Dynamic Marker - Adjusted Therapy Comparing Adjuvant Elacestrant With Standard Endocrine Treatment in Genomically and/or Clinically High-risk ER+/HER2- Early Breast Cancer (ADAPTela)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 1,520
- 试验地点
- 33
- 主要终点
- 5-year invasive disease-free survival (iDFS)
研究概览
简要总结
In this clinical trial, the Sponsor plans to investigate whether patients with HR+/HER2- eBC identified during routine clinical assessments and treatments as having intermediate to high-risk (based on Oncotype DX® or similar tests and on response assessment to 2-6 weeks of preoperative ET) achieve a survival benefit from an initial 5-years use of elacestrant (with or without a CDK 4/6 inhibitor) followed by SoC ET for further 0-2.5 years in comparison to at least 5 up to 7.5 years SoC ET therapy (+/- CDK4/6 inhibitor).
Based on several studies in the metastatic setting, it is reasonable to assume that the adjuvant use of elacestrant with or without CDK 4/6 inhibitors will prevent or delay the activation of mechanisms conferring resistance to ET (e.g., ESR1 mutations).
详细描述
Patients with hormone-receptor positive/HER2-negative (HR+/HER2-) early breast cancer (eBC) remain at risk of recurrence for many years after diagnosis. Current guidelines provide treatment recommendations depending on stage, histological grade, and menopausal status. However, patients with a high-risk HR+/HER2- eBC are at need for more efficacious treatment.
Several new strategies are currently investigated in patients diagnosed with high-risk HR+/HER2- eBC, including extending the duration of adjuvant endocrine therapy (ET), addition of ovarian function suppression (OFS) in case of premenopausal patients, and intensification of adjuvant ET by use of new therapies, such as cyclin-dependent kinase (CDK) 4/6 inhibitors. Moreover, development of algorithms incorporating not only clinical variables, but also key tumor biological variables such as Oncotype DX®/Recurrence Score (RS) or Mammaprint®, and possibly dynamic variables such as ET-response measured by Ki-67 after 2-6 weeks of preoperative standard endocrine induction therapy, could be of immense importance for risk estimation and subsequently optimization of therapy in intermediate to high-risk patients.
Several retrospective studies have shown that Oncotype DX® or other genomic tests are informative regarding prediction of treatment benefit in HR+/HER2- eBC. Therefore, use of RS instead of mostly relying on histological grade provides stronger prognostic and predictive information.
Further, characterization of ET-response has shown to provide important prognostic information in early HR+/HER2- eBC beyond clinical and genomic markers, as shown in the WSG-ADAPT-HR+/HER2-, ALLIANCE, and POETIC trials. The endocrine response has therefore become part of the ESMO guidelines as a prognostic factor.
The combination of classical prognostic markers with genomic assessments (e.g., Oncotype DX®) and endocrine response seems to be the most promising tool for identification of patients with significant relapse risk despite of standard ET and/or chemotherapy.
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All patients, independent from gender
- •Patient must be ≥18 years at diagnosis
- •The patient must be capable of giving informed consent and be willing and able to comply with the requirements and restrictions in this protocol and accessible for treatment and follow-up
- •Sign informed consent prior to any study-specific procedures.
- •Histologically confirmed unilateral, primary invasive carcinoma of the breast Note: bilateral, multicentric, or multifocal carcinoma may only be included after consultation of Sponsor.
- •Histologically confirmed diagnosis of primary hormone-receptor-positive (HR+) (i.e., oestrogen-receptor (ER) ≥ 10% and progesterone-receptor PR ≥ 10%) early breast cancer by local laboratory Note: ER positive according to ASCO / AGO Guidelines, ER 1-10% (low) is not defined as HR+.
- •Patient has HER2-negative breast cancer defined as a negative in-situ hybridization test or an IHC status of 0, 1+, or 2+, if IHC is 2+, a negative in-situ hybridization (FISH, CISH, or SISH) test is required (based on the most recently analysed tissue sample and all tested by a local laboratory).
- •No evidence of distant metastasis (confirmed by CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT, respectively, performed within clinical routine).
- •High genomic risk assessment within clinical routine (Oncotype DX® preferred; In those cases, where Oncotype Dx® is not possible in clinical routine, Oncotype Dx® should be assessed retrospectively after inclusion of the patient and as a study specific measure, provided sufficient tumour tissue from primary diagnosis is available.)
- •10. Completed 2-6 weeks of endocrine induction treatment and Ki-67 response assessment Note: 2-4 weeks recommended, up to 6 weeks allowed. Endocrine induction is highly recommended, but if endocrine induction therapy could not be performed or ET response is not representative, clinical factors should be used.
