A Study Evaluating the Efficacy and Safety of Giredestrant Compared With Physician's Choice of Endocrine Monotherapy in Participants With Previously Treated Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (acelERA Breast Cancer)

• ClinicalTrials.gov Identifier: NCT04576455
• Recruitment Status: Active, not recruiting
• First Posted: October 6, 2020
• Results First Posted: March 10, 2023
• Last Update Posted: February 28, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 30, 2020
• First Posted Date: October 6, 2020
• Results First Submitted Date: February 13, 2023
• Results First Posted Date: March 10, 2023
• Last Update Posted Date: February 28, 2024
• Actual Study Start Date: November 27, 2020
• Actual Primary Completion Date: February 18, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2023)

Progression-Free Survival (PFS), as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) [ Time Frame: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to a clinical cutoff of 15 months) ]

PFS was defined as the time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1, or death from any cause (whichever occurs first). Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.

• Original Primary Outcome Measures (submitted: September 30, 2020): Progression-Free Survival, as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) [ Time Frame: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to 40 months) ]

Current Secondary Outcome Measures (submitted: February 13, 2023)

• Overall Survival (OS) [ Time Frame: From randomization to death from any cause (up to approximately 36 months) ]
  OS is defined as the time from randomization to death from any cause.
• Objective Response Rate, as Determined by the Investigator According to RECIST v1.1 [ Time Frame: From randomization until disease progression or death (up to approximately 36 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. Per RECIST v1.1, CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to <10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
• Duration of Response (DOR), as Determined by the Investigator According to RECIST v1.1 [ Time Frame: From first occurrence of documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 36 months) ]
  DOR is defined as the time from the first occurrence of a documented objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first). Objective response rate is defined as the percentage of participants with a CR or PR on two consecutive occasions at least 4 weeks apart. Per RECIST v1.1, CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to <10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.
• Clinical Benefit Rate, as Determined by the Investigator According to RECIST v1.1 [ Time Frame: From randomization until disease progression or death (up to approximately 36 months) ]
  The clinical benefit rate is defined as the percentage of participants with stable disease for ≥24 weeks or a CR or PR. Per RECIST v1.1, CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to <10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
• Investigator-Assessed PFS, in Subgroups Categorized by Estrogen Receptor 1 (ESR1) Mutation Status [ Time Frame: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to a clinical cutoff of 15 months) ]
  PFS was defined as the time from randomization to the first occurrence of disease progression determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first). Disease progression was defined as ≥20% increase in in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. Investigator-assessed PFS was analyzed in subgroups categorized by baseline ESR1 mutation status (i.e., with or without ESR1 mutation at baseline) from plasma circulating tumor deoxyribonucleic acid (ctDNA).
• Time to Deterioration (TTD) in Pain Severity [ Time Frame: From Baseline until treatment discontinuation (up to approximately 36 months) ]
  TTD in pain severity is defined as time to first documented ≥2-point increase from Baseline in the "Worst Pain" item from the Brief Pain Inventory-Short Form (BPI-SF) Questionnaire. The BPI-SF is a self administered questionnaire developed to assess the severity of pain (the sensory dimension) as well as the degree to which pain interferes with function (the reactive dimension). The BPI-SF uses 10-point numeric rating scale, with 0="No pain", "No interference" to 10="Pain as bad as you can imagine", "Highest imaginable interference". A lower score indicates improvement.
• TTD in Pain Presence and Interference, Defined as Time to First Documented ≥10-Point Increase From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 Linearly Transformed Pain Scale Score [ Time Frame: From Baseline until treatment discontinuation (up to approximately 36 months) ]
  EORTC QLQ-C30 is a validated and reliable self-report measure that consists of 30 questions assessing five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), global health and quality of life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. The functioning and symptoms items are scored on a 4-point scale that ranges from 1=not at all to 4=very much. The Pain scale is scored on a 4-point scale (1=Not at All to 4=Very Much). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate worse pain symptoms.
• TTD in Physical Functioning (PF) [ Time Frame: From Baseline until treatment discontinuation (up to approximately 36 months) ]
  TTD in PF is defined as the time to first documented ≥10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed PF scale score. EORTC QLQ-C30 is a validated and reliable self-report measure that consists of 30 questions assessing five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), global health and quality of life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. The PF scale has 5 questions about participants' physical functioning and is scored on a 4-point scale (1=Not at All to 4=Very Much). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate a higher response level (better physical function).
• TTD in Role Functioning (RF) [ Time Frame: From Baseline until treatment discontinuation (up to approximately 36 months) ]
  TTD in RF is defined as the time to first documented ≥10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed RF scale score. EORTC QLQ-C30 is a validated and reliable self-report measure that consists of 30 questions that assessing five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), global health and quality of life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. The RF scale is scored on a 4-point scale (1=Not at All to 4=Very Much). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate better functioning/support.
• TTD in Global Health Status and Quality of Life (GHS/QoL) [ Time Frame: From Baseline until treatment discontinuation (up to approximately 36 months) ]
  TTD in GHS/QoL is defined as the time to first documented ≥10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed GHS/QoL scale score. EORTC QLQ-C30 is a validated and reliable self-report measure that consists of 30 questions that assessing five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), global health and quality of life, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous week. The GHS/QoL scale has 7 possible scores of responses (1=very poor to 7=excellent). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate a better QoL.
• Number of Participants With Adverse Events (AEs), Severity Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) [ Time Frame: From Baseline until 30 days after final dose of study drug (up to approximately 36 months) ]
  An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product; any new disease or exacerbation of an existing disease; recurrence of an intermittent medical condition; any deterioration in a laboratory value or other clinical test; AEs that are related to a protocol-mandated intervention, including those that occur prior to assignment of study treatment.
• Number of Participants With Vital Sign Abnormalities Over the Course of the Study [ Time Frame: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to approximately 36 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: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to approximately 36 months) ]
  Hematology parameters include white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).
• Number of Participants With Clinical Laboratory Test Abnormalities for Biochemistry Parameters Over the Course of the Study [ Time Frame: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to approximately 36 months) ]
  Biochemistry parameters include bicarbonate or total carbon dioxide, sodium, potassium, chloride, glucose, blood urea nitrogen (BUN) or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, alkaline phosphatase level test (ALP), Alanine transaminase (ALT), aspartate aminotransferase (AST), urate, and lactate dehydrogenase (LDH).
• Plasma Concentration of Giredestrant at Specified Timepoints [ Time Frame: Predose and postdose on Day 1 of Cycles 1 and 2, predose on Day 1 of Cycles 3, 5, 7, 9, 11, 13, and 15 (1 cycle is 28 days), and 30 days after final dose of study drug (up to approximately 36 months) ]

