barcelona, 08023, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital General Universitario Gregorio Maranon

Madrid, 28007, Spain

Location

Centro Oncologioco MD Anderson Internacional

Madrid, 28033, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario HM Sanchinarro

Madrid, 28050, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, 46010, Spain

Location

Barts Health NHS Trust

London, E1 2ES, United Kingdom

Location

The Royal Marsden Hospital

Suttton, SM2 5PT, United Kingdom

Location

Related Publications (2)

• Malhi V, Agarwal P, Gates MR, Liu L, Wang J, De Bruyn T, Lam S, Eng-Wong J, Perez-Moreno P, Chen YC, Yu J. Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer. Cancer Res Commun. 2023 Dec 15;3(12):2551-2559. doi: 10.1158/2767-9764.CRC-23-0324.

  PMID: 38019116 DERIVED

• Jhaveri KL, Bellet M, Turner NC, Loi S, Bardia A, Boni V, Sohn J, Neilan TG, Villanueva-Vazquez R, Kabos P, Garcia-Estevez L, Lopez-Miranda E, Perez-Fidalgo JA, Perez-Garcia JM, Yu J, Fredrickson J, Moore HM, Chang CW, Bond JW, Eng-Wong J, Gates MR, Lim E. Phase Ia/b Study of Giredestrant +/- Palbociclib and +/- Luteinizing Hormone-Releasing Hormone Agonists in Estrogen Receptor-Positive, HER2-Negative, Locally Advanced/Metastatic Breast Cancer. Clin Cancer Res. 2024 Feb 16;30(4):754-766. doi: 10.1158/1078-0432.CCR-23-1796.

  PMID: 37921755 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

giredestrant; palbociclib; Gonadotropin-Releasing Hormone

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2017
• First Posted: November 6, 2017
• Study Start: November 24, 2017
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2026
• Last Updated: February 13, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2); GB (2); KR (5); US (6); ES (8)