Phase 1-2 Study of Safety and Efficacy of Intrathecal Trastuzumab Administration in Metastatic HER2 Positive Breast Cancer Patients Developing Carcinomatous Meningitis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 34
- 试验地点
- 10
- 主要终点
- Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route.
研究概览
简要总结
The purpose of this study is:
Phase I: To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route to reach a intra CSF target concentration (30 µg/mL) near the conventional therapeutic concentration and depending on the dose-limiting toxicity (DLT)
Phase II: Determination of antitumor activity trastuzumab when administrated by IT or intra-ventricular in terms of neurological progression-free survival at 2 months
详细描述
Phase I: Secondary Outcome Measures:
Recommended dose (RD will be used in Phase II) Toxicity during treatment Clinical response to specific neurologic symptoms Time to neurologic progression Biological response: CSF cellularity and protein concentration Radiological response: cerebrospinal meningitis and neuraxis RMI Impact on quality of life Impact on survival (overall survival, survival without neurological progression, progression-free survival) Pharmacokinetics: dose of trastuzumab in CSF and plasma FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer
Phase II: Secondary Outcome Measures :
Toxicity during treatment Clinical response to specific neurologic symptoms Time to neurologic progression Biological response: CSF cellularity and protein concentration Radiological response: cerebrospinal meningitis and neuraxis MRI Impact on quality of life Impact on survival (overall survival, survival without neurological progression, progression-free survival) Pharmacokinetics: dose of trastuzumab in CSF and plasma (confirmation of phase I data with 5 patients) FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer
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
- •Metaplastic Infiltrating adenocarcinoma of the breast
- •HER2 Overexpression by IHC and / or amplification (FISH and or ICHS)
- •Positive diagnosis of neoplastic meningitis: positive CSF cytology (obtained within 28 days before inclusion) AND / OR clinical symptoms of neoplastic meningitis and aspect of tumoral meningitis on MRI
- •Brain metastases are allowed without prior treatment, if they are asymptomatics and without engagement. In cases of symptomatic brain metastases, subjects could be included only if surgery and / or radiotherapy (stereotactic or in toto) were performed and if the cerebral metastatic localization allow IT or intra-ventricular treatment. The last radiotherapy session or the surgery must have been done 3 weeks before.
- •Aged 18 years old or more
- •Male and female
- •Life expectancy more than 2 months
- •Satisfactory Cardiac function: left ventricular ejection fraction (LVEF) determined by ultrasound scan or myocardial scintigraphy
- •Adequate Biological functions 14 days before inclusion, according to the criteria below: Neutrophils > 1.0 x 109/L, Hemoglobin > 9.0 g/dL (+ transfusion if needed,Platelets > 50 x 109/L,Bilirubin < 3 x N, ALT & AST < 10 x N, Creatinine < 2.0 mg/dL, Clearance > 25 mL/min (Cockcroft and Gault formula), Prothrombin time > 70 %, Kaolin cephalin coagulation time < 1.5 x N.
- •Women of childbearing potential, must take adequate birth control measure during the study period and must have a negative pregnancy test (BetaHCG serum)
- •The subjects must perform all evaluations of pre-inclusion, as provided by the protocol
- •Signed written inform consent
排除标准
- •CSF circulation disorders suspected on MRI brain (obstructive hydrocephalus) or medullar (obstacle) with, in case of a focal radiotherapy on obstructive lesion, checking the restoration of transit traffic by isotope CSF
- •Anti-coagulant effective dose treatment when trastuzumab administration by lumbar puncture
- •Patient on Lapatinib (wash out> 2 weeks from the date of first dose intrathecal trastuzumab)
- •Known or suspected trastuzumab allergy
- •Contraindications of trastuzumab administration, including cardiac diseases: LVEF <laboratory lower limit of normal or any other heart condition which would expose the subject to an unreasonable risk if he were to participate in the study
- •Severe toxicity unresolved or unstable related to another previous study restricted drug and / or a cancer treatment
- •Ventriculoperitoneal or atrial shunting excepted if the valve could be turn off (on-off switch) and the patient can stand it during 6 h after each injection of trastuzumab
- •Dementia, altered mental status or psychiatric condition that would prevent the subject to understand or give informed consent
- •Pre-existing severe cerebrovascular disease, such as stroke in a major vessel, vasculitis in the central nervous system or malignant hypertension
- •Uncontrolled infection
- •Participation in a clinical study with an experimental molecule
- •No affiliation to a Social insurance (beneficiary or assignee)
- •Pregnant women, breastfeeding or of childbearing age not taking contraceptive
- •Subject unable to make follow up schedule
- •Persons deprived of liberty or under guardianship (including curators)
研究组 & 干预措施
Trastuzumab intrathecal
干预措施: Trastuzumab (Drug)
结局指标
主要结局
Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route.
时间窗: 2 months
Phase I : To determine the Trastuzumab maximimum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route to reach a intra CSF target concentration (30 µg/mL) near the conventional therapeutic concentration and depending on the dose-limiting toxicity (DLT).
次要结局
- Phase I&II : Toxicity during treatment(2 months)
- Biological response: CSF cellularity and protein concentration(2 years)
- Pharmacokinetics: dose of trastuzumab in CSF and plasma(2 months)
- FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer(2 years)
- Phase II : Determination of antitumor activity trastuzumab when administrated by IT or intra-ventricular in terms of neurological progression free survival at 2 months(2 month)
- Impact on quality of life(2 years)
- Phase I : Recommended dose (RD will be used in Phase II)(2 months)
- Time to neurologic progression(2 years)
- Radiological response: cerebrospinal meningitis and neuraxis MRI(2 years)
- Impact on survival (overall survival, survival without neurological progression, progression-free survival)(2 years)