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A Study Evaluating the Efficacy and Safety of Giredestrant Plus Everolimus Compared With The Physician's Choice of Endocrine Therapy Plus Everolimus in Participants With Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer (evERA Breast Cancer)

Primary Purpose

Estrogen Receptor (ER)-Positive, HER2-negative, Locally Advanced or Metastatic Breast Cancer

Status

Recruiting

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Giredestrant

Exemestane

Fulvestrant

Tamoxifen

Everolimus

LHRH Agonist

Dexamethasone Mouth Rinse

About this trial

This is an interventional treatment trial for Estrogen Receptor (ER)-Positive, HER2-negative, Locally Advanced or Metastatic Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Locally advanced unresectable or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
Documented estrogen receptor-positive (ER+) tumor and HER2-negative tumor, assessed locally
Availability of blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) Estrogen Receptor 1 (ESR1) mutation status determination by central testing
Prior endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors in either setting as follows:
- Metastatic setting: Disease progression ≥6 months after initiating ET plus CDK4/6 inhibitor in the locally advanced or metastatic setting. If ET plus CDK4/6 inhibitor is not the most recent therapy, then patient must also have had disease progression after ≥4 months on most recent ET
- Adjuvant Setting: Relapse either while taking or within 12 months of exposure to combination adjuvant ET and CDK4/6 inhibitor. Patients must have taken at least 12 months of adjuvant ET, 6 months of which was in combination with a CDK4/6 inhibitor.
Measurable disease as defined per RECIST v.1.1 or evaluable bone metastases. Patients with evaluable bone disease in the absence of measurable disease outside of the bone must have at least one predominantly lytic bone lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) which can be followed
Eastern Cooperative Oncology Group Performance Status 0-1
For women who are premenopausal or perimenopausal and for men: treatment with approved luteinizing hormone-releasing hormone (LHRH) agonist therapy for the duration of the study treatment

Exclusion Criteria:

Prior treatment with another oral selective estrogen receptor degrader (SERD), proteolysis targeting chimera (PROTAC), complete estrogen receptor antagonist (CERAN), or novel oral selective estrogen receptor modulator (SERM) in any setting. Prior fulvestrant is allowed if treatment was terminated at least 28 days prior to randomization
Progression on no more than 2 prior lines of systemic endocrine therapy in the locally advanced unresectable or metastatic breast cancer setting
Prior chemotherapy for locally advanced unresectable or metastatic disease
Treatment with the multidrug efflux pump P-glycoprotein (P-gp) and strong Cytochrome P450 3A4 (CYP3A4) inhibitors within 14 days or 5 drug elimination half-lives prior to randomization
Treatment with any investigational therapy within 28 days prior to initiation of study treatment
Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days prior to randomization
History of any other malignancy other than breast cancer within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, papillary thyroid cancer treated with surgery, Stage I endometrial cancer, or other non-breast cancers at very low risk of recurrence
Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
Active cardiac disease or history of cardiac dysfunction
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C including active viral or other hepatitis virus, current alcohol abuse, or cirrhosis
Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection
Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy
Serious infection requiring oral or intravenous (IV) antibiotics, or other clinically significant infection, within 14 days prior to randomization
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
Known allergy or hypersensitivity to any of the study drugs or any of their excipients
For premenopausal or perimenopausal women and for men: known hypersensitivity to LHRH agonists
Pregnant or breastfeeding

