2025-524846-85-00招募中3 期
A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase III Study to Evaluate the Efficacy and Safety of Letrozole SIE Compared to Femara® (both in Combination with the CDK4/6 Inhibitor Ribociclib) in Postmenopausal Women with HR-Positive, HER2-Negative, Inoperable Locally Advanced or Metastatic Breast Cancer (SIE-3)
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 97
- 试验地点
- 30
- 主要终点
- PFS per Investigator assessment, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST v1.1. PFS as assessed through a blinded independent central review will be used for supportive evidence of the primary efficacy endpoint.
研究概览
简要总结
To evaluate the superiority of Letrozole SIE compared with Femara® (both in combination with the CDK4/6 inhibitor ribociclib), as measured by PFS.
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female participants must be ≥ 18 of age at the time of signing the informed consent.
- •Adequate organ and marrow function defined as follows: a. ANC ≥ 1,500/mm3 (1.5 × 10^9/L). b. Platelets ≥ 100,000/mm3 (100 × 10^9/L). c. Hemoglobin ≥ 10 g/dL (1000 g/L). d. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m², as determined by the 2021 CKD-EPI creatinine equation e. Total serum bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN with direct bilirubin within normal range if well documented Gilbert’s disease). f. AST and ALT ≤ 3 × ULN (≤ 5.0 × ULN if liver metastases present). g. Potassium, calcium (corrected for serum albumin), magnesium, and phosphorus within normal limits of the local laboratory. h. INR≤1.
- •Resolution of all acute toxic effects of prior anticancer therapy or surgical procedures to NCI CTCAE version 6.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the participant at the Investigator's discretion).
- •Participant has BMI ≥ 19 and ≤ 39 kg/m²
- •Participant is able to understand, willing to provide, and capable of giving signed informed consent as described in Protocol Appendix 1, Section 10.1.3 which includes compliance with the requirements and restrictions listed in the ICF and in the protocol, and able to comply with the study procedures and restrictions.
- •Female participants with histologically and/or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated
- •Postmenopausal woman, defined as a woman fulfilling any one of the following criteria: a.Prior bilateral oophorectomy; oophorectomized participants should have absence of menses for at least 6 weeks and a medical report from hospital or participant’s family doctor documenting history of bilateral oophorectomy (with or without hysterectomy) and confirmed absence of malignant disease; if unable to obtain the previously mentioned report, a lower abdomen-pelvic ultrasound should be done to confirm bilateral oophorectomy and rule out any image compatible with a malignant pathology. b.Age ≥ 60 years; postmenopausal participants ≥ 60 years should have absence of menses for 12 or more months. c.Age < 60 years and amenorrheic for 12 or more months in the absence of prior chemotherapy, tamoxifen, toremifene, or ovarian suppression. d.Age < 60 years: chemotherapy-induced amenorrhea for ≥ 12 months with FSH and E2 in postmenopausal range on serial assessments. e.Age < 60 years: on tamoxifen with FSH and E2 level in postmenopausal range.
- •Baseline serum FSH and plasma 17β-E2 compatible with postmenopausal status according to reference values of the local laboratory assay, confirmed at Screening.
- •Histologically and/or cytologically confirmed diagnosis of ER-positive and/or PR-positive, HER2-negative breast cancer by local laboratory.
- •Participants eligible to receive letrozole and the CDK4/6 inhibitor ribociclib for the treatment of HR-positive/HER2-negative advanced breast cancer who have been either diagnosed de novo in the advanced setting or who have relapsed with the advanced disease after receiving adjuvant endocrine therapy for earlier stage disease (either tamoxifen and/or AIs).
- •Previously untreated with any systemic anticancer therapy for their locoregionally recurrent or metastatic HR-positive disease. Participants may have received cytotoxic chemotherapy within (neo) adjuvant previous treatment of breast cancer but must show PD prior to enrolment.
- •The participant must have one of the following as defined by RECIST v1.1 a. Measurable disease: Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if PD at the treated site after completion of therapy is clearly documented. b. Non-measurable bone-only disease: Participants must have at least one evaluable bone lesion (lytic or mixed lytic/blastic). Blastic lesions only are not evaluable and are not allowed. Participants with no measurable disease and only one evaluable bone lesion that has been previously irradiated are eligible if there is documented evidence of PD of the bone lesion after irradiation.
- •ECOG performance status 0-2.
排除标准
- •Participants with advanced, symptomatic, visceral spread who are at risk of life-threatening complications in the short term (including participants with massive uncontrolled effusions [pleural, pericardial, peritoneal] and pulmonary lymphangitis)
- •History of ILD/pneumonitis
- •Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation/behavior, or laboratory or ECG abnormalities that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- •Presence of detectable viral infection, including HBV, HCV, and HIV. Screening is not required for enrollment.
- •History of substance or alcohol use disorder.
- •Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anticancer therapy within 14 days (2 weeks) before randomization. Participants who received prior radiotherapy to > 25% of bone marrow are not eligible independent of when it was received
- •Bisphosphonates or RANKL inhibitors initiated or have their dose changed within 14 days prior to randomization, i.e., participants should be on stable dose treatment for at least 14 days prior to randomization.
- •Hormonal medications or medications or products known to affect serum LH, FSH (except spironolactone which is allowed if medically indicated), or estrogen/E2 levels within 3 months prior to randomization. This includes, but is not limited to, estrogen or progesterone hormone replacement therapy, oral contraceptives, androgens, LHRH analogs, prolactin inhibitors, or antiandrogens and other medications, herbal remedies, and/or supplements for the treatment of vasomotor hot flush symptoms administered via any route, including topical or intravaginal administration.
