A Study to Evaluate Efficacy and Safety of Giredestrant Compared With Fulvestrant (Plus a CDK4/6 Inhibitor), in Participants With ER-Positive, HER2-Negative Advanced Breast Cancer Resistant to Adjuvant Endocrine Therapy (pionERA Breast Cancer)

• ClinicalTrials.gov Identifier: NCT06065748
• Recruitment Status: Recruiting
• First Posted: October 4, 2023
• Last Update Posted: May 14, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 26, 2023
• First Posted Date: October 4, 2023
• Last Update Posted Date: May 14, 2024
• Actual Study Start Date: December 11, 2023
• Estimated Primary Completion Date: July 30, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 26, 2023)

• Progression-Free Survival (PFS) in the ESR1 mutation (ESR1m) Subgroup [ Time Frame: From randomization to first occurrence of progressive disease (PD) or death (up to 5 years) ]
  PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), or death from any cause during the study.
• PFS in the Full Analysis Set (FAS) Population [ Time Frame: From randomization to first occurrence of PD or death (up to 5 years) ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 26, 2023)

• PFS in the ESR1 no-mutation-detected (ESR1nmd) Subgroup [ Time Frame: From randomization to first occurrence of PD or death (up to 5 years) ]
• Overall Survival (OS) [ Time Frame: From randomization until death from any cause (up to 5 years) ]
  OS is defined as the time from randomization to death from any cause. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• Confirmed Objective Response Rate (cORR) [ Time Frame: From randomization until treatment discontinuation (up to 5 years) ]
  The cORR 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, as determined by the investigator according to RECIST v1.1. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• Duration of Response (DOR) [ Time Frame: From the first occurrence of a documented objective response to PD or death (up to 5 years) ]
  DOR is defined as the time from the first occurrence of a documented objective response to PD, as determined by the investigator according to RECIST v1.1, or death from any cause (whichever occurs first). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• Clinical Benefit Rate (CBR) [ Time Frame: From randomization until treatment discontinuation (up to 5 years) ]
  The CBR is defined as the percentage of participants with stable disease for at least (≥)24 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• Time to Chemotherapy [ Time Frame: From randomization until the start of chemotherapy or death (up to 5 years) ]
  Time to chemotherapy is defined as the time from randomization until the start date of the first chemotherapy or death from any cause (whichever occurs first). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• Time to Confirmed Deterioration (TTCD) in Pain Severity [ Time Frame: From randomization until end of follow-up (up to 5 years) ]
  TTCD 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 of the Brief Pain Inventory-Short Form (BPI-SF). It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• TTCD in Pain Presence and Interference [ Time Frame: From randomization until end of follow-up (up to 5 years) ]
  TTCD in pain presence and interference is defined as the time from randomization to the first documentation of ≥10-point increase in pain score, as determined using the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• TTCD in Physical Functioning [ Time Frame: From randomization until end of follow-up (up to 5 years) ]
  TTCD in physical functioning (PF) is defined as the time from randomization to the first documentation of ≥10-point decrease in PF score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• TTCD in Role Functioning [ Time Frame: From randomization until end of follow-up (up to 5 years) ]
  TTCD in role functioning (RF) is defined as the time from randomization to the first documentation of ≥10-point decrease in RF score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• TTCD in Global Health Status/Quality of Life [ Time Frame: From randomization until end of follow-up (up to 5 years) ]
  TTCD in in Global Health Status/Quality of Life (GHS/QoL) is defined as the time from randomization to the first documentation of ≥10-point decrease in GHS/QoL score, as determined using the EORTC QLQ-C30 questionnaire. It will be analyzed in the FAS and in the ESR1m and ESR1nmd subgroups.
• Incidence and Severity of Adverse Events [ Time Frame: From Baseline until 28 days after the final dose of study treatment (up to 5 years) ]
  Incidence will be reported as the number of participants with at least one adverse event, with severity determined according to the 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 [ Time Frame: From Baseline until 28 days after the final dose of study treatment (up to 5 years) ]
  Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and temperature.
• Number of Participants with Clinical Laboratory Test Abnormalities for Hematology and Biochemistry Parameters Over the Course of the Study [ Time Frame: From Baseline until 28 days after the final dose of study treatment (up to 5 years) ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate Efficacy and Safety of Giredestrant Compared With Fulvestrant (Plus a CDK4/6 Inhibitor), in Participants With ER-Positive, HER2-Negative Advanced Breast Cancer Resistant to Adjuvant Endocrine Therapy (pionERA Breast Cancer)
• Official Title: A Phase III Randomized, Open-Label Study Evaluating Efficacy and Safety of Giredestrant Compared With Fulvestrant, Both Combined With a CDK4/6 Inhibitor, in Patients With Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer With Resistance to Prior Adjuvant Endocrine Therapy
• Brief Summary: This is a Phase III, randomized, open-label multicenter study that will evaluate the efficacy and safety of giredestrant compared with fulvestrant, both in combination with the investigator's choice of a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib), in participants with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer who have developed resistance to adjuvant endocrine therapy.
• 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-Positive, HER2-Negative Advanced Breast Cancer

