Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer
Conditions
Keywords
oral Selective Estrogen Receptor Degrader (SERD), CDK4/6 inhibitor (CDK4/6i), ESR1 mutation
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.
Interventions
DRUGGiredestrant
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.
DRUGFulvestrant
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.
DRUGAbemaciclib
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.
DRUGPalbociclib
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.
DRUGRibociclib
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.
DRUGLHRH 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_TESTFoundationOne 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 \[ESR1nmd\]).
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 an archived tumor sample if a recent tumor sample is not available for testing) * Confirmed ESR1 mutation status (ESR1m versus ESR1nmd) in baseline circulating tumor DNA (ctDNA) through central laboratory testing * Resistance to prior adjuvant endocrine therapy (ET), which is defined as having relapsed with prior standard adjuvant ET, on-treatment after \>/=12 months or off-treatment within 12 months of completion. Prior use of adjuvant CDK4/6i is allowed (if relapse occurred \>/=12 months since completion). * No prior systemic anti-cancer therapy for advanced disease * Measurable disease as defined per RECIST v.1.1 or non-measurable (including bone-only) disease * Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 * For pre/perimenopausal women and for men: willing to undergo and maintain treatment with approved LHRH agonist therapy (as per local guidelines) for the duration of study treatment
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) in the ESR1 mutation (ESR1m) Subgroup | 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 | From randomization to first occurrence of PD or death (up to 5 years) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS in the ESR1 no-mutation-detected (ESR1nmd) Subgroup | From randomization to first occurrence of PD or death (up to 5 years) | — |
| Overall Survival (OS) | 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) | 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) | 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) | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | From Baseline until 28 days after the final dose of study treatment (up to 5 years) | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Costa Rica, Finland, France, Germany, Greece, Guatemala, Hong Kong, Hungary, India, Israel, Italy, Kenya, Mexico, New Zealand, Peru, Poland, Portugal, Puerto Rico, Romania, Singapore, Slovenia, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed