Phase 1 Trial of Tucatinib, Trastuzumab, and Capecitabine With Stereotactic Radiosurgery (SRS) in Patients With Brain Metastases From HER-2 Positive Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 1
- 试验地点
- 2
- 主要终点
- Incidence of dose-limiting toxicities (DLTs)
研究概览
简要总结
This research study will evaluate how well brain metastases associated with HER-2 positive breast cancer can be controlled using a type of radiation known as stereotactic radiosurgery (SRS) when combined with three therapeutic agents, tucatinib, capecitabine, and trastuzumab.
The combined use of SRS with the three drugs 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
- All
- 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, 2
- •Patients with 1-10 brain metastases will be candidates for tucatinib, capecitabine, and trastuzumab with SRS at the discretion of the treating radiation oncologist. Intra-cranial brain metastasis must measure 3 cm or less in the greatest dimension
- •Age 18 years or greater and being willing and able to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures
- •Life expectancy at least 12 weeks
- •Any number of prior systemic therapies will be allowed, except tucatinib and capecitabine.
- •Hemoglobin ≥ 9g/dL, White blood count ≥3.0 × 10^9/ L , Absolute Granulocyte count ≥1.5x 10^9/ L and platelet count ≥100 × 10^9/ L.
- •Serum bilirubin ≤ 1.5 × 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 > 60mL/min
- •Ability to comply with study procedures and monitoring
- •For women of childbearing potential, a negative pregnancy test should be obtained within one week prior to the start of therapy
- •Male or female patients 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 tucatinib, capecitabine and trastuzumab.
- •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 woman 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 women under 50
- •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
- •Patients with leptomeningeal metastases documented by MRI or CSF evaluation
- •Evidence of intra-tumoral or peri-tumoral hemorrhage deemed 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 4
- •Unable to undergo brain MRI
- •Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C
- •All toxicities from prior therapies must have resolved to CTCAE v 5.0 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 within 4 weeks prior to start of study treatment with the exception of continuing therapy with GnRH analogues
- •Mean QT interval corrected heart rate (QTc) ≥ 470ms calculated from 3 electrocardiograms using Frediricia's Correction
- •Left ventricular ejection fraction (LVEF) <50%
- •Concomitant use of strong cytochrome P450 (CYP)3A inhibitors including macrolide antibiotics (e.g., Telithromycin), antifungals (e.g., Itraconazole), antivirals (e.g., ritonavir), and Nefazodone
- •Concomitant use of strong CYP2C8 inhibitor within 5 half-lives of the inhibitor
- •Concomitant use of strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John's Wort) within 5 days prior to the first dose of study treatment
- •Concomitant use of a strong CYP2C8 inducer within 5 days prior to the first dose of study treatment
- •History of hypersensitivity to tucatinib, capecitabine, and trastuzumab, or any of its excipients
- •History and/or confirmed corneal ulceration
- •Pregnant or breast feeding
- •Use of anthracyline will be prohibited on the protocol
结局指标
主要结局
Incidence of dose-limiting toxicities (DLTs)
时间窗: During first 4 weeks following SRS
Toxicities will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). DLTs are defined as any of the following events: 1. Grade 3 or 4 thrombocytopenia 2. Grade 4 anemia 3. Grade 4 neutropenia lasting more than 7 days 4. Febrile neutropenia 5. Any non-hematologic toxicity of grade 3 or greater (excluding alopecia) despite maximal medical therapy 6. Grade 4 radiation-induced skin changes 7. Any episode of noninfectious pneumonitis.
Incidence of radiation-related toxicities
时间窗: 30 days of progression or last dose of drug
Toxicities presumed to be due to radiation are defined as: 1. Acute, \< 90 days from treatment start: Expected toxicities include hair loss (for lesions abutting skull), erythema of the scalp (for lesions abutting skull), headache, nausea, and vomiting. Reactions in the ear canals and on the ear should be observed and treated symptomatically. Pin site infection, pin site pain, facial swelling/bruising, and scalp numbness are other common acute effects. Acute toxicity is defined by CTCAE v5.0. 2. Both acute and delayed, \> or = 90 days from treatment start (lethargy, transient worsening of existing neurological deficits) or late (radiation necrosis, cognitive dysfunction, accelerated atherosclerosis, radiation-induced neoplasms) effects of radiotherapy are to be recorded and included in the toxicity evaluation. Late or delayed toxicity is defined by CTCAE v5.0.
次要结局
- Progression-free survival (PFS)(Six months)
- Overall survival(One year)
- Overall response rate (ORR)(One year)