Sites / Locations

Alabama Oncology - Bruno Cancer CenterRecruiting
Gulf Health Hospitals, Inc. d/b/a Infirmary Cancer CareRecruiting
Alaska Oncology and HematologyRecruiting
Arizona Oncology Associates, PC-CASARecruiting
Genesis Cancer CenterRecruiting
University of Arkansas for Medical Sciences; Winthrop Rockefeller Cancer InstituteRecruiting
Pacific Cancer Medical CenterRecruiting
Alta Bates Summit Medical Center; Comprehensive Cancer CenterRecruiting
Beverly Hills Cancer CenterRecruiting
TOI Clinical ResearchRecruiting
Newport Beach UC Irvine Medical CenterRecruiting
Women's Cancer CareRecruiting
Scripps Health; Scripps Cancer CenterRecruiting
Los Angeles Hematology Oncology Medical GroupRecruiting
University of California, Irvine Medical CenterRecruiting
Emad Ibrahim, Md, IncRecruiting
Brian LeBerthon, Med CorpRecruiting
Yale Cancer Center; Medical OncologyRecruiting
Eastern CT Hematology and Oncology AssociatesRecruiting
ASCLEPES Research Centers - BrooksvilleRecruiting
Mount Sinai Medical CenterRecruiting
Orlando Health Cancer InstituteRecruiting
Cancer Care Centers of BrevardRecruiting
Florida Cancer SpecialistsRecruiting
Piedmont Atlanta HospitalRecruiting
Piedmont Fayette HospitalRecruiting
Northwest Georgia Oncology Centers PC - MariettaRecruiting
Piedmont Newnan HospitalRecruiting
Summit Cancer Care PCRecruiting
Piedmont Henry HospitalRecruiting
St Luke?s Cancer InstituteRecruiting
Northwestern University; Robert H. Lurie Comp Can CtrRecruiting
Duly Health and CareRecruiting
Southern Illinois University, School of Medicine, Simmons Cancer InstituteRecruiting
Springfield Clinic; Department of Hematology and OncologyRecruiting
Indiana University Melvin and Bren Simon Cancer CenterRecruiting
Des Moines Oncology Research AssociationRecruiting
University of Kansas Cancer CenterRecruiting
Pikeville Medical CenterRecruiting
LSU Health Baton Rouge; North ClinicRecruiting
Our Lady of the Lake Physicians Group; Hematology/OncologyRecruiting
Woman's HospitalRecruiting
Pontchartrain Cancer CenterRecruiting
Northern Light Cancer Center/Oncology ResearchRecruiting
New England Cancer SpecialistsRecruiting
Anne Arundel Health System Research InstituteRecruiting
Mercy Medical CenterRecruiting
TidalHealth Peninsula Regional; Richard A. Henson ResearchRecruiting
Sinai Hospital of Baltimore IncRecruiting
TidalHealth Peninsula RegionalRecruiting
Sinai Hospital of Baltimore; Wiliam E. Kahlert Regional Cancer CenterRecruiting
Dana Farber Cancer InstituteRecruiting
Michigan Center of Medical ResearchRecruiting
Metro-Minnesota Community Oncology Research ConsortiumRecruiting
Oncology Hematology West PCRecruiting
Nebraska Cancer Specialists; Oncology Hematology West, PCRecruiting
Renown Regional Medical CenterRecruiting
Summit Medical Group; MD Anderson Cancer CenterRecruiting
San Juan Oncology AssociatesRecruiting
The Blavatnik Family ? Chelsea Medical Center at Mount SinaiRecruiting
Icahn School of Medicine at Mount Sinai; Department of PharmacyRecruiting
Icahn School of Medicine at Mount SinaiRecruiting
Stony Brook University Medical CenterRecruiting
Cape Fear Valley Medical CenterRecruiting
The Gabrail Pharmacology Phase 1 Research Center LLCRecruiting
SCRI Mark H. Zangmeister CenterRecruiting
University of Oklahoma Health Sciences Center; Peggy and Charles Stephenson Oklahoma Cancer CenterRecruiting
Oklahoma Cancer Specialists and Research InstituteRecruiting
St Charles Medical Center Bend; ATTN: ResearchRecruiting
Oncology Research OfficeRecruiting
Abramson Cancer Center; Univ of PennsylvaniaRecruiting
UPMC Hillman Cancer Center - Magee-Women?s HospitalRecruiting
Abramson Cancer Center Chester County Hospital; Hematology, Medical OncologyRecruiting
McGlinn Cancer Institute at Reading HospitalRecruiting
Avera Cancer InstituteRecruiting
West Cancer CenterRecruiting
Thompson Cancer Survival CenterRecruiting
Texas Oncology P.A - BeaumontRecruiting
Texas OncologyRecruiting
Texas Oncology - Baylor Charles A. Sammons Cancer CenterRecruiting
Texas Oncology-Denton SouthRecruiting
Texas Oncology, P.A. - El Paso; El Paso Cancer Treatment Center, WestRecruiting
Methodist Hospital Research InstituteRecruiting
Millennium Research & Clinical DevelopmentRecruiting
Lumi ResearchRecruiting
Texas Oncology (McAllen) - USORRecruiting
USOR - Texas Oncology - San Antonio NortheastRecruiting
Virginia Cancer SpecialistsRecruiting
Inova Fairfax HospitalRecruiting
Virginia Oncology AssociatesRecruiting
Multicare Institute for Research and InnovationRecruiting
Northwest Medical Specialties, PLLC; Research DepartmentRecruiting
UW Cancer Center at ProHealthRecruiting
Instituto Angel RoffoRecruiting
Consultorios Médicos Dr. DoreskiRecruiting
Centro de Neurociencias Invest y TratamientoRecruiting
Centro Medico Privado CEMAICRecruiting
Fundacion Centro Oncologico de Integracion Regional (COIR)Recruiting
Instituto Medico de la Fundacion Estudios ClinicosRecruiting
Hospital Provincial del CentenarioRecruiting
Organizacion Medica de InvestigacionRecruiting
Aichi Cancer CenterRecruiting
Nagoya University HospitalRecruiting
Chiba Cancer CenterRecruiting
National Cancer Center Hospital EastRecruiting
Shikoku Cancer CenterRecruiting
Fukushima Medical University HospitalRecruiting
Hiroshima City Hiroshima Citizens HospitalRecruiting
Hiroshima University HospitalRecruiting
Hokkaido University HospitalRecruiting
Hyogo Cancer CenterRecruiting
University of Tsukuba HospitalRecruiting
Kanagawa Cancer CenterRecruiting
Tokai University HospitalRecruiting
Kumamoto University HospitalRecruiting
Kyoto University HospitalRecruiting
Niigata Cancer Center HospitalRecruiting
Naha-nishi ClinicRecruiting
National Hospital Organization Osaka National HospitalRecruiting
Osaka International Cancer InstituteRecruiting
Juntendo University HospitalRecruiting
The Cancer Institute Hospital of JFCRRecruiting
Chungbuk National University HospitalRecruiting
Soon Chun Hyang University Cheonan HospitalRecruiting
National Cancer CenterRecruiting
CHA Bundang Medical CenterRecruiting
Seoul National University Bundang HospitalRecruiting
Seoul National University HospitalRecruiting
Severance Hospital Yonsei University Health System - PPDSRecruiting
Korea University Guro HospitalRecruiting
Changhua Christian HospitalRecruiting
National Cheng Kung University HospitalRecruiting
Koo Foundation Sun Yat-Sen Cancer Center; Hemato-OncologyRecruiting
National Taiwan University HospitalRecruiting
Chang Gung Memorial Hospital - Linkou BranchRecruiting
Dorset County HospitalRecruiting
North Middlesex Uni Hospital; Haematology DeptRecruiting
The Christie NHS Foundation TrustRecruiting
Nottingham City HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Giredestrant plus Everolimus

