A Study to Evaluate the Efficacy and Safety of Giredestrant Plus Everolimus Compared with Exemestane Plus Everolimus in Patients with Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer

Phase 1

• Conditions: Estrogen Receptor (ER)-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer previously treated with a CDK4/6 inhibitor and endocrine therapy; MedDRA version: 20.0Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 23.0Level: LLTClassification code 10070575Term: Estrogen receptor positive breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: LLTClassification code 10072740Term: Locally advanced breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 23.0Level: PTClassification code 10083232Term: HER2 negative breast cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2022-000199-20-ES
• Lead Sponsor: Genentech, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2022-06-09
• Last Update Posted: 8 August 2022

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 224

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)] < 1.5 x upper limit of normal (ULN) and partial thromboplastin time (PTT) [or activated partial thromboplastin time (aPTT)] < 1.5 x ULN
? Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE v5.0 Grade <= 1
? For women: postmenopausal or premenopausal/perimenopausal status
Postmenopausal, as defined by at least one of the following criteria:
o >/=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

? 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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified