| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 that elacestrant compared with the SOC options of either fulvestrant or an AI is superior in prolonging PFS based on a blinded Imaging Review Committee (IRC) assessment in post-menopausal women and men with ER+/HER2-mBC, either in subjects with ESR1 mutations (ESR1-mut subjects) or in all subjects which includes subjects without detectable ESR1 mutations (ESR1-mut-nd)
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| E.2.2 | Secondary objectives of the trial |
● To compare overall survival (OS) between treatment groups in ESR1-mut subjects
● To compare OS between treatment groups in all subjects (ESR1-mut and ESR1-mut-nd)
● To compare PFS based on blinded IRC assessment between treatment groups
● To compare OS between treatment groups
● To compare PFS based on local Investigator assessment between treatment groups
● To compare ORRs, DoR and CBR based on blinded IRC assessment between treatment groups
● To compare ORR, DoR and CBR based on local Investigator assessment between treatment groups
● To compare the safety and tolerability between treatment groups
● To assess the PK of elacestrant
● To describe the changes in Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL) and the changes in PROs/HRQOL between treatment groups
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
● Must have histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of either locally advanced disease not amenable to resection or radiation therapy with curative intent or metastatic disease not amenable to curative therapy
● Must be appropriate candidates for endocrine monotherapy
● Must have 1 of the following as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1:
a. Measurable disease
b. Bone-only disease with evaluable lesions. Subjects must have at least 1 lytic or mixed lytic-/blastic bone lesion; blastic- lesions only are not evaluable and allowed. Subjects who have had prior radiation to bone must have at least 1 evaluable lesion in a nonirradiated area
● Female or male age ≥ 18 years of age
● Female subjects must be post-menopausal, defined by 1 of the following criteria:
a. Documented bilateral surgical oophorectomy
b. Age ≥ 60 years with amenorrhea ≥ 1 year since last menses
c. Age < 60 years with amenorrhea ≥ 1 year since last menses with no alternative pathological or physiological cause (including ongoing or recent chemotherapy, treatment with tamoxifen or toremifene, or a GnRH agonist), and serum estradiol and follicle stimulating hormone (FSH) levels within the laboratory reference range for post-menopausal women
d. Age < 60 years with tamoxifen or toremifene therapy within the last 12 months, with documentation of 12 months of amenorrhea prior to tamoxifen or toremifene therapy and serum estradiol and FSH levels within the laboratory reference range for post-menopausal women
e. Females with hormonally-induced menopause (ie, requiring ongoing hormone suppression) are not eligible
● Male subjects must, even if surgically sterilized (ie, status post-vasectomy):
a. Agree to practice highly effective barrier contraception (use condoms) during the entire study treatment period and through 120 days after the last dose of study drug. For subjects (who have not undergone vasectomy) with female partners of childbearing potential, the subject and his partner must, in addition to condoms, use highly effective contraceptive measures when engaging in sexual intercourse throughout the treatment period and for at least 120 days after the last dose of study drug (ie, oral contraceptive and condoms; intrauterine device and condoms; diaphragm with spermicide and condoms; other forms of contraception must be approved by the medical monitor) OR Agree to practice true abstinence during the entire study treatment period and through 120 days after the last dose of study drug
Note: Abstinence should only be used as a contraceptive method if it is in line with the subject's usual and preferred lifestyle. Periodic abstinence (calendar symptothermal, post-ovulation methods) is not an acceptable method of contraception.
b. Agree not to donate sperm during the course of treatment period or within 120 days after receiving the last dose of the study drug
● Must have ER+ and HER2- tumor status confirmed per local laboratory testing. Status may be confirmed on original diagnosis tissue samples or post-treatment samples (most recent biopsy preferred, if testing available).
● Must have previously received at least 1 and no more than 2 lines of endocrine therapy, either as monotherapy or as a combination therapy with another agent (eg, phosphoinositide 3-kinase [PI3K] inhibitor), for mBC
● Must have progressed during or within 28 days of completion of prior treatment with a CDK4/6 inhibitor in combination with either fulvestrant or an AI (this counts as a line of prior endocrine therapy) for mBC
● Must have received no more than 1 line of cytotoxic chemotherapy in the advanced/metastatic setting
a. Cytotoxic chemotherapy does not include: CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, or immunotherapy. There are no restrictions on prior use of these agents
b. There is no requirement for documentation of progressive disease to prior chemotherapy
c. Chemotherapy given in combination with endocrine therapy counts as both a line of endocrine therapy and a line of chemotherapy
d. Chemotherapy administered for less than 1 cycle will not be counted as a prior line of chemotherapy
e. For subjects who progress within 12 months of neoadjuvant or adjuvant chemotherapy, this will count as 1 prior line of therapy for advanced/metastatic
disease
● Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
● Resolution of all toxic effects of prior therapies or surgical procedures to Grade ≤ 1 (except alopecia and peripheral neuropathy)
● Adequate organ function as defined below:
a. Hematologic function
b. Renal function
c. Hepatic function
d. Chemistry
e. Coagulation
● Ability to understand the protocol and provide informed consent |
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| E.4 | Principal exclusion criteria |
● Prior treatment with elacestrant or investigational SERD or ER antagonist (eg, D-0502, GDC-0810, GDC-0927, GDC-9545, GIT-48, LSZ102, AZD9496, SAR439859, ZN-c5, H3B-6545, bazedoxifene, lasofoxifene)
● Prior anti-cancer or investigational drug treatment
● Radiation therapy within 14 days (28 days for brain lesions per Exclusion Criterion 4) before the first dose of study drug
● Presence of symptomatic metastatic visceral disease, including but not limited to, extensive hepatic involvement, untreated or progressive central nervous system (CNS) metastases, or symptomatic pulmonary lymphangitic spread. Subjects with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not significantly compromised as a result of disease in the opinion of the Investigator. Subjects with previously treated CNS metastases are eligible provided that that all known lesions were previously treated, they have completed radiotherapy at least 28 days prior to first dose of study drug, and are clinically stable. If anticonvulsant medication is required, subjects must be stable on a non-enzyme inducing anticonvulsant regimen
● Intact uterus with a history of endometrial intraepithelial neoplasia (atypical endometrial hyperplasia or higher-grade lesion)
● Diagnosis of any other malignancy within 5 years before enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix or second primary breast cancer
● Any of the following within 6 months before enrollment: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE v5.0 Grade ≥2, prolonged QTcF ≥ Grade 2 (i.e. ≥480 msec), uncontrolled atrial fibrillation of any grade, coronary/peripheral artery bypass graft, heart failure > Class II as defined by the New York Heart Association guidelines (Appendix 6), or cerebrovascular accident including transient ischemic attack
● Child-Pugh Score greater than Class A (ie, score >6)
● Coagulopathy or any history of coagulopathy within the past 6 months, including history of deep vein thrombosis or pulmonary embolism. However, subjects with the following conditions will be allowed to participate:
a.Adequately treated catheter-related venous thrombosis occurring >28 days prior to the first dose of study drug
b.Treatment with an anticoagulant, eg, warfarin or heparin, for a thrombotic event occurring >6 months before enrollment, or for an otherwise stable and allowed medical condition (eg, well controlled atrial fibrillation), provided dose and coagulation parameters (as defined by local standard of care) are stable for at least 28 days prior to the first dose of study drug, and provided that an AI would be an appropriate therapy for the subject
● Known bleeding disorder which, in the opinion of the Investigator, would prohibit administration of fulvestrant if that would be SOC choice for the subject
● Known difficulty in tolerating oral medications or conditions which would impair absorption of oral medications such as: uncontrolled nausea or vomiting (ie, CTCAE ≥ Grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motility disorder, malabsorption syndrome, or prior gastric bypass
● Unable or unwilling to avoid prescription medications, over the counter medications, dietary/herbal supplements (eg, St. John's wort), and/or foods (eg, grapefruit, pomelos, star fruit, Seville oranges, and their juices) that are moderate/strong inhibitors or inducers of CYP3A4 activity. Participation will be allowed if the medication, supplements and/or foods are discontinued for at least five half-lives or 14 days (whichever is longer) prior to study entry and for the duration of the study
● Major surgery <28 days before the first dose of study drug
● Any concurrent severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study
● Known hypersensitivity reaction to drugs chemically related to elacestrant or their excipients
● Known hypersensitivity to fulvestrant, anastrozole, letrozole, or exemestane (or to any of their excipients), unless treatment with 1 of the other 3 of these 4 treatment options would be appropriate therapy
● Subjects who meet any contraindication, according to the respective PI or SmPC, for any SOC drug that the Investigator would choose for that subject should the subject be randomized to the SOC group |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
● IRC-assessed PFS in ESR1-mut subjects
● IRC-assessed PFS in all subjects (ESR1-mut and ESR1-mut-nd)
IRC-assessed PFS is defined as the length of time from randomization until the date of objective disease progression per RECIST v1.1 as assessed by the blinded IRC or death from any cause.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The date of objective disease progression per RECIST v1.1 or the date of subject's death. |
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| E.5.2 | Secondary end point(s) |
● OS in ESR1-mut subjects
● OS in all subjects (ESR1-mut and ESR1-mut-nd)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The date of subject's death. |
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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 | Yes |
| 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 | Yes |
| 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 | Yes |
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 101 |
| 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 |
| Canada |
| Israel |
| Korea, Republic of |
| United States |
| Austria |
| France |
| Spain |
| Greece |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| Ireland |
| Portugal |
| United Kingdom |
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| 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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| The study will be complete when approximately 50% of subjects have died. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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