| 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 previously treated with a CDK4/6 inhibitor and endocrine therapy |
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| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer is a cancer that develops in the tissues of the breast. ER-positive, HER2-negative breast cancer is breast cancer which tests positive for ER and negative for HER2. |
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| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic 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 | 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072740 |
| E.1.2 | Term | Locally advanced 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 giredestrant plus everolimus compared with exemestane plus everolimus in the estrogen receptor 1 mutant subpopulation (ESR1m subpopulation) and in the intent-to-treat (ITT) population on the basis of investigator-assessed progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
● To evaluate the efficacy of giredestrant plus everolimus compared with exemestane plus everolimus in the ESR1m subpopulation and the ITT population on the basis of overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), time to confirmed deterioration (TTCD) in pain severity, 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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
● Age >= 18 years
● Locally advanced unresectable 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
● 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 10 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 period
● For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 10 days after the final dose of giredestrant, 4 weeks after the final dose of everolimus, and 1 month after the final dose of exemestane. Men must refrain from donating sperm during this same period
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|
| E.4 | Principal exclusion criteria |
● Prior treatment with another oral selective estrogen receptor degrader (SERD), proteolysis targeting chimera (PROTAC), complete estrogen receptor antagonist (CERAN), or novel oral selective estrogen receptor modulator (SERM) in any setting. Prior fulvestrant is allowed if treatment was terminated at least 28 days prior to randomization
● Progression on no more than 2 prior lines of systemic endocrine therapy in the locally advanced unresectable or metastatic breast cancer setting
● Prior chemotherapy for locally advanced unresectable 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 14 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, Stage I endometrial cancer or other non-breast cancers at very low risk of recurrence
● 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 10 days after the final dose of giredestrant, and 1 month after the final dose exemestane, and 8 weeks after the final dose of everolimus
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. PFS in the ESR1m subpopulation determined by the investigator
2. PFS in the ITT population, determined by the investigator, PFS is 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)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1-2. Up to approximately 42 months |
|
| E.5.2 | Secondary end point(s) |
1. OS after randomization, defined as the time from randomization to death from any cause
2. 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
3. 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
4. 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
5. TTCD in pain severity, defined as the time from randomization to the first documentation of a ≥2-point increase from baseline on the "worst pain" item score from the Brief Pain Inventory-Short Form (BPI-SF) held for two consecutive time points, or a ≥2-point increase followed by death attributable to cancer progression with 28 days from the last assessment.
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 with 28 days from the last assessment
9. TTCD in HRQoL 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 GHS/QoL 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
10. Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0
11. Change from baseline in targeted vital signs
12. Change from baseline in targeted clinical laboratory test results
13. Plasma concentration of giredestrant at specified timepoints
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-10. Up to approximately 42 months
11-12. Baseline up to 42 months
13. Day 1 and Day 15 of Cycle 1, Day 1 of Cycle 2 and 3
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|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Japan |
| Singapore |
| South Africa |
| United States |
| Turkey |
| Germany |
| Greece |
| Italy |
| Spain |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
|
| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 42 |
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