- •Use of the following medications within the 3 previous days or a period of 5 half-lives, (whichever is longer) prior to randomization: a. Any medications or products including St. John’s wort, known to be strong inducers of CYP3A. b. Any medications or products known to be strong inhibitors of CYP3A (e.g., grapefruit or grapefruit juice). c. Any medications known to be inducers of CYP2A
- •d. Any medications known to be inhibitors of CYP2A6
- •Any medications or products with a known risk to prolong the QT interval or induce Torsades de Pointes.
- •Concurrently use of other anticancer therapy.
- •Known uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, spinal cord compression, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Participants with a history of CNS metastases are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and systemic steroids for at least 28 days (4 weeks) before randomization.
- •Participation in another investigational drug study within 30 days prior to randomization or 5 half-lives (whichever is longer) prior to randomization.
- •Current participation in another clinical study.
- •Participant has a known hypersensitivity to letrozole, or ribociclib, or any of their excipients, or peanut, or soya.
- •History of, or difficulty of, access to veins for venipuncture.
- •Participants with inflammatory breast cancer.
- •Concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.
- •Active cardiac disease or documented history of cardiac dysfunction including any of the following: a. Angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to randomization. b. Long QT syndrome. c. Congestive heart failure (New York Heart Association functional classification III-IV). d. Cardiomyopathy. e. Severe aortic stenosis. f. Any cardiac arrhythmias e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months.
- •At Screening, any of the following cardiac parameters: a. Bradycardia (heart rate < 50 bpm at rest). b. Tachycardia (heart rate > 90 bpm at rest). c. PR interval > 220 msec. d. QRS interval > 109 msec. e. QTcF ≥ 450 msec
- •Uncontrolled hypertension, defined as diastolic blood pressure ≥ 100 mmHg and/or systolic blood pressure ≥ 160 mmHg.
- •History of symptomatic vertebral fragility fracture or any fragility fracture of the hip, pelvis, wrist, or other location (defined as any fracture without a history of trauma or because of a fall from standing height or less, excluding fingers, toes, face and skull).
- •Presence of any of the following medical conditions associated with low bone mass, including: a. Metabolic bone disease (such as osteogenesis imperfecta, Paget’s disease of the bone, osteomalacia/rickets). b. Collagen vascular diseases (such as Marfan’s syndrome and Ehrler’s-Danlos syndrome). c. Vitamin D levels less than 10 ng/mL. d. Gastrointestinal (malabsorptive) disease including inflammatory bowel disease and gastric bypass surgery. e. Use of any of the following medications associated with decreased bone mass including: depo medroxyprogesterone acetate, raloxifene, anticonvulsants (phenytoin, phenobarbital, carbamazepine) within 14 days prior to randomization.
研究组 & 干预措施
Placebo for Femara
Placebo
干预措施: Placebo for Femara (Drug)
FEMARA 2,5 mg, comprimé pelliculé
Comparator
干预措施: FEMARA 2,5 mg, comprimé pelliculé (Drug)
Kisqali 200 mg film-coated tablets
Auxiliary
干预措施: Kisqali 200 mg film-coated tablets (Drug)
Placebo for Letrozole SIE
Placebo
干预措施: Placebo for Letrozole SIE (Drug)
LETROZOLE SIE suspension for intramuscular injection
Test
干预措施: LETROZOLE SIE suspension for intramuscular injection (Drug)
结局指标
主要结局
PFS per Investigator assessment, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST v1.1. PFS as assessed through a blinded independent central review will be used for supportive evidence of the primary efficacy endpoint.
PFS per Investigator assessment, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed via a local radiology assessment according to RECIST v1.1. PFS as assessed through a blinded independent central review will be used for supportive evidence of the primary efficacy endpoint.
次要结局
- OS, defined as the time from the date of randomization to date of death from any cause.
- ORR defined as the proportion of participants with a BOR of CR or PR by Investigator assessment per RECIST v1.1 criteria.
- The incidence rate of a combined event of arthralgia/arthritis and/or myalgia.
- • TTR, defined for those participants with response (CR or PR) by Investigator assessment per RECIST v1.1 criteria as the interval between randomization and the earliest documentation of response. • DOR, defined for those participants with response (CR or PR) as the time from first documented evidence of CR or PR until disease progression by Investigator assessment per RECIST v1.1 criteria, or death from any cause, whichever occurs first.
- • CBR, defined as the proportion of participants with CR, PR, or SD ≥ 6 months according to Investigator assessment per RECIST v1.1 criteria. • TTF, defined as the time from randomization to study intervention discontinuation for any reason.
- • FACT-B. • FACT-ES. • FACT-G. • FACT-G subscales. • FACT-ES Endocrine symptoms subscale. • FACT-B Breast cancer subscale. • Time to deterioration in quality of life, as measured by these scales
- • Percentage of participants with ESR1 mutations at the time of disease progression among those without ESR1 mutations at baseline. • ESR1 mutant allele frequency at the time of disease progression.
- • Incidence of AEs (type, severity, seriousness, and relationship to study intervention) including the incidence of TEAEs, the incidence of serious TEAEs, and the incidence of TEAEs leading to study intervention discontinuation. • Incidence of injection site reactions. • Changes in injection-related pain score assessed by NRS. • Changes in BMD assessed by DXA.
研究者
Rovi Medical Department
Scientific
Laboratorios Farmaceuticos Rovi S.A.
研究点 (30)
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