A Study Evaluating the Efficacy and Safety of Giredestrant Plus Everolimus Compared With Exemestane Plus Everolimus in Participants With Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer (evERA Breast Cancer)
Study Details
Study Description
Brief Summary
This Phase III, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant plus everolimus compared with exemestane 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Giredestrant plus Everolimus
|
Drug: Giredestrant
Participants will receive treatment with giredestrant 30 milligrams (mg) by mouth (PO) once a day (QD) during 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).
Other Names:
Drug: Everolimus
Participants will receive treatment with everolimus 10 mg PO QD during each 28-day cycle until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.
Drug: LHRH Agonist
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.
Drug: Dexamethasone Mouth Rinse
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.
|
| Active Comparator: Exemestane plus Everolimus
|
Drug: Exemestane
Participants will receive treatment with exemestane 25 mg PO QD during each 28-day cycle until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.
Drug: Everolimus
Participants will receive treatment with everolimus 10 mg PO QD during each 28-day cycle until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.
Drug: LHRH Agonist
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.
Drug: Dexamethasone Mouth Rinse
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.
|
Outcome Measures
Primary Outcome Measures
- Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1 [From randomization until the first occurrence of disease progression or death from any cause, whichever occurs first (up to 42 months)]
Secondary Outcome Measures
- Investigator-Assessed Progression-Free Survival, in Subgroups Categorized Prospectively by Baseline Estrogen Receptor 1 (ESR1)-Mutation Status, as Measured by 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)]
- Overall Survival [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 [From randomization until progressive disease or death (up to 42 months)]
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 [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 [From Baseline until progressive disease or death (up to 42 months)]
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 (TTCD) in Pain Presence and Interference, as Determined Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire Linearly Transformed Pain Scale Score [From randomization until 90 days after treatment discontinuation (up to 42 months)]
TTCD 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.
- Time to Confirmed Deterioration (TTCD) in Physical Functioning (PF), as Determined Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire Linearly Transformed PF Scale Score [From randomization until 90 days after treatment discontinuation (up to 42 months)]
TTCD 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.
- Time to Confirmed Deterioration (TTCD) in Role Functioning (RF), as Determined Using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) Questionnaire Linearly Transformed RF Scale Score [From randomization until 90 days after treatment discontinuation (up to 42 months)]
TTCD 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.
- Time to Confirmed Deterioration (TTCD) in Health-Related Quality of Life (HRQoL), as Determined Using the EORTC Quality of Life-Core 30 (QLQ-C30) Questionnaire Linearly Transformed Global Health Status (GHS)/QoL Scale Score [From randomization until 90 days after treatment discontinuation (up to 42 months)]
TTCD 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.
- 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 [From Baseline until 30 days after the final dose of study treatment (up to 42 months)]
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 [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)]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
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Documented estrogen receptor-positive (ER+) tumor and HER2-negative tumor, assessed locally
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Patients who have bilateral breast cancers that are both ER+ and HER2-negative are eligible. If patients have bilateral tumors that are of different biomarker status, then proof of the ER and HER2 status of the metastases is required for study entry.
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Availability of blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) Estrogen Receptor 1 (ESR1) mutation status determination by central testing
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Prior endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors in either setting as follows:
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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
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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.
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Measurable disease as defined per RECIST v.1.1 or evaluable bone metastases which must have at least one predominantly lytic bone lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) and that can be followed
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Eastern Cooperative Oncology Group Performance Status 0-1
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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:
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Prior treatment with another oral selective estrogen receptor degrader (SERD) in any setting. Prior fulvestrant is allowed if treatment was terminated at least 28 days prior to randomization
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No more than 2 prior lines of systemic endocrine therapy in the locally advanced or metastatic breast cancer setting
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Prior chemotherapy for locally advanced or metastatic disease
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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
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Treatment with any investigational therapy within 28 days prior to initiation of study treatment
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Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 28 days prior to randomization
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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, or Stage I endometrial cancer
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Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
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Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
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Active cardiac disease or history of cardiac dysfunction
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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
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Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection
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Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy
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Serious infection requiring oral or intravenous (IV) antibiotics, or other clinically significant infection, within 14 days prior to randomization
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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
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Known allergy or hypersensitivity to any of the study drugs or any of their excipients
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For premenopausal or perimenopausal women and for men: known hypersensitivity to LHRH agonists
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Pregnant or breastfeeding
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | California Oncology of the Central Valley | Fresno | California | United States | 93710 |
| 2 | Emad Ibrahim, Md, Inc | Redlands | California | United States | 92373 |
| 3 | Eastern CT Hematology and Oncology Associates | Norwich | Connecticut | United States | 06360-2740 |
| 4 | Northwest Georgia Oncology Centers PC - Marietta | Marietta | Georgia | United States | 30060 |
| 5 | Summit Cancer Care PC | Savannah | Georgia | United States | 31405 |
| 6 | Oncology Hematology West PC | Grand Island | Nebraska | United States | 68803 |
| 7 | Nebraska Cancer Specialists; Oncology Hematology West, PC | Omaha | Nebraska | United States | 68130 |
| 8 | San Juan Oncology Associates | Farmington | New Mexico | United States | 87401 |
| 9 | Northwest Medical Specialties, PLLC; Research Department | Tacoma | Washington | United States | 98405 |
Sponsors and Collaborators
- Genentech, Inc.
Investigators
- Study Director: Clinical Trials, Genentech, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ML43171
- 2022-000199-20