| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Estrogen receptor (ER)-positive, HER2 negative locally advanced or metastatic breast cancer who have received one or two prior lines of systemic therapy in the locally advanced (recurrent or progressed) or metastatic setting | |
| E.1.1.1 | Medical condition in easily understood language | | Breast cancer is cancer that develops from breast tissue, Hormone receptor (HR)-positive, HER2-negative breast cancer which tests positive for ER and negative for HER2 | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10070575 | | E.1.2 | Term | Estrogen receptor positive breast cancer | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10070577 | | E.1.2 | Term | Oestrogen receptor positive breast cancer | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10083232 | | E.1.2 | Term | HER2 negative breast cancer | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | -To evaluate the efficacy of GDC-9545 compared with physician's choice of endocrine monotherapy on the basis of progression free survival | |
| E.2.2 | Secondary objectives of the trial | -To evaluate the efficacy of GDC-9545 compared with physician's choice of endocrine monotherapy on the basis of overall survival, objective response rate, duration of response, clinical benefit rate, investigator-assessed progression free survival, time to deterioration in pain severity, pain presence and interference, physical functioning, role functioning and global health status and quality of life after randomization
-To evaluate the safety of GDC-9545 compared with physician's choice of endocrine monotherapy
-To characterize the GDC-9545 pharmacokinetics profile
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | •Age >= 18 years of age
•For women: postmenopausal or premenopausal/perimenopausal status
oAge >= 60 years
oAge < 60 years and >= 12 months of amenorrhea plus follicle-stimulating hormone 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
oDocumented bilateral oophorectomy
oPremenopausal/perimenopausal or men, be willing to undergo and maintain treatment with approved LHRH-agonist therapy
•Histologically or cytologically confirmed diagnosis of locally advanced (recurrent or progressed) or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
•Disease progression after treatment with one or two lines of systemic therapy in the locally advanced or metastatic setting
•Documented ER-positive tumor according to American Society of Clinical Oncology/College of American Pathologists guidelines
•Documented HER2-negative tumor assessed locally
•Availability of the most recently collected and representative tumor tissue specimen, with associated de identified pathology report, and whenever possible, from a metastatic site of disease
•Measurable disease as defined per Response Evaluation Criteria in Solid Tumors, Version 1
•Eastern Cooperative Oncology Group Performance Status 0-1
•Life expectancy of > 6 months
•Adequate organ function
•INR < 1.5 × upper limit of normal (ULN) and PTT (or aPTT) < 1.5 × ULN
•Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE v5.0 Grade <= 1
•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, for 8 days after the final dose of GDC-9545
•For men: agreement to remain abstinent or use a condom, and must refrain from donating sperm for 8 days after the final dose of GDC-9545 to avoid exposing the embryo
•For the assigned to the control arm, women or men must comply with local prescribing guidelines regarding contraception for the chosen endocrine monotherapy Willing and able to use an electronic device for PRO data collection
•For patients enrolled in an extended China enrollment phase: current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry | |
| E.4 | Principal exclusion criteria | •Prior treatment with a 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
•Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days prior to randomization
•History of malignancy other than breast cancer within 5 years prior to screening
•Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
•Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease
•Active cardiac disease or history of cardiac dysfunction
•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
•Known HIV infection
•Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery, including gastric resection, potentially affecting enteral absorption
•Serious infection requiring oral or IV antibiotics 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 patients or male patients: known hypersensitivity to LHRH agonists
•Pregnant or breastfeeding, or intending to become pregnant during the study or within 8 days after the final dose of GDC-9545, or within the time period specified per local prescribing guidelines after the final dose of physician's choice of endocrine monotherapy | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | 1. Progression free Survival as determined by the investigator | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | 1. Approximately 40 months | |
| E.5.2 | Secondary end point(s) | 1. Overall survival
2. Objective response rate as determined by the investigator
3. Duration of response as determined by the investigator
4. Clinical benefit rate as determined by the investigator
5. Investigator-assessed progression free survival n subgroups categorized by baseline ESR1 mutation status
6. Time to deterioration in pain severity
7. Time to deterioration in pain presence and interference
8. Time to deterioration in physical functioning
9. Time to deterioration in role functioning
10. Time to deterioration in global health status and quality of life
11. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0
12. Change from baseline in targeted vital signs
13. Change from baseline in targeted clinical laboratory test results
14. Plasma concentration of GDC-9545 at specified timepoints
| |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | 1-11. Approximately 40 months
12-13. From Baseline (Day -28 to Day -1) to 40 months
14. Day 1 of Cycle 1-3 and Day 1 of every two cycles thereafter through Cycle 15 and at treatment discontinuation visit
| |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Argentina | | Australia | | Brazil | | China | | Germany | | Israel | | Korea, Republic of | | Poland | | Russian Federation | | Serbia | | South Africa | | Thailand | | Turkey | | Ukraine | | United Kingdom | | United States | |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | | The end of this study (global phase and potential China extension phase combined) is defined as the date when the last patient, last visit occurs or the date at which the last data point required for statistical analysis or overall survival follow-up is received from the last patient, whichever occurs later. The end of the study is expected to occur at least 25 months after the last patient is enrolled in the global study. In addition, the Sponsor may decide to terminate the study at any time. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 40 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 40 |
