E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced or Metastatic ER+/HER2- Breast Cancer with an ESR1 Mutation |
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E.1.1.1 | Medical condition in easily understood language |
Locally Advanced or Metastatic Breast Cancer with an estrogen receptor mutation |
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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 |
Evaluate the progression free survival (PFS) of 5 mg lasofoxifene relative to fulvestrant for the treatment of pre- and postmenopausal women with locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2 negative (HER2−) breast cancer with an estrogen receptor 1 (ESR1) mutation. |
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E.2.2 | Secondary objectives of the trial |
Evaluate: • Clinical benefit rate (CBR) • Objective Response Rate (ORR) • Duration of response • Time to response • Overall Survival (OS) • Pharmacokinetics of lasofoxifene • Quality of Life (QoL): vaginal assessment scale (VAS) and vulvar assessment scale (VuAS) questionnaires • Safety of lasofoxifene • Response to various ESR1 mutation subtypes (Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Pre- or postmenopausal. Postmenopausal women are defined as: a. >=60 years of age with no vaginal bleeding over the prior year, or b. <60 years with "premature menopause" or "premature ovarian failure” manifest itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards, or c. surgical menopause with bilateral oophorectomy. Note: Premenopausal women who meet all of the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy. 2. If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide histological or cytological confirmation of estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2−) disease as assessed by a local laboratory, according to ASCO/CAP guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue obtained at the time of the original diagnosis must confirm that the subject’s cancer is ER+ and HER2−. 3. Locally advanced or metastatic breast cancer with radiological or clinical evidence of progression while on an AI in combination with a CDK4/6 inhibitor for advanced breast cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or progression after at least 12 months of treatment in the metastatic setting). The AI/CDK treatment must be their last endocrine treatment prior to entry into the study. 4. Locally advanced or metastatic breast cancer with measurable (according to RECIST 1.1) and/or non-measurable lesions. 5. At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood (plasma) or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. The ctDNA sample collection must be obtained within 90 days prior to randomization to determine eligibility and baseline. Note: a prior genomic test done confirming that the subject has an ESR1 mutation can be used to determine eligibility; however, an ESR1 sample must also be collected within 30 days of randomization. 6. Subjects who have not received cytotoxic chemotherapy or who have received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial; and/or no more than one chemotherapy regimen for metastatic breast cancer. Subjects must be free of all chemotherapy acute toxicity excluding alopecia and Grade II peripheral neuropathy before study entry. 7. ECOG performance score of 0 or 1. 8. Adequate organ function as shown by: a. absolute neutrophil count (ANC) >=1,500 cells/mm3 b. platelet count >=100,000 cells/mm3 c. hemoglobin >=9.0 g/dl d. ALT and AST levels ≤2.5 upper limit of normal (ULN) or <5 in the presence of visceral metastasis e. total serum bilirubin ≤1.5 X ULN (≤3.0 X ULN for subjects known to have Gilbert Syndrome) f. alkaline phosphatase level <2.5 X ULN g. creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula h. international normalized ratio (INR) and activated partial thromboplastin (aPTT) <2.0 X ULN. 9. Able to swallow tablets. 10. Able to understand and voluntarily sign a written informed consent before any screening procedures.
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E.4 | Principal exclusion criteria |
1. Prior use of everolimus or other mammalian target of rapamycin (mTOR) inhibitor phosphoinositide 3-kinase inhibitor (PI3K) inhibitors are excluded unless discontinued due to reasons other than disease progression. 2. Presence of brain metastasis. 3. Lymphangitic carcinomatosis involving the lung. 4. Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator. 5. Radiotherapy within 30 days prior to randomization except in case of localized radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which can then be completed within 7 days prior to randomization. Subjects must have recovered from radiotherapy toxicities prior to randomization. 6. History of long QTC syndrome or a QTC of >480 msec. 7. History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6 months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance are eligible as long as the DVT and/or PE occurred >6 months prior to enrollment and there is no evidence for active thrombosis. The use of low dose acetylsalicylic acid (ASA) is permitted. 8. Any significant co-morbidity that would impact the study or the subject’s safety. 9. History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening. Subjects cured of hepatitis C (no viral load) are eligible. 10. History of malignancy within the past 5 years (excluding breast cancer), except basal cell or squamous cell carcinoma of the skin curatively treated by surgery, or early stage cervical cancer. 11. History of vaginal bleeding over the last year unless it is documented that the bleeding was due to non-uterine causes (e.g. vaginal atrophy). Premenopausal women on ovarian suppression with breakthrough bleeding can be enrolled in the study 12. Uncontrolled hypertension defined as sitting systolic pressure >160 mm Hg or diastolic pressure >100 mm Hg at Screening. 13. History of non-compliance to medical regimens. 14. Unwilling or unable to comply with the protocol. 15. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-Free Survival (PFS): • PFS is defined as the interval from the date of randomization to the earlier date of first documented radiographic progression or death due to any cause
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Radiographic assessment every 8 weeks until disease progression |
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E.5.2 | Secondary end point(s) |
The secondary objectives of the study are to evaluate: • Clinical benefit rate (CBR) • Objective Response Rate (ORR) • Duration of response • Time to response • Overall Survival (OS) • Pharmacokinetics of lasofoxifene • Quality of Life (QoL): vaginal assessment scale (VAS) and vulvar assessment scale (VuAS) questionnaires • Safety of lasofoxifene • Response to various ESR1 mutation subtypes (Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The ESR1 mutation assessments will be done at Screening visit, Visit 3 (Week 8) and Final/ET Visit. 2. Serum samples for Lasofoxifene PK will be collected at each visit until Final/ET visit. 3. ECGs will be performed at Screening, at the end of 1, 6, and 12 months of treatment, at the Final/ET visit. 4. Hematology, blood chemistry, coagulation tests will be performed at each visit until Final/ET visit. 5. Physical examinations, a brief neurological examination, and body weight measurement will be done at every visit. 6. Adverse events assessment will be recorded at each visit until Final/ET visit.
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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 | No |
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) | 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 | 4 |
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 | 5 |
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 |
Canada |
Israel |
United States |
Lithuania |
Czechia |
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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
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Death of the last subject |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |