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 Palbociclib) in Postmenopausal Women With HR-Positive, HER2-Negative, Inoperable Locally Advanced or Metastatic Breast Cancer (SIE-3)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 300
- 主要终点
- Progression Free Survival (PFS)
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of Letrozole SIE (injectable) compared to Femara® (oral tablet), both given together with palbociclib, for the first-line treatment of postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer.
详细描述
This is a multicenter, randomized, double-blind, double-dummy, active-controlled Phase III study comparing Letrozole SIE with Femara® (both in combination with the CDK4/6 inhibitor palbociclib) in postmenopausal women with HR-positive, HER2-negative, inoperable locally advanced or metastatic breast cancer. The study employs double-blinding with matching placebos (double-dummy technique) to minimize bias on the part of participants, investigators, and analysts. Participants will be randomized in a 1:1 ratio to receive either Letrozole SIE (experimental use) or Femara® (active comparator), both in combination with the CDK4/6 inhibitor palbociclib. Randomization occurs after Screening and confirmation of eligibility and will be stratified by visceral metastasis (Yes/No) and prior adjuvant endocrine therapy (Yes/No).
The Treatment Period will last from Cycle 1 Day 1 (C1D1) until study intervention discontinuation due to disease progression, symptomatic deterioration, unacceptable toxicity, withdrawal of consent, loss to follow-up, participant's death, or end of study, whichever occurs first. After study intervention discontinuation, a post-discontinuation visit will be performed. Then, participants will be followed until withdrawal of consent, loss to follow-up, the participant's death, or end of study, whichever occurs first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female participants with inoperable locally advanced or metastatic breast cancer.
- •Confirmed diagnosis of HR-positive/HER2-negative breast cancer.
- •Postmenopausal woman.
- •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 progressive disease prior to enrolment.
- •Have either measurable disease or non-measurable bone-only disease.
- •ECOG performance status 0-
- •Adequate organ and marrow function.
- •Resolution of all acute toxic effects of prior anticancer therapy or surgical procedures to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the participant at the investigator's discretion).
- •BMI ≥ 19 and ≤ 39 kg/m2.
排除标准
- •Participants with advanced, symptomatic, visceral spread who are at risk of life-threatening complications in the short term.
- •Known uncontrolled or symptomatic central nervous system (CNS) metastases.
- •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 a history of cardiac dysfunction.
- •Uncontrolled hypertension.
- •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 medical conditions associated with low bone mass.
- •Presence of detectable viral infection, including HBV, HCV, and HIV. Screening is not required for enrollment. Note: Participants who have been effectively treated and have a sustained virologic response are eligible for enrollment.
- •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 receptor activator of nuclear factor kappa-β ligand (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.
- •Use of estrogen or progesterone hormone replacement therapy, oral contraceptives, androgens, LHRH analogs, prolactin inhibitors, or antiandrogens within 3 months prior to randomization.
- •Use of the following medications within the three previous days or a period of 5 half-lives, whichever is longer prior to randomization:
- •Any medications including St. John's wort, known to be potent or moderate inducers of Cytochrome P450 (CYP) 3A.
- •Any medications or products known to be potent or moderate inhibitors of CYP3A (e.g., grapefruit juice).
- •Any medications known to be inducers of CYP2A
- •Any medications known to be inhibitors of CYP2A
- •Concurrently use of other anticancer therapy.
研究组 & 干预措施
Letrozole SIE
干预措施: Letrozole SIE + Palbociclib + Oral placebo (Drug)
Femara® 2.5 mg
干预措施: Oral Femara® + Palbociclib + Injectable placebo (Drug)
结局指标
主要结局
Progression Free Survival (PFS)
时间窗: From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 32 months).
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
- Overall Survival (OS): Primary analysis(From the date of randomization to date of death from any cause (up to approximately 32 months).)
- Overall Survival (OS): Final analysis(From the date of randomization to date of death from any cause (up to approximately 60 months).)
- Objective Response Rate (ORR): Primary analysis(From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 32 months).)
- Objective Response Rate (ORR): Final analysis(From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 60 months).)
- Incidence of arthralgias/arthritis and/or myalgias(From the date of the first dose of study intervention to the post-discontinuation visit (up to approximately 32 months).)
- Time to Response (TTR)(From the date of randomization to the date of the first documented evidence of complete response or partial response (up to approximately 32 months).)
- Duration of response (DOR)(From first documented evidence of complete response (CR) or partial response (PR) until disease progression or death from any cause, whichever occurs first (up to approximately 32 months).)
- Clinical benefit rate (CBR)(From the date of randomization to the date of the first documented progression or death due to any cause, assessed according to RECIST version 1.1 (up to approximately 32 months).)
- Time to treatment failure (TTF)(From date of randomization to study intervention discontinuation for any reason (up to approximately 32 months).)
- Change from baseline in the FACT-G total score(From the date of randomization to the post-discontinuation visit (up to approximately 32 months).)
- Change from baseline in the FACT-G Physical well-being subscale score(From the date of randomization to the time of disease progression (up to approximately 32 months).)
- Change from baseline in the FACT-G Social/Familiy well-being subscale score(From the date of randomization to the time of disease progression (up to approximately 32 months).)
- Change from baseline in the FACT-G Emotional well-being subscale score(From the date of randomization to the time of disease progression (up to approximately 32 months).)
- Change from baseline in the FACT-G Functional well-being subscale score(From the date of randomization to the post-discontinuation visit (up to approximately 32 months).)
- Change from baseline in the FACT-B total score(From the date of randomization to the post-discontinuation visit (up to approximately 32 months).)
- Change from baseline in the FACT-B Breast Cancer subscale score(From the date of randomization to the post-discontinuation visit (up to approximately 32 months).)
- Change from baseline in the FACT-ES total score(From the date of randomization to the post-discontinuation visit (up to approximately 32 months).)
- Change from baseline in the FACT-ES Endocrine Symptoms subscale score(From the date of randomization to the post-discontinuation visit (up to approximately 32 months).)
- Time to deterioration in the FACT-G total score(From the date of randomization to to the first occurrence of a decrease from baseline of at least 5 points for FACT-G (up to approximately 32 months).)
- Time to deterioration in the FACT-B total score(From the date of randomization to to the first occurrence of a decrease from baseline of at least 7 points for FACT-B (up to approximately 32 months).)
- Time to deterioration in the FACT-ES total score(From the date of randomization to to the first occurrence of a decrease from baseline of at least 7 points for FACT-ES (up to approximately 32 months).)
- ESR1 mutation status(From the date of randomization to the time of disease progression (up to approximately 32 months).)
- ESR1 mutant allele frequency(At the time of disease progression (up to approximately 32 months).)
- Incidence of Adverse Events (AEs)(From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 60 months).)
- Incidence of injection site reactions(From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 60 months).)
- Changes in injection-related pain score(From the date of the first dose of study intervention to the post-discontinuation visit (approximately up to 60 months).)
- Change from baseline in Bone mineral density (BMD)(From the Informed Consent Form signature to the post-discontinuation visit (approximately up to 32 months).)