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)

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: Giredestrant
* Drug: Exemestane
* Drug: Fulvestrant
* Drug: Tamoxifen
* Drug: Everolimus
* Drug: LHRH Agonist
* Drug: Dexamethasone Mouth Rinse


Participation Criteria
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Eligibility Criteria
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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 Ability to provide a 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 after ≥6 months on 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), novel oral selective estrogen receptor modulator (SERM), or everolimus in any setting. Prior fulvestrant is allowed if treatment was terminated at least 28 days prior to randomization. Prior treatment with tamoxifen is allowed. Progression on 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 strong Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Giredestrant plus Everolimus<br> | Drug: Giredestrant<br>* 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).<br>* Other names: RG6171;Drug: Everolimus<br>* 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.<br>Drug: LHRH Agonist<br>* 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.<br>Drug: Dexamethasone Mouth Rinse<br>* 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.<br>|
| Active Comparator: Physician's Choice of Endocrine Therapy plus Everolimus<br>The physician's choice of endocrine therapy is defined as either exemestane, fulvestrant, or tamoxifen. | Drug: Exemestane<br>* 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.<br>Drug: Fulvestrant<br>* 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.<br>Drug: Tamoxifen<br>* 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.<br>Drug: Everolimus<br>* 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.<br>Drug: LHRH Agonist<br>* 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.<br>Drug: Dexamethasone Mouth Rinse<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From randomization until the first occurrence of disease progression or death from any cause, whichever occurs first (up to 42 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival, in the ESR1m Subpopulation and ITT Population |  | From randomization until death from any cause (up to 42 months) | 
| 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. | From randomization until progressive disease or death (up to 42 months) | 
| Duration of Response (DOR), as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population |  | From the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 42 months) | 
| 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. | From Baseline until progressive disease or death (up to 42 months) | 
| 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. | From randomization until 90 days after treatment discontinuation (up to 42 months) | 
| 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 | From randomization until 90 days after treatment discontinuation (up to 42 months) | 
| 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 | From randomization until 90 days after treatment discontinuation (up to 42 months) | 
| 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 | From randomization until 90 days after treatment discontinuation (up to 42 months) | 
| 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 | From randomization until 90 days after treatment discontinuation (up to 42 months) | 
| 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) |  | From Baseline until 30 days after the final dose of study treatment (up to 42 months) | 
| 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. | From Baseline until 30 days after the final dose of study treatment (up to 42 months) | 
| Number of Participants with Clinical Laboratory Test Abnormalities for Hematology Parameters Over the Course of the Study |  | From Baseline until 30 days after the final dose of study treatment (up to 42 months) | 
| Number of Participants with Clinical Laboratory Test Abnormalities for Biochemistry Parameters Over the Course of the Study |  | From Baseline until 30 days after the final dose of study treatment (up to 42 months) | 
| Plasma Concentration of Giredestrant at Specified Timepoints |  | Predose and 3 hours postdose on Days 1 and 15 of Cycle 1, and predose on Day 1 of Cycles 2 and 3 (1 cycle is 28 days) |