| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Estrogen Receptor-Positive, HER2-Negative Early Breast Cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer is a disease in which cells in the breast grow out of control. |
|
| 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 demonstrate superiority of the giredestrant over the control treatment in preventing breast cancer recurrence. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of giredestrant compared with Endocrine Therapy of Physician’s Choice (TPC) in terms of overall survival and other measures
• To evaluate the safety of giredestrant compared with TPC
• To characterize giredestrant pharmacokinetics (PK)
• To evaluate health status utility scores of participants treated with giredestrant compared with TPC
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Participants (females, regardless of menopausal status, and males) who are age >=18 years at the time of signing Informed Consent Form
• Participants who have multicentric (the presence of two of more tumor foci within different quadrants of the same breast) and/or multifocal (the presence of two or more tumor foci within a single quadrant of the breast) breast cancer are eligible if all examined tumors meet pathologic criteria for estrogen receptor (ER) positivity and HER2 negativity
• Participants who have documented ER+ tumor by immunohistochemistry (IHC), as assessed locally on a primary disease specimen and defined as >=1% of tumor cells stained positive according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
• Participants who have documented HER2- (negative) tumor, as assessed locally on a primary disease specimen and defined according to ASCO/CAP guidelines
• Participants must have undergone definitive surgery of the primary breast tumor(s)
• Participants who received or will be receiving adjuvant chemotherapy must have completed adjuvant chemotherapy prior to randomization. Participants may also have received neoadjuvant chemotherapy. A washout period of at least 21 days is required between last adjuvant chemotherapy dose and randomization
• Participants for whom resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) Grade 1 or better
• Participants have received (neo)adjuvant chemotherapy and/or had surgery and had no prior endocrine therapy (ET) are eligible, provided that they are enrolled within 12 months following definitive breast cancer surgery
• Participants who have confirmed availability of a tumor tissue specimen suitable for biomarker testing, with associated de-identified pathology report is required
• Participants with no pathological involved nodes (pN0) are eligible if they meet additional criteria
• Participants with N1 disease are eligible if they meet additional criteria
• Any T and N2
• Any T and N3
• T4 and any N
• Participant who have Eastern Cooperative Oncology Group Performance (ECOG) Performance Status 0, 1 or 2
• Participants who are able and willing to swallow and retain oral medication
• Participants who have adequate organ function
• For women of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception (women assigned to tamoxifen must also agree to refrain from donating eggs) during the treatment period and for 9 days after the final dose of giredestrant or within the time period specified per local prescribing guidelines after the final dose of TPC (i.e., 60 days after the final dose of tamoxifen-women must refrain from donating eggs during this same period; 21 days after the final dose of letrozole or anastrozole; 30 days after the final dose of exemestane)
• For men assigned: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm during the treatment period and for 9 days after the final dose of giredestrant within the time period specified per local prescribing guidelines after the final dose of TPC (i.e., 90 days after the final dose of tamoxifen; 21 days after the final dose of letrozole or anastrozole; 30 days after the final dose of exemestane) to avoid exposing the embryo
• Participants are willing and able to use the electronic device(s) or application for electronic patient-reported outcome (ePRO)
• For participants enrolled in the extended China enrollment phase: participants who are current residents of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
|
|
| E.4 | Principal exclusion criteria |
• Participants who are pregnant or breastfeeding, or intending to become pregnant during the study or within 9 days after the final dose of giredestrant, or within the time period specified per local prescribing guidelines after the final dose of TPC
• Participants who have received treatment with investigational therapy within 28 days prior to initiation of study treatment or is currently enrolled in any other type of medical research judged by the sponsor not to be scientifically or medically compatible with this study
• Participants receiving or planning to receive a CDK4/6i as adjuvant therapy
• Participants who have active cardiac disease or history of cardiac dysfunction
• Participants who have been diagnosed with Stage IV breast cancer or inflammatory breast cancer
• Participants who have a history of any prior (ipsilateral and/or contralateral) invasive breast cancer or ductal carcinoma in situ (DCIS) Participants with a history of contralateral DCIS treated by only local regional therapy at any time may be eligible