Physician's Choice of Endocrine Therapy plus Everolimus

Arm Description

The physician's choice of endocrine therapy is defined as either exemestane, fulvestrant, or tamoxifen.

Outcomes

Primary Outcome Measures

Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population

The Intent-to-Treat (ITT) population consists of all randomized participants, and the ESR1m subpopulation is defined as participants in the ITT population whose tumors harbor a detectable Estrogen Receptor 1 (ESR1) mutation at baseline as measured in circulating tumor DNA (ctDNA).

Secondary Outcome Measures

Overall Survival, in the ESR1m Subpopulation and ITT Population

Objective Response Rate (ORR), as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population

The objective response rate is defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions at least 4 weeks apart.

Duration of Response (DOR), as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population

Clinical Benefit Rate (CBR), as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population

The clinical benefit rate is defined as the percentage of participants with stable disease for at least (≥)24 weeks or a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart.

Time to Confirmed Deterioration in Pain Severity, as Determined Using the Brief Pain Inventory Short-Form (BPI-SF) Worst Pain Item Score, in the ESR1m Subpopulation and ITT Population

Time to confirmed deterioration in pain severity is defined as the time from randomization to the first documentation of ≥2-point increase from baseline on the "worst pain" item score (scale from 0 = "No pain" to 10 = "Pain as bad as you can imagine") held for 2 consecutive time points, or a ≥2-point increase followed by death attributable to cancer progression within 28 days from the last assessment.

Time to Confirmed Deterioration in Pain Presence and Interference, as Determined Using the EORTC QLQ-C30 Questionnaire Linearly Transformed Pain Scale Score, in the ESR1m Subpopulation and ITT Population

Time to confirmed deterioration in pain presence and interference is defined as the time from randomization to the first documentation of ≥10-point increase in pain score held for 2 consecutive time points, or a ≥10-point increase followed by death attributable to cancer progression within 28 days from the last assessment. EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life-Core 30

Time to Confirmed Deterioration in Physical Functioning (PF), as Determined Using the EORTC QLQ-C30 Questionnaire Linearly Transformed PF Scale Score, in the ESR1m Subpopulation and ITT Population

Time to confirmed deterioration in physical functioning (PF) is defined as the time from randomization to the first documentation of ≥10-point decrease in PF score held for 2 consecutive time points, or a ≥10-point decrease followed by death attributable to cancer progression within 28 days from the last assessment. EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life-Core 30

Time to Confirmed Deterioration in Role Functioning (RF), as Determined Using the EORTC QLQ-C30 Questionnaire Linearly Transformed RF Scale Score, in the ESR1m Subpopulation and ITT Population

Time to confirmed deterioration in role functioning (RF) is defined as the time from randomization to the first documentation of ≥10-point decrease in RF score held for 2 consecutive time points, or a ≥10-point decrease followed by death attributable to cancer progression within 28 days from the last assessment. EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life-Core 30

Time to Confirmed Deterioration in Health-Related Quality of Life (HRQoL), as Determined Using the EORTC QLQ-C30 Questionnaire Linearly Transformed Global Health Status (GHS)/QoL Scale Score, in the ESR1m Subpopulation and ITT Population

Time to confirmed deterioration in HRQoL is defined as the time from randomization to the first documentation of ≥10-point decrease in GHS/QoL score held for 2 consecutive time points, or a ≥10-point decrease followed by death attributable to cancer progression within 28 days from the last assessment. EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life-Core 30

Number of Participants with at Least One Adverse Event, with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE v5.0)

Number of Participants with Vital Sign Abnormalities Over the Course of the Study

Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature.

Number of Participants with Clinical Laboratory Test Abnormalities for Hematology Parameters Over the Course of the Study

Number of Participants with Clinical Laboratory Test Abnormalities for Biochemistry Parameters Over the Course of the Study

Plasma Concentration of Giredestrant at Specified Timepoints

Full Information

NCT ID

NCT05306340

First Posted

March 23, 2022

Last Updated

October 12, 2023

Sponsor

Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT05306340

Brief Title

A Study Evaluating the Efficacy and Safety of Giredestrant Plus Everolimus Compared With The Physician's Choice of Endocrine Therapy Plus Everolimus in Participants With Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer (evERA Breast Cancer)

Official Title

A Phase III, Randomized, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Giredestrant Plus Everolimus Compared With The Physician's Choice of Endocrine Therapy Plus Everolimus in Patients With Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 3, 2022 (Actual)

Primary Completion Date

October 3, 2024 (Anticipated)

Study Completion Date

March 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This Phase III, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant plus everolimus compared with the physician's choice of endocrine therapy plus everolimus in participants with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who have had previous treatment with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) and endocrine therapy, either in the locally advanced/metastatic or the adjuvant setting.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Estrogen Receptor (ER)-Positive, HER2-negative, Locally Advanced or Metastatic Breast Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

320 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Giredestrant plus Everolimus

Arm Type

Experimental

Arm Title

Physician's Choice of Endocrine Therapy plus Everolimus

Arm Type

Active Comparator

Arm Description

The physician's choice of endocrine therapy is defined as either exemestane, fulvestrant, or tamoxifen.