Intervention

• Drug: Giredestrant
  Giredestrant 30 milligrams (mg) orally (PO) once a day (QD) on Days 1-28 of each 28-day cycle until progressive disease (PD) or unacceptable toxicity.
  Other Names:

  • RO7197597
  • RG6171
  • GDC-9545
• Drug: Fulvestrant
  Fulvestrant 500 mg intramuscularly (IM) on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle until PD or unacceptable toxicity.
• Drug: Abemaciclib
  If chosen by the investigator as the CDK4/6i, participants will receive abemaciclib 150 mg PO twice per day (BID) on Days 1-28 of each 28-day cycle until PD or unacceptable toxicity.
• Drug: Palbociclib
  If chosen by the investigator as the CDK4/6i, participants will receive palbociclib 125 mg PO QD on Days 1-21 of each 28-day cycle until PD or unacceptable toxicity.
• Drug: Ribociclib
  If chosen by the investigator as the CDK4/6i, participants will receive ribociclib 600 mg PO QD on Days 1-21 of each 28-day cycle until PD or unacceptable toxicity.
• Drug: LHRH Agonist
  Only pre/perimenopausal female participants and male participants will receive a luteinizing hormone-releasing hormone (LHRH) agonist locally approved for use in breast cancer on Day 1 of each 28-day treatment cycle.
• Diagnostic Test: FoundationOne Liquid CDx Assay (F1LCDx)
  F1LCDx is a next-generation sequencing (NGS)-based in vitro diagnostic test that detects and analyses genomic alterations in circulating cell-free DNA (cfDNA) isolated from plasma derived from the anti-coagulated peripheral whole blood of cancer patients. It will be used to determine the eligibility of participants requiring confirmation of ESR1 mutation status (mutation detected [ESR1m] vs. no mutation detected [ESR1nmd]).
  Other Name: F1LCDx

Study Arms

• Experimental: Giredestrant + Investigator's Choice of CDK4/6i
  Participants in the experimental arm will receive giredestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
  Interventions:

  • Drug: Giredestrant
  • Drug: Abemaciclib
  • Drug: Palbociclib
  • Drug: Ribociclib
  • Drug: LHRH Agonist
  • Diagnostic Test: FoundationOne Liquid CDx Assay (F1LCDx)
• Active Comparator: Fulvestrant + Investigator's Choice of CDK4/6i
  Participants in the control arm will receive fulvestrant plus the investigator's choice of CDK4/6 inhibitor (CDK4/6i): palbociclib, ribociclib, or abemaciclib.
  Interventions:

  • Drug: Fulvestrant
  • Drug: Abemaciclib
  • Drug: Palbociclib
  • Drug: Ribociclib
  • Drug: LHRH Agonist
  • Diagnostic Test: FoundationOne Liquid CDx Assay (F1LCDx)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 26, 2023): 1050
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2028
• Estimated Primary Completion Date: July 30, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
• Documented estrogen receptor-positive (ER+), HER2-negative (HER2-) tumor assessed locally on the most recent tumor biopsy (or archived tumor sample)
• Confirmed ESR1 mutation status (ESR1m vs. ESR1nmd) in baseline circulating tumor DNA (ctDNA) through central laboratory testing
• Resistance to prior adjuvant endocrine therapy (ET). Prior use of neo/adjuvant CDK4/6i is allowed.
• No prior systemic anti-cancer therapy for advanced disease
• Measurable disease as defined per RECIST v.1.1 or non-measurable bone-only disease
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1
• For pre/perimenopausal women and for men: treatment with LHRH agonist therapy (as per local guidelines) for the duration of study treatment is required

Exclusion Criteria:

• Prior systemic therapy (e.g., prior chemotherapy, immunotherapy, or biologic therapy) for locally advanced unresectable or metastatic breast cancer
• Prior treatment with another SERD (e.g., fulvestrant, oral SERDs) or novel ER-targeting agents
• Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
• Active cardiac disease or history of cardiac dysfunction
• Clinically significant history of liver disease

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: CO44657 https://forpatients.roche.com/; 888-662-6728 (U.S. Only); global-roche-genentech-trials@gene.com

• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Colombia, Costa Rica, France, Germany, Guatemala, Hong Kong, Hungary, India, Israel, Italy, Korea, Republic of, New Zealand, Poland, Portugal, Spain, Taiwan, Thailand, United States

Administrative Information

• NCT Number: NCT06065748
• Other Study ID Numbers: CO44657; 2022-502980-39-00 ( Registry Identifier: EU CT 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: Yes

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 the Sharing of Clinical 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: May 2024