Original Secondary Outcome Measures (submitted: September 30, 2020)

• Overall Survival [ Time Frame: From randomization to death from any cause (up to 40 months) ]
• Objective Response Rate, as Determined by the Investigator According to RECIST v1.1 [ Time Frame: From randomization until disease progression or death (up to 40 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, as Determined by the Investigator According to RECIST v1.1 [ Time Frame: From first occurrence of documented objective response to disease progression or death from any cause, whichever occurs first (up to 40 months) ]
• Clinical Benefit Rate, as Determined by the Investigator According to RECIST v1.1 [ Time Frame: From randomization until disease progression or death (up to 40 months) ]
  The clinical benefit rate is defined as the percentage of participants with stable disease for ≥24 weeks or a complete response (CR) or partial response (PR).
• Investigator-Assessed Progression-Free Survival, in Subgroups Categorized by ESR1 Mutation Status [ Time Frame: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs first (up to 40 months) ]
• Time to Deterioration in Pain Severity, Defined as the Time to First Documented ≥2-Point Increase from Baseline in the "Worst Pain" Item from the Brief Pain Inventory-Short Form (BPI-SF) Questionnaire [ Time Frame: From Baseline until treatment discontinuation (up to 40 months) ]
• Time to Deterioration in Pain Presence and Interference, Defined as the Time to First Documented ≥10-Point Increase from Baseline in the EORTC QLQ-C30 Linearly Transformed Pain Scale Score [ Time Frame: From Baseline until treatment discontinuation (up to 40 months) ]
  EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30
• Time to Deterioration in Physical Functioning (PF), Defined as the Time to First Documented ≥10-Point Decrease from Baseline in the EORTC QLQ-C30 Linearly Transformed PF Scale Score [ Time Frame: From Baseline until treatment discontinuation (up to 40 months) ]
• Time to Deterioration in Role Functioning (RF), Defined as the Time to First Documented ≥10-Point Decrease from Baseline in the EORTC QLQ-C30 Linearly Transformed RF Scale Score [ Time Frame: From Baseline until treatment discontinuation (up to 40 months) ]
• Time to Deterioration in Global Health Status and Quality of Life (GHS/QoL), Defined as the Time to First Documented ≥10-Point Decrease from Baseline in the EORTC QLQ-C30 Linearly Transformed GHS/QoL Scale Score [ Time Frame: From Baseline until treatment discontinuation (up to 40 months) ]
• Number of Participants with Adverse Events, Severity Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) [ Time Frame: From Baseline until 30 days after final dose of study drug (up to 40 months) ]
• Number of Participants with Vital Sign Abnormalities Over the Course of the Study [ Time Frame: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to 40 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: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to 40 months) ]
• Number of Participants with Clinical Laboratory Test Abnormalities for Biochemistry Parameters Over the Course of the Study [ Time Frame: Assessed at Baseline and predose on Day 1 of every cycle (1 cycle is 28 days) until 30 days after the final dose of study drug (up to 40 months) ]
• Plasma Concentration of GDC-9545 at Specified Timepoints [ Time Frame: Predose and postdose on Day 1 of Cycles 1 and 2, predose on Day 1 of Cycles 3, 5, 7, 9, 11, 13, and 15 (1 cycle is 28 days), and 30 days after final dose of study drug (up to 40 months) ]

