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)

• ClinicalTrials.gov Identifier: NCT05306340
• Recruitment Status: Recruiting
• First Posted: April 1, 2022
• Last Update Posted: May 7, 2024
• Sponsor: Genentech, Inc.
• Information provided by (Responsible Party): Genentech, Inc.

Tracking Information

• First Submitted Date: March 23, 2022
• First Posted Date: April 1, 2022
• Last Update Posted Date: May 7, 2024
• Actual Study Start Date: August 3, 2022
• Estimated Primary Completion Date: October 3, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 4, 2022)

Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population [ Time Frame: From randomization until the first occurrence of disease progression or death from any cause, whichever occurs first (up to 42 months) ]

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).

• Original Primary Outcome Measures (submitted: March 23, 2022): Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1 [ Time Frame: From randomization until the first occurrence of disease progression or death from any cause, whichever occurs first (up to 42 months) ]

Current Secondary Outcome Measures (submitted: October 4, 2022)

• Overall Survival, in the ESR1m Subpopulation and ITT Population [ Time Frame: 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 [ Time Frame: 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, 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) ]
• Clinical Benefit Rate (CBR), as Determined by the Investigator According to RECIST v1.1, in the ESR1m Subpopulation and ITT Population [ Time Frame: 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 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 Frame: From randomization until 90 days after treatment discontinuation (up to 42 months) ]
  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 Frame: From randomization until 90 days after treatment discontinuation (up to 42 months) ]
  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 Frame: From randomization until 90 days after treatment discontinuation (up to 42 months) ]
  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 Frame: From randomization until 90 days after treatment discontinuation (up to 42 months) ]
  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 Frame: From randomization until 90 days after treatment discontinuation (up to 42 months) ]
  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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: From Baseline until 30 days after the final dose of study treatment (up to 42 months) ]
• Plasma Concentration of Giredestrant at Specified Timepoints [ Time Frame: 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) ]

Original Secondary Outcome Measures (submitted: March 23, 2022)

• Investigator-Assessed Progression-Free Survival, in Subgroups Categorized Prospectively by Baseline Estrogen Receptor 1 (ESR1)-Mutation Status, as Measured by circulating-tumor DNA (ctDNA) [ Time Frame: From randomization until the first occurrence of disease progression or death from any cause, whichever occurs first (up to 42 months) ]
• Overall Survival [ Time Frame: 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 [ Time Frame: 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 [ 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) ]
• Clinical Benefit Rate (CBR), as Determined by the Investigator According to RECIST v1.1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: From Baseline until 30 days after the final dose of study treatment (up to 42 months) ]
• Plasma Concentration of Giredestrant at Specified Timepoints [ Time Frame: 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) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Estrogen Receptor (ER)-Positive, HER2-negative, Locally Advanced or Metastatic Breast Cancer

Intervention

• Drug: Giredestrant
  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).
  Other Names:

  • GDC-9545
  • RO7197597
  • RG6171
• Drug: Exemestane
  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.
• Drug: Fulvestrant
  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.
• Drug: Tamoxifen
  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.
• Drug: Everolimus
  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.
• 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.

Study Arms

• Experimental: Giredestrant plus Everolimus
  Interventions:

  • Drug: Giredestrant
  • Drug: Everolimus
  • Drug: LHRH Agonist
  • Drug: Dexamethasone Mouth Rinse
• Active Comparator: Physician's Choice of Endocrine Therapy plus Everolimus
  The physician's choice of endocrine therapy is defined as either exemestane, fulvestrant, or tamoxifen.
  Interventions:

  • Drug: Exemestane
  • Drug: Fulvestrant
  • Drug: Tamoxifen
  • Drug: Everolimus
  • Drug: LHRH Agonist
  • Drug: Dexamethasone Mouth Rinse

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 4, 2022): 320
• Original Estimated Enrollment (submitted: March 23, 2022): 224
• Estimated Study Completion Date: March 31, 2026
• Estimated Primary Completion Date: October 3, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Locally advanced unresectable or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
2. Documented estrogen receptor-positive (ER+) tumor and HER2-negative tumor, assessed locally
3. Ability to provide a blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) Estrogen Receptor 1 (ESR1) mutation status determination by central testing

4. 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.
5. 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
6. Eastern Cooperative Oncology Group Performance Status 0-1
7. 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:

1. 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.
2. Progression on more than 2 prior lines of systemic endocrine therapy in the locally advanced unresectable or metastatic breast cancer setting
3. Prior chemotherapy for locally advanced unresectable or metastatic disease
4. 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
5. Treatment with any investigational therapy within 28 days prior to initiation of study treatment
6. Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days prior to randomization
7. 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
8. Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
9. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
10. Active cardiac disease or history of cardiac dysfunction
11. 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
12. Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection
13. Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy
14. Serious infection requiring oral or intravenous (IV) antibiotics, or other clinically significant infection, within 14 days prior to randomization
15. 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
16. Known allergy or hypersensitivity to any of the study drugs or any of their excipients
17. For premenopausal or perimenopausal women and for men: known hypersensitivity to LHRH agonists
18. Pregnant or breastfeeding

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Reference Study ID Number: ML43171 https://forpatients.roche.com/; 888-662-6728 (U.S. Only); global-roche-genentech-trials@gene.com

• Listed Location Countries: Argentina, Germany, Greece, Italy, Japan, Korea, Republic of, Singapore, South Africa, Spain, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05306340
• Other Study ID Numbers: ML43171; 2022-000199-20 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

For eligible studies, 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/innovation/process/clinical-trials/data-sharing/).

• Current Responsible Party: Genentech, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Genentech, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Genentech, Inc.

• PRS Account: Genentech, Inc.
• Verification Date: May 2024