• Participants who have a or history of any other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, or Stage I uterine cancer
• Participants who have had any prior endocrine treatment with selective ER down-regulators or degraders or aromatase inhibitor (AI)
• Participants who have a known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C virus [HCV]), current alcohol abuse, cirrhosis, or positive test for viral hepatitis
• Participants who have a known allergy or hypersensitivity to any of the study drugs or any of their excipients
• Pre- and perimenopausal participants or male participants who have a known hypersensitivity to luteinizing hormone-releasing hormone (LHRH) agonists
• Participants who have known issues with swallowing oral medication
• Participants who have a documented history of hemorrhagic diathesis, coagulopathy, or thromboembolism
• Participants who have a malabsorption syndrome or other condition that would interfere with enteral absorption
• Participants who have uncontrolled inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery
• Participants who have had a major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during study treatment
• Participants who have had a serious infection requiring oral or intravenous (IV) antibiotics within 14 days prior to screening or other clinically significant infection (e.g., COVID-19) within 14 days prior to screening
• Participants who have had any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study
• Participants who are unable or unwilling to comply with the requirements of the protocol in the opinion of the investigator
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of one of the following IDFS events; ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, and death from any cause |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Randomization until the first occurrence of IDFS event or death, through the end of study (Up to approximately 10 years [Screening: Day -28 to -1; Treatment: At least 5 years; Follow-up: 5 years]) |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival, defined as the time from randomization to death from any cause
2. IDFS (per STEEP), including second primary non-breast cancer, defined in the same way as the primary IDFS, but including second primary non-breast invasive cancer as an event (with the exception of non-melanoma skin cancers and in situ carcinomas of any site)
3. Disease-free survival (DFS), defined as the time from randomization to first occurrence of an IDFS (per STEEP) event, including second primary non-breast cancer event or contralateral or ipsilateral DCIS
4. Distant recurrence-free interval (DRFI), defined as the time from randomization to first occurrence of a DRFI event
5. Locoregional recurrence-free interval (LRRFI), defined as the time from randomization to first occurrence of a LRRFI event
6. Mean and mean change from baseline in physical functioning, role functioning, and global health status/ quality of life (QoL) at relevant timepoints as assessed through use of the European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire - Core 30 (EORTC QLQ-C30) respective scale scores
7. Incidence and severity of adverse events, with severity determined according to NCI CTCAE 5.0
8. Change from baseline in targeted vital signs and clinical laboratory test results
9. Plasma concentrations of giredestrant at specified timepoints
10. Change from baseline in EuroQol 5-Dimension Questionnaire, 5-level version (EQ 5D-5L) index-based and visual analogue scale scores at relevant timepoint
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1-10. Up to approximately 10 years (Screening: Day -28 to -1; Treatment: At least 5 years; Follow-up: 5 years) |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| health status of participants. |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 250 |
| 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 |
| Australia |
| Belarus |
| Bosnia and Herzegovina |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Costa Rica |
| Egypt |
| Georgia |
| Guatemala |
| Hong Kong |
| India |
| Israel |
| Japan |
| Kenya |
| Korea, Republic of |
| North Macedonia |
| Malaysia |
| Mexico |
| Peru |
| Philippines |
| Russian Federation |
| Serbia |
| South Africa |
| Taiwan |
| Thailand |
| Turkey |
| Uganda |
| Ukraine |
| United States |
| Vietnam |
| Austria |
| Belgium |
| Bulgaria |
| Croatia |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Latvia |
| Netherlands |
| Poland |
| Portugal |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Czechia |
| Argentina |
| Greece |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 is defined as the date of the last scheduled procedure shown in the schedule of activities for the last participant in the study globally (i.e.: last participant in the global and extended China enrollment phases combined), or the date at which the last data point required for statistical analysis or safety follow-up is received from the last participant (global and extended China enrollment phases combined), whichever occurs later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 12 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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