Intrathecal Trastuzumab Administration in Metastatic Breast Cancer Patients Developing Carcinomatous Meningitis
- Conditions
- Metastatic Breast CancerCarcinomatous Meningitis
- Interventions
- Registration Number
- NCT01373710
- Lead Sponsor
- Institut Curie
- Brief Summary
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
- Detailed Description
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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 34
- 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
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Trastuzumab intrathecal Trastuzumab -
- Primary Outcome Measures
Name Time Method Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route. 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).
- Secondary Outcome Measures
Name Time Method Radiological response: cerebrospinal meningitis and neuraxis MRI 2 years Phase I&II : Toxicity during treatment 2 months Issued the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 National Cancer Institute (NCI)
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 Impact on survival (overall survival, survival without neurological progression, progression-free survival) 2 years
Trial Locations
- Locations (10)
Institut du Cancer de Montpellier
🇫🇷Montpellier, France
Institut Curie - Claudius Regaud Hospital
🇫🇷Paris, Ile De France, France
Oscar Lambret Center
🇫🇷Lille, Nord, France
Institut Bergonié
🇫🇷Bordeaux, France
Institut Univesitaire du Cancer de Toulouse
🇫🇷Toulouse, France
CHU Grenoble
🇫🇷Grenoble, France
Pitie Salpetriere Hospital
🇫🇷Paris, Ile De France, France
François Baclesse Center
🇫🇷Caen, Calvados, France
Rene Huguenin Hospital
🇫🇷Saint-Cloud, Haut De Seine, France
Léon Bérard Center
🇫🇷Lyon, Rhone, France