NCT04739761进行中（未招募）3 期
An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in Patients With or Without Baseline Brain Metastasis With Previously Treated Advanced/Metastatic HER2-Positive Breast Cancer (DESTINY-Breast12)
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 506
- 试验地点
- 82
- 主要终点
- Objective Response Rate (ORR) in Cohort 1 (Participants Without Brain Metastasis at Baseline)
研究概览
简要总结
This is open-label, multicenter, international study, assessing the efficacy and safety of Trastuzumab deruxtecan (T-DXd) in participants with or without brain metastasis (BMs), with previously-treated advanced/metastatic HER2-positive breast cancer whose disease has progressed on prior anti-HER2-based regimens and who received no more than 2 lines/regimens of therapy in the metastatic setting (excluding tucatinib).
详细描述
Approximately 500 eligible participants will be enrolled into 1 of 2 cohorts (250 participants in each cohort) according to the presence or absence of BMs at baseline. Cohort 1 will include participants without BM at baseline and Cohort 2 will consist of participants with BM at baseline.
After study intervention discontinuation, all participants will undergo an end-of-treatment visit (within 7 days of discontinuation) and will be followed up for safety assessments 40 (+ up to 7) days after the discontinuation of all study intervention.
All participants will be followed up for survival status and duration of treatment on subsequent therapies after intervention discontinuation every 3 months (± 14 days) from the date of the safety follow-up until death, withdrawal of consent, or the end of the study, as per defined in the protocol.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants should have pathologically documented breast cancer that is: unresectable/advanced or metastatic; confirmed HER2-positive status expression as determined according to American Society of Clinical Oncology/College of American Pathologists guidelines
- •Participant must have either: no evidence of BM, or untreated BM on screening contrast brain magnetic resonance imaging/ computed tomography (MRI/CT) scan, not needing immediate local therapy or previously-treated stable or progressing BM
- •Participants with BMs must be neurologically stable
- •For participants requiring radiotherapy due to BMs, there should be an adequate washout period before day of first dosing:
- •≥ 7 days since stereotactic radiosurgery or gamma knife
- •≥ 21 days since whole brain radiotherapy
- •Eastern Cooperative Oncology Group performance status 0-1
- •Previous breast cancer treatment: radiologic or objective evidence of disease progression on or after HER2 targeted therapies and no more than 2 lines/regimens of therapy in the metastatic setting
- •Participant with the following measurable: at least 1 lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter with CT or MRI and is suitable for accurate repeated measurements; or following Non-measurable diseases: Non-measurable, bone-only disease that can be assessed by CT or MRI or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-ray in the absence of measurable disease as defined above is acceptable; Participants with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible; and Non-measurable CNS disease (Cohort 2 only)
- •Adequate organ and bone marrow function within 14 days before the day of first dosing as defined in the protocol
- •Left ventricular ejection fraction ≥ 50% within 28 days before enrollment
- •Negative pregnancy test (serum) for women of childbearing potential
排除标准
- •Known or suspected leptomeningeal disease
- •Prior exposure to tucatinib treatment
- •Refractory nausea and vomiting, chronic gastrointestinal disease, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of T-DXd
- •History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence
- •Based on screening contrast brain MRI/CT scan, participants must not have any of the following: any untreated brain lesions > 2.0 cm in size; ongoing use of systemic corticosteroids for control of symptoms of BMs; any brain lesion thought to require immediate local therapy; have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to BMs not withstanding CNS-directed therapy
- •Has spinal cord compression
- •Known active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day
- •Participants with past or resolved hepatitis B virus infection are eligible, if negative for hepatitis B surface antigen and positive for anti-hepatitis B core antigen
- •Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
- •Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- •Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd
- •Participants with a medical history of myocardial infarction within 6 months before screening, symptomatic congestive heart failure (New York Heart Association Class II to IV)
- •History of (non-infectious) 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 and any autoimmune, connective tissue or inflammatory disorders
- •Prior exposure, without adequate treatment washout period before the day of first dosing, to chloroquine/hydroxychloroquine: < 14 days
- •Anticancer chemotherapy: immunotherapy (non-antibody-based therapy), retinoid therapy, hormonal therapy: < 3 weeks
- •< 6 weeks for nitrosoureas or mitomycin
- •Antibody-based anticancer therapy: < 4 weeks
- •Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer- related conditions is allowed
- •Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline
- •Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation, radiation to the chest, or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention
- •Participants with prior exposure to immunosuppressive medication within 14 days prior to first study dose
- •Participants with a known hypersensitivity to study intervention or any of the excipients of the product or other monoclonal antibodies
研究组 & 干预措施
Trastuzumab Deruxtecan
Experimental
Participants with or without BM at baseline will receive intravenous (IV) T-DXd, 5.4 mg/kg, every 3 weeks (21-day cycle) until Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) defined radiological progression outside central nervous system, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.
干预措施: Trastuzumab Deruxtecan (Drug)
结局指标
主要结局
Objective Response Rate (ORR) in Cohort 1 (Participants Without Brain Metastasis at Baseline)
时间窗: From first dose (Day 1) to progression of disease (up to 2 years 7 months)
The ORR is defined as the percentage (%) of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Progression-free Survival (PFS) Rate at 12 Months in Cohort 2 (Participants With Brain Metastasis at Baseline)
时间窗: At 12 months
The PFS rate is the percentage of participants alive and free of disease progression at 12 months, estimated by the Kaplan-Meier method.
次要结局
- Survival Rate at 12 Months(At 12 Months)
- Objective Response Rate in Cohort 2 (Participants With Brain Metastasis at Baseline)(From first dose (Day 1) to progression of disease (up to 2 years 7 months))
- Duration of Response (DoR)(From the date of first documented confirmed response until date of documented progression (up to 2 years 7 months))
- Time to Progression(From first dose (Day 1) to progression of disease (up to 2 years 7 months))
- Duration of Treatment on Subsequent Lines of Therapy(From the date of first dose of a subsequent therapy until date of last dose of therapy (up to 2 years 7 months))
- Second Progression-Free Survival Rate at 12 Months(At 12 Months)
- Incidence of New Symptomatic Central Nervous System (CNS) Metastasis During Treatment Without CNS Metastasis at Baseline (Cohort 1)(From first dose (Day 1) to end of treatment (up to 2 years 7 months))
- Time to Next Progression (CNS or Extracranial) or Death(From date of first documented isolated CNS progression to the date of the next documented disease progression (up to 2 years 7 months))
- Site (CNS vs Extracranial vs Both) of Next Progression(From the date of the first documented isolated CNS progression to the date of the next documented CNS disease progression (up to 2 years 7 months))
- Central Nervous System Progression-free Survival Rate at 12 Months in Participants With Brain Metastasis at Baseline (Cohort 2)(At 12 Months)
- Time to New CNS Lesions in Participants With Brain Metastasis at Baseline (Cohort 2)(From first dose (Day 1) to the date of documented new CNS lesions (up to 2 years 7 months))
- Central Nervous System Objective Response Rate in Participants With Brain Metastasis at Baseline by ICR (Cohort 2)(From first dose (Day 1) until CNS progression of disease (up to 2 years 7 months))
- Central Nervous System Duration of Response in Participants With Brain Metastasis at Baseline (Cohort 2)(From date of first documented confirmed CNS response until CNS progression of disease (up to 2 years 7 months))
- Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30)(Time from first dose up to 47 days after last dose, or prior to starting any subsequent therapy, or for up to 2 years 7 months, whichever occurred first)
- Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale)(Time from first dose up to 47 days after last dose, or prior to starting any subsequent therapy, or for up to 2 years 7 months, whichever occurred first)
- Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS)(Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle))
- Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA)(Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle))
- Cognitive Functions Tests: Reaction Time (RTI)(Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle))
- Cognitive Functions Tests: Spatial Working Memory (SWM)(Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle))
- Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS)(Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle))
- St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis(From time of ILD/pneumonitis diagnosis (every week) until end of safety follow-up (47 days post last dose) (up to 2 years 7 months))
- MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants(Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 39 Day 1 (21 days cycle))
- Number of Participants With Adverse Events (AEs)(From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months))
- Number of Participants With Investigator-assessed ILD/Pneumonitis(From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months))
- Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid(From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months))
研究者
研究点 (82)
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相关资讯
Enhertu Demonstrates Maintained Quality of Life in HER2-Positive Metastatic Breast Cancer Patients- The DESTINY-Breast12 trial evaluated Enhertu's impact on health-related quality of life (HRQOL) and neurological function in HER2-positive metastatic breast cancer patients.
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- NATALEE trial's 4-year update showed ribociclib plus aromatase inhibition significantly improved invasive disease-free survival in high-risk, hormone receptor-positive early breast cancer.
- DESTINY-Breast12 trial demonstrated trastuzumab deruxtecan's significant intracranial activity in HER2-positive metastatic breast cancer patients with brain metastases.
- ICARUS-BREAST01 trial revealed promising objective response rates and progression-free survival with patritumab deruxtecan in HER3-positive, hormone receptor-positive, HER2-negative metastatic breast cancer.last yearTrastuzumab Deruxtecan Shows Promise in HER2+ Breast Cancer with Brain Metastases- Trastuzumab deruxtecan (T-DXd) demonstrates substantial and durable clinical activity in HER2-positive advanced breast cancer patients, including those with brain metastases.
- The DESTINY-Breast12 trial showed a 12-month progression-free survival rate of 61.6% in patients with baseline brain metastases treated with T-DXd.
- Central nervous system overall response rate was 71.7% in patients with measurable CNS disease, indicating significant intracranial activity of T-DXd.
- Safety profile of T-DXd was consistent with previous reports, though interstitial lung disease remains an important risk, especially with concomitant steroid use.2 years ago