2022-501504-95-00招募中2 期
A Randomized Trial of Trastuzumab Deruxtecan and Biology-Driven Selection of Neoadjuvant Treatment for HER2-positive Breast Cancer: ARIADNE
Karolinska University Hospital20 个研究点 分布在 3 个国家目标入组 370 人开始时间: 2023年4月19日最近更新:
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 370
- 试验地点
- 20
- 主要终点
- Locally assessed rate of pCR at the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined at the surgical specimen by a pathologist blinded to treatment assignment (intention-to-treat analysis).
研究概览
简要总结
To compare, in terms of locally assessed pathologic complete remission (pCR) rates, standard neoadjuvant therapy versus trastuzumab deruxtecan (T-DXd) monotherapy in patients with molecularly Human Epidermal Growth Factor Receptor 2 (HER2)-enriched and clinically HER2-positive, non-metastatic breast cancer (BC).
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 是
入选标准
- •Women or men 18 years or older
- •Negative serum pregnancy test for women of childbearing potential or for patients who have experienced menopause onset <12 months prior to randomisation
- •Patients of childbearing potential must be willing to use one highly effective contraception or two effective forms of nonhormonal contraception.
- •Participants must be able to communicate with the investigator and comply with the requirements of the study procedures
- •Written informed consent must be given according to ICH/GCP, and national/local regulations
- •Histologically confirmed breast cancer with an invasive component measuring > 20 mm and/or with morphologically confirmed spread to regional lymph nodes (stage cT2-cT4 with any cN, or cN1-cN3 with cT1-4). Ipsilateral multifocal and multicentric tumors are allowed if they fulfill inclusion criterion
- •Performance status 0 or 1 at the time of randomisation
- •Known estrogen-receptor and/or progesterone receptor status, as assessed locally by IHC. The cut-off for positivity for ER/PR for this study is at least 10% of cell nuclei staining for ER or PR, respectively
- •Known HER2-positive breast cancer defined as an IHC status of 3+. If IHC is 2+, a positive in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. ISH positivity is defined as a ratio of ≥ 2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies.
- •Left Ventricular Ejection Fraction (LVEF) ≥ 50% within 28 days before randomization
- •Adequate bone-marrow, hepatic and renal function
- •Availability of tumor and blood samples as described in the protocol
排除标准
- •Participation in other interventional trials
- •Any 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, diarrhea, malabsorption syndrome, or small bowel resection).
- •Receipt of live, attenuated vaccine within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study drug
- •Pre-treatment axillary surgery
- •Any psychological, including substance abuse, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
- •Allergic reactions or hypersensitivity to the study drugs or other monoclonal antibodies
- •Administration of other experimental drugs, either concomitantly or during the past 30 days before treatment initiation
- •A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
- •Recent major surgery
- •Known presence of distant metastases, including node metastases in the contralateral thoracic region or in the mediastinum. Synchronous contralateral breast cancer is allowed if the tumor is HER2 positive according to the definition of inclusion criterion
- •Other malignancy diagnosed during the past five years
- •Concomitant medication(s) with a known risk to prolong the QT interval
- •History of invasive breast cancer
- •History of DCIS, except for patients treated exclusively with mastectomy >5 years prior to diagnosis of current breast cancer
- •Active cardiac disease or a history of cardiac dysfunction
- •Patients with ER-positive breast cancer being treated with drugs recognized as strong inhibitors or inducers of the isoenzyme CYP3A which cannot be discontinued at least 7 days prior to planned treatment with ribociclib.
- •Uncontrolled infection requiring intravenous antibiotics, antivirals or antifungals
- •Pregnant or breastfeeding female patients, or patients who are planning to become pregnant
- •History of (non-infectious) Interstitial Lung Disease (ILD) / pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
- •Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.)
- •Any autoimmune, connective tissue or inflammatory disorders (e.g. Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for patients who are included in the study.
- •Prior pneumonectomy
- •History of positive testing for HIV or known AIDS
- •Acute or chronic infection with hepatitis B or C virus. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
结局指标
主要结局
Locally assessed rate of pCR at the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined at the surgical specimen by a pathologist blinded to treatment assignment (intention-to-treat analysis).
Locally assessed rate of pCR at the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined at the surgical specimen by a pathologist blinded to treatment assignment (intention-to-treat analysis).
次要结局
- Locally assessed rate of pCR, defined as ypT0/Tis, ypN0, at the two patient groups of the initial randomization of TCHP versus T-DXd, regardless of administered therapy after cycle 3
- Locally assessed rate of pCR at ER-positive and luminal subgroup
- Locally assessed rate of pCR at ER-negative and luminal subgroup, at the basal-like subgroup and the normal-like subgroup
- Locally assessed rate of pCR at all molecular subgroups in the evaluable population
- Rates of radiologic complete response after three courses of either standard therapy or T-DXd
- Overall survival (OS), defined as time from randomization to death by any cause, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Distant relapse-free survival (DRFS), defined as time from randomization to distant metastases or death by any cause, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Event-free survival (EFS), defined as time from randomization to disease progression, breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death by any cause, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Rates of complete radiologic response, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Pathologic response according to Residual Cancer Burden Class, as described in 1, 2, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Rate of breast conserving surgery, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Rate of de-escalation of breast surgery (conversion from mastectomy to breast conserving surgery or de-escalation of complexity from an oncoplastic breast-conserving procedure to simple wide local excisions) for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Rate of Sentinel Lymph Node Dissection (SLND), for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Rate of de-escalation of axillary surgery (conversion from axillary lymph node dissection to either targeted axillary dissection or sentinel lymph node dissection) for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd.
- Rate of Sentinel Lymph Node detection, Targeted Axillary Dissection success and false-negative rates of these procedures in initially node-positive patients for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd
- Frequency and grade of adverse events (AE) (according to NCI CTCAE v. 5.0, see https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf) and rate of discontinuation due to toxicity
- PRO endpoints including health related quality of life scores [European Organization for Research and Treatment of Cancer Quality of Life Instrument (EORTC QLQ-C30); European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ-BR23)].
- Exploratory analyses of clinicopathologic characteristics as predictors for response
- Discovery of biomarkers of response/resistance to administered neoadjuvant therapy at the protein, RNA and DNA levels in both tumor tissue and blood/plasma, as described in detail in protocol section 9.
研究者
Theodoros Foukakis
Scientific
Karolinska University Hospital
研究点 (20)
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