- •11. Completed (neo)adjuvant chemotherapy, if applicable
- •Completed radiotherapy, if applicable
- •Patient meets any of the following three conditions at end of primary treatment (including endocrine induction treatment, biopsy/surgery, and if necessary, chemotherapy and radiotherapy and up to 12 months standard-of-care endocrine treatment, excluding previous treatment > 4 weeks with any SERD):
- •Pathological Stage * Genomical High-Risk (Oncotype Dx®)** Age Clinical High-Risk Factors Stage I T1 N0
- •RS>25 Any age High risk (≤ 1 factor applies):
- •ET non-response (post ET Ki-67 >10%)***
- •No Chemotherapy
- •G3 or PR negative and Ki-67 >25%***
- •Non-pCR after NACT*
- •RS 16-25 Age <50 High risk (≤ 1 factor applies):
- •ET non-response (post ET Ki-67 >10%)***
- •No Chemotherapy
- •G3 or PR negative and Ki-67 >25%***
- •Non-pCR after NACT* Any genomic risk Any age G3 and Ki-67>40%
- •Stage IIa with T2 N0
- •RS 0-25 Age>50 High risk (≤ 1 factor applies):
- •ET non-response (post ET Ki-67 >10%)***
- •G3 and Ki-67>40%
- •G3 or PR negative and Ki-67 >25%***
- •Non-pCR after NACT*
- •RS 0-15 Age<50 No chemotherapy AND high risk (≤ 1 factor applies):
- •ET non-response (post ET Ki-67 >10%)***
- •G3 and Ki-67>40%
- •G3 or PR negative and Ki-67 >25%***
- •Non-pCR after NACT*
- •RS 16-25 Age<50 No chemotherapy, AND/OR high risk (≤ 1 factor applies):
- •ET non-response (post ET Ki-67 >10%)***
- •G3 and Ki-67>40%
- •G3 or PR negative and Ki-67 >25%***
- •Non-pCR after NACT*
- •RS >25 Any age Any clinical risk
- •Any genomic risk Any age G3 and Ki-67 >40%
- •Stage IIa with T1 N1, G1-2
- •RS 0-25 Age>50 High risk (≤ 1 factor applies):
- •ET non-response (post ET Ki-67 >10%)***
- •PR negative and Ki-67 >25%***
- •Non-pCR after NACT*
- •3 positive LN
- •RS 0-25 Age <50 No chemotherapy, AND/OR high risk (≤ 1 factor applies):
- •ET non-response (post ET Ki-67 >10%)***
- 另有 42 项未显示
排除标准
- •Known hypersensitivity to any of the compounds or incorporated substances of the IMPs
- •Prior malignancy with a disease-free survival of <5 years, except curatively treated basalioma of the skin or pTis of the cervix uteri
- •Any history of invasive cancer within the last 10 years Note: adequately treated, basal or squamous-cell skin carcinoma, non-melanomatous skin cancer, curatively resected cervical cancer, and contralateral DCIS treated by mastectomy (contralateral in relation to current invasive breast cancer diagnosis) are excepted. Previous ipsilateral DCIS, irrespective of treatment, is excluded!
- •Patient with distant metastases of breast cancer beyond regional lymph nodes.
- •Concurrent treatment with cytotoxic agents for any non-oncological reason unless clarified with sponsor
- •Concurrent treatment with other experimental drugs
- •Participation in another interventional clinical trial with or without any investigational, not marketed drug within 30 days or 5 half-lives of the respective drug, whichever is longer, prior to study entry. In case of other interventional trial contact Sponsor.
- •Previous treatment (>4 weeks) with any SERD
- •Concurrent pregnancy; patients of childbearing potential or potentially childbearing partners of male patients must implement a highly effective (less than 1% failure rate) non-hormonal contraceptive measures during the study treatment
- •Breast feeding woman
- •Use of oral, transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy (oestrogen or progesterone).
- •Reasons indicating risk of poor compliance
- •Patient not able to consent
- •Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤
- •Severe and relevant co-morbidity that would interact with the application of endocrine treatment of any kind or the participation in the study
- •For patients planned for ribociclib treatment: Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
- •history of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry,
- •documented cardiomyopathy,
- •left ventricular ejection fraction (LVEF) < 50 % as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO),
- •long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome, or any of the following:
- •risk factors for Torsades de Pointe (TdP, polymorphic ventricular tachycardia in patients with long QT syndrome) including uncorrected hypokalaemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia,
- •concomitant medications with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug),
- •inability to determine the QTcF interval,
- •clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left-bundle branch block, high-grade AV block (e.g., bi-fascicular block, Mobitz type II, and 3rd-degree AV block),
- •systolic blood pressure (SBP) > 160 or < 90 mmHg.
- •Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small-bowel resection).
- •Uncontrolled infection requiring i.v. antibiotics, antivirals, or antifungals
- •Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection. Patients should be tested for HIV prior to randomization if required by local regulations or ethics committee (EC). Patients who test positive for HIV-antibody are excluded.
- •Patient has known active hepatitis-B-virus (HBV) or hepatitis-C-virus (HCV) infection. Screening for HBV or HBC-infection and testing for hepatitis-B or -C is highly recommended according to current valid (local) clinical guidelines, but neither part of the interventional study procedures, nor required for enrolment.
- •Patient has received live vaccines within 30 days prior to randomization.
- •Patient was submitted to an institution by virtue of an order of a court or a governmental authority must be excluded from participation.
研究组 & 干预措施
Standard-of-care endocrine treatment (SoC-ET)
Patients will be treated with SoC ET for 5-10 years. In case further treatment, e.g., CDK4/6 inhibitors, is indicated, this may be added according to SoC and per investigator´s discretion.
干预措施: Standard-of-care endocrine treatment (Drug)
Elacestrant upfront (ELA)
Patients will be treated with elacestrant (ELA) for 5 years. In case further treatment, e.g., CDK4/6 inhibitors, is indicated, ribociclib (RIBO) may be added for 3 years in parallel
干预措施: Elacestrant (Drug)
结局指标
主要结局
5-year invasive disease-free survival (iDFS)
时间窗: iDFS 5 years
iDFS after 5 years, compared between patients randomized to adjuvant elacestrant (+/-CDK4/6i) or SOC ET (+/- CDK4/6i)
次要结局
- 5-year distant disease-free survival (dDFS)(dDFS 5 years)
- 5-year DCIS disease-free survival (DFS-DCIS)(DFS-DCIS 5 years)
- 5-year locoregional relapse-free survival (LRFS)(LRFS 5 years)
- 5-year relapse-free survival (RFS)(RFS 5 years)
- 5-year invasive breast cancer-free survival (IBCFS)(IBCFS 5 years)
- 5-year overall survival (OS)(OS 5 years)