Intervention Type

Drug

Intervention Name(s)

Giredestrant

Other Intervention Name(s)

GDC-9545, RO7197597, RG6171

Intervention Description

Participants will receive treatment with giredestrant 30 milligrams (mg) orally once a day (QD) on Days 1-28 of each 28-day cycle until unacceptable toxicity or disease progression as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).

Intervention Type

Drug

Intervention Name(s)

Exemestane

Intervention Description

If exemestane is chosen as the physician's choice of endocrine therapy, the participant will receive exemestane at a dose of 25 mg orally once a day (QD) on Days 1-28 of each 28-day cycle or as per local label, until unacceptable toxicity or disease progression as determined by investigator according to RECIST v1.1.

Intervention Type

Drug

Intervention Name(s)

Fulvestrant

Intervention Description

If fulvestrant is chosen as the physician's choice of endocrine therapy, the participant will receive fulvestrant in the clinic at a dose of 500 mg intramuscularly on Day 1 and Day 15 of Cycle 1, then Day 1 of each cycle thereafter (1 cycle is 28 days) or as per local prescribing information, until unacceptable toxicity or disease progression as determined by investigator according to RECIST v1.1.

Intervention Type

Drug

Intervention Name(s)

Tamoxifen

Intervention Description

If tamoxifen is chosen as the physician's choice of endocrine therapy, the participant will receive tamoxifen at a dose of 20 mg orally QD on Days 1-28 of each 28-day cycle or as per local prescribing information, until unacceptable toxicity or disease progression as determined by investigator according to RECIST v1.1.

Intervention Type

Drug

Intervention Name(s)

Everolimus

Intervention Description

Participants will receive treatment with everolimus 10 mg orally QD during each 28-day cycle until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

Intervention Type

Drug

Intervention Name(s)

LHRH Agonist

Intervention Description

Only premenopausal/perimenopausal female participants and male participants will receive a luteinizing hormone-releasing hormone (LHRH) agonist on Day 1 of each 28-day treatment cycle. The investigator will determine and supply the appropriate LHRH agonist locally approved for use in breast cancer.

Intervention Type

Drug

Intervention Name(s)

Dexamethasone Mouth Rinse

Intervention Description

A compounded alcohol-free mouthwash of dexamethasone (0.5 mg in 5 mL) will be supplied, where feasible. It is strongly recommended for prophylaxis or treatment of stomatitis/mucositis. Participants should use the alcohol-free mouthwash of dexamethasone four times QD for 8 weeks started concurrently with study treatment, and use it reactively thereafter with the first appearance of symptoms.

Primary Outcome Measure Information:

Title

Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population

Description

Time Frame

From randomization until the first occurrence of disease progression or death from any cause, whichever occurs first (up to 42 months)

Secondary Outcome Measure Information:

Title

Overall Survival, in the ESR1m Subpopulation and ITT Population

Time Frame

From randomization until death from any cause (up to 42 months)

Title

Objective Response Rate (ORR), as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population

Description

The objective response rate is defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions at least 4 weeks apart.

Time Frame

From randomization until progressive disease or death (up to 42 months)

Title

Duration of Response (DOR), as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population

Time Frame

From the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 42 months)

Title

Clinical Benefit Rate (CBR), as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population

Description

Time Frame

From Baseline until progressive disease or death (up to 42 months)

Title

Time to Confirmed Deterioration in Pain Severity, as Determined Using the Brief Pain Inventory Short-Form (BPI-SF) Worst Pain Item Score, in the ESR1m Subpopulation and ITT Population

Description

Time Frame