Estrogen Receptor (ER)-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer previously treated with a CDK4/6 inhibitor and endocrine therapy MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 23.0 Level: LLT Classification code 10070575 Term: Estrogen receptor positive breast cancer System Organ Class: 10029104 - Neoplasms
Conditions
Interventions
Product Name: giredestrant
Product Code: RO7197597
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Giredestrant
Current Sponsor code: RO7197597
Other descriptive name: GDC-9545
Concentration u
Sponsors
Genentech, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: ? Age >= 18 years ? Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent ? Documented estrogen receptor-positive (ER+) tumor according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society for Medical Oncology (ESMO) guidelines, assessed locally and defined as >= 1% of tumor cells stained positive based on the most recent tumor biopsy (or archived tumor sample) ? Documented human epidermal growth factor receptor 2 (HER2)-negative tumor assessed locally ? Availability of blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) ESR1 mutation status determination by central testing prior to study treatment randomization ? 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 ? Prior endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in either setting as follows: Metastatic Setting: o 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 Adjuvant Setting: o 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 ? 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 CT or MRI which can be followed ? Eastern Cooperative Oncology Group Performance Status 0-1 ? Life expectancy of >6 months ? Adequate organ function ? International normalized ratio (INR) [or prothrombin time (PT)] /=12 months of amenorrhea without an alternate medical cause plus follicle stimulating hormone (FSH) and plasma estradiol levels within postmenopausal range by local laboratory assessment, in the absence of oral contraceptive pills, hormone replacement therapy, or gonadotropin releasing hormone agonist or antagonist o Documented bilateral oophorectomy o Premenopausal/perimenopausal willing to undergo and maintain treatment with approved luteinizing hormone-releasing hormone (LHRH)-agonist therapy ? For men: willing to undergo and maintain treatment with approved LHRH agonist therapy for the duration of study treatment, or documented bilateral orchiectomy ? For women of childbearing potential: agreement to remain abstinent or use non-hormonal contraceptive methods with a failure rate of < 1% per year during the treatment period and for 9 days after the final dose of giredestrant, 8 weeks after the final dose of everolimus, and 1 month after the final dose of exemestane. Women must refrain from donating eggs during this same perio
Exclusion criteria
Exclusion criteria: ? 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 ? No more than 2 prior lines of systemic endocrine therapy in the locally advanced or metastatic breast cancer setting ? Prior chemotherapy for locally advanced or metastatic disease ? 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 ? Treatment with any investigational therapy within 28 days prior to initiation of study treatment ? Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 28 days prior to randomization ? 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 ? Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term ? Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease ? Active cardiac disease or history of cardiac dysfunction ? Patients known to be positive for human immunodeficiency viruses (HIV) are excluded if they meet any of the following criteria: o CD4+ T-cell count of < 350 cells/µL o Detectable HIV viral load o History of an opportunistic infection within the past 12 months o On stable antiretroviral therapy for < 4 weeks ? 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 ? Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection, potentially affecting enteral absorption, or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea ? Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy ? Serious infection requiring oral or intravenous (IV) antibiotics, or other clinically significant infection, within 14 days prior to randomization ? 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 ? Known allergy or hypersensitivity to any of the study drugs or any of their excipients ? For premenopausal/perimenopausal or male patients known hypersensitivity to LHRH agonists ? Pregnant or breastfeeding, or intending to become pregnant during the study or within 9 days after the final dose of giredestrant, and 1 month after the final dose exemestane, and 8 weeks after the final dose of everolimus
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: ? To evaluate the efficacy of giredestrant plus everolimus compared with exemestane plus everolimus on the basis of investigator-assessed progression-free survival (PFS);Secondary Objective: ? To evaluate the efficacy of giredestrant plus everolimus compared with exemestane plus everolimus on the basis of investigator-assessed progression-free survival (PFS) in subgroups based on Estrogen Receptor 1 (ESR1)-mutation status, overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), time to confirmed deterioration (TTCD) in pain presence and interference, TTCD in Physical Functioning (PF), TTCD in Role Functioning (RF) and TTCD in health-related quality of life (HRQoL) ? To evaluate the safety of giredestrant plus everolimus compared with exemestane plus everolimus ? To characterize the giredestrant pharmacokinetic (PK) profile when given in combination with everolimus;Primary end point(s): 1. PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1);Timepoint(s) of evaluation of this end point: 1. Up to approximately 42 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Investigator-assessed PFS, in subgroups categorized prospectively by baseline ESR1-mutation status, as measured by ctDNA 2. OS after randomization, defined as the time from randomization to death from any cause 3. ORR, defined as the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST v1.1 4. DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 5. CBR, defined as the proportion of patients with stable disease for >= 24 weeks or a CR or PR on two consecutive occasions >= 4 weeks apart, as determined by the investigator according to RECIST v1.1 6. TTCD in pain presence and interference after randomization, defined as the time from randomization to the first documentation of >= 10-point increase in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 Questionnaire (QLQ-C30) linearly transformed pain scale score held for two consecutive time points, or a >=10-point increase followed by death attributable to cancer progression with 28 days from the last assessment 7. TTCD in PF after randomization, defined as the time from randomization to the first documentation of >= 10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed PF scale score held for two consecutive time points, or a >= 10-point decrease followed by death attributable to cancer progression with 28 days from the last assessment 8. TTCD in RF after randomization, defined as the time from randomization to the first documentation of >= 10-point decrease from baseline in the EORTC QLQ-C30 linearly transformed RF scale score held for two consecutive time points, or a >= 10-point decrease followed by death attributable to cancer progression w | — |
Countries
Spain, United States
Contacts
Public ContactTrial Information Support Line TISL
F. Hoffman-La Roche Ltd/Genentech
Outcome results
None listed