Phase 1 Trial of Trastuzumab Deruxtecan With Stereotactic Radiosurgery (SRS) in Participants With Brain Metastases From HER-2 Positive Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicities (DLTs)
研究概览
简要总结
A phase I clinical trial (a type of research study) for people with human epidermal growth factor receptor 2 (HER-2) positive breast cancer with metastasis to the brain. This research study will evaluate how well brain metastases can be controlled using a type of radiation therapy known as stereotactic radiosurgery (SRS) when combined with the therapeutic agent Trastuzumab Deruxtecan (T-DXd). The combined use of SRS with T-DXd is considered investigational.
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 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed HER-2-positive breast cancer with newly diagnosed brain metastases.
- •ECOG Performance Status (PS) of 0, 1,
- •Participants with 1-10 brain metastases will be candidates for T-DXd with SRS at the discretion of the treating radiation oncologist. Intra-cranial metastasis must measure 3 cm or less in the greatest dimension.
- •Age ≥ 18 years
- •Signed written informed consent by patient or legally authorized representative. A signed informed consent must be obtained prior to any study-specific procedures.
- •Life expectancy of at least 12 weeks.
- •Any number of prior systemic therapies will be allowed, except T-DXd.
- •Hemoglobin ≥ 9 g/dL, White blood count ≥ 3.0 × 109/L, Absolute Neutrophil count ≥ 1.5 × 109/L and platelet count ≥ 100 × 109/L.
- •Serum bilirubin ≤ 1.5 × upper limit of normal (ULN).
- •AST and/or ALT ≤ 2 × ULN (≤ 5 × ULN when clearly attributable to the presence of liver metastases).
- •Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance > 60 mL/min.
- •Ability to comply with study procedures and monitoring.
- •For individuals of childbearing potential, a negative pregnancy test should be obtained within 7 days prior to the start of therapy.
- •Participants must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days before enrollment (to be assessed as clinically indicated).
- •Male or female participants of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 7 months after last dose of T-DXd.
- •Highly effective and acceptable forms of contraception are:
- •Male condom plus spermicide
- •Cap plus spermicide
- •Diaphragm plus spermicide
- •Progesterone T
- •Levonorgestrel-releasing intrauterine system (e.g., Mirena®)
- •Hormone shot or injection
- •Combined pill
- •Mini-pill
- •Postmenopausal individuals on the study (that will not need contraception) is defined as:
- •Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments.
- •LH and FSH levels in the postmenopausal range for individuals < 50 years.
- •Radiation-induced oophorectomy with last menses > 1 year ago.
- •Chemotherapy-induced menopause with > 1 year interval since last menses.
- •Surgical sterilization (bilateral oophorectomy or hysterectomy).
- •Men and women and members of all races and ethnic groups are eligible for this trial.
排除标准
- •Participants with leptomeningeal metastases documented by MRI or CSF evaluation.
- •Evidence of intra-tumoral or peri-tumoral hemorrhage deemed clinically significant by the treating physician.
- •Brain metastases within 5 mm of the optic chiasm or optic nerve.
- •Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom, e.g., Crohn's disease, malabsorption, or CTCAE grade > 2 diarrhea of any etiology at baseline.
- •History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, New York Heart Association (NYHA) functional classification of 3 or
- •Unable to undergo brain MRI.
- •Screen for human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. HIV/HBV/HCV testing per institutional practice.
- •All toxicities from prior therapies must have resolved to CTCAE v5.0 grade 1 or better by the time of study enrollment.
- •Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active, or uncontrolled infection, uncontrolled diabetes, second active malignancy) that could cause unacceptable safety risks or compromise compliance with the protocol.
- •Currently receiving other investigational cancer therapy (with the exception of continuing therapy with GnRH analogues) within 4 weeks prior to start of study treatment.
- •Mean QT interval corrected heart rate (QTc) ≥ 470 ms calculated from 3 electrocardiograms using Fredericia's Correction, calculated as: 8.22 ∛(RR interval)
- •LVEF <50%.
- •Ineligible for treatment with T-DXd.
- •Ineligible for treatment with SRS.
- •Active or prior documented ILD/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
- •History of hypersensitivity to T-DXd.
- •History and/or confirmed corneal ulceration.
- •Pregnant or breast feeding. The patients should not breast feed for 7 months after stopping the drug.
- •Use of anthracyclines will be prohibited while on the protocol.
- •Prior cranial radiation is not allowed.
研究组 & 干预措施
T-DXd + SRS
All participants will receive SRS and the drug T-DXd. The goal is to evaluate safety and determine an appropriate dose.
干预措施: Trastuzumab Deruxtecan (Drug)
T-DXd + SRS
All participants will receive SRS and the drug T-DXd. The goal is to evaluate safety and determine an appropriate dose.
干预措施: Stereotactic Radiosurgery (Radiation)
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs)
时间窗: 3 weeks
DLTs will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 starting from the first dose of T-DXd through 3 weeks after SRS. DLT is defined as the appearance of side effects during treatment that are severe enough to prevent continuation of treatment at a participant's assigned dose. Any of the following events will be considered a DLT if treatment-related: * ≥ Grade 4 non-hematologic toxicity except nausea and vomiting (if manageable with supportive care measures), alopecia, drug-related fever, and toxicities secondary to neutropenia and sepsis * ≥ Grade 3 neurologic toxicity (sensory or autonomic) * Grade 4 platelet count (\<25,000/mm³) 50 days beyond the start of the most recent chemotherapy (not related to recurrent leukemia) * Grade 4 neutropenia 50 days beyond the start of the most recent chemotherapy (not related to recurrent leukemia) * Grade 3 non-hematologic toxicity (excluding alopecia or toxicities secondary to neutropenia
Determination of the maximum tolerated dose (MTD) of T-DXd in combination with SRS
时间窗: 3 weeks
The MTD will be determined using a standard 3+3 dose de-escalation design across predefined dose levels of T-DXd (5.4 mg/kg, 4.4 mg/kg, and 3.2 mg/kg IV every 21 days), based on the number of participants who experience a DLT at each dose level.
次要结局
- Intracranial Progression-free survival (PFS) at 6 months (PFS-6)(6 months)
- Extracranial PFS-6(6 months)
- Overall survival (OS)(2 years)
- Objective response rate (ORR)(2 years)
- Intracranial PFS-6 comparison to historical data(6 months)
- Extracranial PFS-6 comparison to historical data(6 months)
- OS comparison to historical data(2 years)
- ORR comparison to historical data(2 years)