Premedication With Dexamethasone for Preventing Interstitial Lung Disease in Patients With Breast Cancer Treated With Trastuzumab Deruxtecan - MARGARET Trial
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 244
- 主要终点
- Primary endpoint
研究概览
简要总结
Trastuzumab deruxtecan (T-DXd) has recently received approval as an antibody-drug conjugate for treating patients with metastatic breast cancer (BC) who have HER-2 protein expression as determined by immunohistochemistry, including HER2-positive, -low and -ultralow BC. Its use has shown significant effectiveness in terms of response and survival rates. Pulmonary toxicity, specifically interstitial lung disease (ILD), is of significant clinical interest in 10-15% of patients. For cases of mild toxicity, namely grade 1, the diagnosis relies exclusively on radiological findings in the absence of symptoms. In such cases, T-DXd is temporarily stopped and steroids might be used as treatment. Once the radiological findings have been resolved, the drug can be resumed. Grade 2 is distinguished by the presence of clinical signs such as difficulty breathing and coughing, as well as radiological evidence. In such instances, the medication must be permanently stopped. As a consequence, it is recommended that patients receiving T-DXd treatment should be closely monitored with high-resolution (HR) CT scans every 6-12 weeks. The precise mechanism responsible for this toxicity has not yet been fully elucidated; but it is thought to be inflammatory in origin The risk factors for ILD include lower baseline SpO2, lung comorbidities, reduced renal function, time from initial diagnosis, and drug dose. Administering dexamethasone as a premedication twice a day from the day before T-DXd infusion (D-1) through day 4 (D4) may lower ILD incidence and help prevent permanent T-DXd treatment discontinuation. Primary objective To assess the efficacy of dexamethasone premedication in reducing the occurrence of ILD >G1 in breast cancer patients receiving T-DXd treatment.
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
- •Provision of signed, written and dated study informed consent, data protection informed consent and any locally required
- •Women or men aged ≥18 years (or the minimum age of consent in accordance with the local law), at the time of informed consent signature.
- •Histologically or cytologically confirmed metastatic breast cancer for which T-DXd treatment is approved and available at the participating center.
- •Diagnosis of metastatic breast cancer candidate to start a treatment with T-DXd in the subsequent settings:
- •HR-positive with expression of HER2 (low or ultralow) ≤ 2 lines of chemotherapy in advanced disease
- •HR-negative with expression of HER2-low ≤ 2 lines of chemotherapy in advanced disease
- •HER2-positive independently from HR-positivity ≤ 3 lines of treatment in advanced disease
- •ECOG performance status of 0 or
- •Adequate bone marrow as defined by the following laboratory values:
- •ANC ≥1.5 × 109 /L
- •Platelets ≥100 × 109 /L
- •Hemoglobin ≥9.0 g/dL
- •Adequate hepatic function: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or know history of Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) < 1.
- •Adequate washout before randomization, including ≥4 weeks from major surgery or chest radiotherapy (≥2 weeks for non-chest stereotactic radiotherapy)
- •Patient willing and able to comply with the protocol procedures for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
排除标准
- •Patients with uncontrolled diabetes mellitus both type 1 and type 2 (HbA1c > 8.5%).
- •Patients with contraindications to dexamethasone, as determined by the investigator in consultation with medical monitoring before enrolment.
- •Patients already undergoing chronic steroid treatment (e.g. 10 mg/day of prednisone/prednisolone or equivalent).
- •Patients requiring oxygen therapy at rest.
- •Documented pneumonitis/ILD prior to Cycle 1 Day
- •Uncontrolled or significant cardiovascular disease, including recent myocardial infarction (within 6 months), symptomatic heart failure (NYHA II-IV), elevated troponin without symptoms requiring cardiology evaluation, uncontrolled hypertension or arrhythmias, and QTcF prolongation >470 ms in females or >450 ms in males.
- •Impaired renal function with creatinine clearance <30 mL/min (calculated by Cockcroft-Gault formula).
- •Active or newly diagnosed CNS metastases, including meningeal carcinomatosis.
- •Patients with recent (<28 days) respiratory infections.
- •Inability to take oral medications, refractory or chronic nausea, gastrointestinal conditions (including significant gastric or bowel resection), history of malabsorption syndrome, or any other uncontrolled gastrointestinal condition that impacts the absorption of the study drug.
- •Palliative limited-field radiotherapy: <2 weeks (non-chest) or <4 weeks (chest or >30% bone marrow).
- •Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) 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 390 days after the last dose of IMP.
- •Active and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
- •Evidence of ongoing alcohol or drug abuse as assessed by the Investigator.
- •Any severe medical or psychiatric condition that, in the Investigator's opinion, would preclude the patient's participation in a clinical study
- •Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during study participation. Female subjects without childbearing potential are defined as women who are surgically sterile (hysterectomy or documented bilateral tubal ligation) or postmenopausal, defined as at least 12 months of spontaneous amenorrhea.
- •Known allergy or hypersensitivity to study drugs or any excipient.
研究组 & 干预措施
Arm A (experimental arm)
patients will receive premedication with dexamethasone 4 mg twice a day from D-1 to D4, in addition to recommended standard antiemetic premedication. For both arms, the recommended standard antiemetic premedication consists of a three-drug combination-5-HT3 receptor antagonists, NK1 receptor antagonists, and dexamethasone-administered on the first day of T-DXd infusion.
干预措施: antiemetic premedication (Drug)
Arm B (control arm)
patients will receive recommended standard antiemetic premedication. For both arms, the recommended standard antiemetic premedication consists of a three-drug combination-5-HT3 receptor antagonists, NK1 receptor antagonists, and dexamethasone-administered on the first day of T-DXd infusion.
干预措施: antiemetic premedication (Drug)
Arm B (control arm)
patients will receive recommended standard antiemetic premedication. For both arms, the recommended standard antiemetic premedication consists of a three-drug combination-5-HT3 receptor antagonists, NK1 receptor antagonists, and dexamethasone-administered on the first day of T-DXd infusion.
干预措施: T-DXd (Drug)
Arm A (experimental arm)
patients will receive premedication with dexamethasone 4 mg twice a day from D-1 to D4, in addition to recommended standard antiemetic premedication. For both arms, the recommended standard antiemetic premedication consists of a three-drug combination-5-HT3 receptor antagonists, NK1 receptor antagonists, and dexamethasone-administered on the first day of T-DXd infusion.
干预措施: Dexamethasone (Drug)
Arm A (experimental arm)
patients will receive premedication with dexamethasone 4 mg twice a day from D-1 to D4, in addition to recommended standard antiemetic premedication. For both arms, the recommended standard antiemetic premedication consists of a three-drug combination-5-HT3 receptor antagonists, NK1 receptor antagonists, and dexamethasone-administered on the first day of T-DXd infusion.
干预措施: T-DXd (Drug)
结局指标
主要结局
Primary endpoint
时间窗: 12 months
Cumulative incidence of patients who experience an ILD \> G1 on high-resolution thorax CT scan during the treatment with T-DXd at 12 months from randomization by local Investigator's judgement according to CTCAE, version 6.0. Discontinuation of T-DXd treatment for any reason other than ILD \>G1 will be considered as a competing event.
次要结局
未报告次要终点