• 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 Compared With Physician's Choice of Endocrine Monotherapy in Participants With Previously Treated Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (acelERA Breast Cancer)
• Official Title: A Phase II, Randomized, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of GDC-9545 Compared With Physician's Choice of Endocrine Monotherapy in Patients With Previously Treated Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer
• Brief Summary: This Phase II, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant compared with physician's choice of endocrine monotherapy in participants with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who have received one or two prior lines of systemic therapy in the locally advanced or metastatic setting.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer

Intervention

• Drug: Giredestrant
  Giredestrant is taken orally once per day on Days 1-28 of each 28-day cycle.
  Other Names:

  • GDC-9545
  • RO7197597
  • RG6171
• Drug: Fulvestrant or an Aromatase Inhibitor (Physician Choice)
  Physician choice of endocrine monotherapy (fulvestrant or an aromatase inhibitor) is taken in accordance with the local prescribing information for the respective product.
• Drug: LHRH Agonist
  Only premenopausal/perimenopausal 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.

Study Arms

• Experimental: Giredestrant
  Interventions:

  • Drug: Giredestrant
  • Drug: LHRH Agonist
• Active Comparator: Physician Choice of Endocrine Monotherapy
  The physician choice of endocrine monotherapy will be limited to fulvestrant or an aromatase inhibitor.
  Interventions:

  • Drug: Fulvestrant or an Aromatase Inhibitor (Physician Choice)
  • Drug: LHRH Agonist

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 11, 2021): 303
• Original Estimated Enrollment (submitted: September 30, 2020): 300
• Estimated Study Completion Date: June 27, 2024
• Actual Primary Completion Date: February 18, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Women who are postmenopausal or premenopausal/perimenopausal
• For women who are premenopausal or perimenopausal and for men: willing to undergo and maintain treatment with approved LHRH agonist therapy for the duration of study treatment
• Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
• Documented ER-positive tumor and HER2-negative tumor, assessed locally
• Disease progression after treatment with one or two lines of systemic therapy (but not more than one prior targeted therapy) in the locally advanced or metastatic setting
• Measurable disease as defined per RECIST v.1.1 or bone only disease which must have at least one predominantly lytic bone lesion confirmed by CT or MRI which can be followed
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Adequate organ function

Exclusion Criteria:

• Prior treatment with a selective estrogen receptor degrader (SERD), with the exception of fulvestrant, if fulvestrant treatment was terminated at least 28 days prior to randomization
• Treatment with any investigational therapy within 28 days prior to randomization
• Advanced, symptomatic, visceral spread that is at risk of life-threatening complications
• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease
• Active cardiac disease or history of cardiac dysfunction
• Pregnant or breastfeeding

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Brazil, China, Germany, Israel, Korea, Republic of, Poland, Russian Federation, Singapore, South Africa, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04576455
• Other Study ID Numbers: WO42312; 2020-001984-10 ( EudraCT Number )
• Has Data Monitoring Committee: No

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

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: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: February 2024