Intrathecal Trastuzumab Administration in Metastatic Breast Cancer Patients Developing Carcinomatous Meningitis

Study Overview
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Brief Summary
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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
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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

Official Title
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Phase 1-2 Study of Safety and Efficacy of Intrathecal Trastuzumab Administration in Metastatic HER2 Positive Breast Cancer Patients Developing Carcinomatous Meningitis

Conditions
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Metastatic Breast Cancer, Carcinomatous Meningitis

Intervention / Treatment
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* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab intrathecal<br> | Drug: Trastuzumab<br>* One injection per week during 8 weeks by lumbar puncture or Ommaya Reservoir. 4 levels of doses are expected from 30 mg to 150 mg<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route. | 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). | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I : Recommended dose (RD will be used in Phase II) |  | 2 months | 
| Phase I&II : Toxicity during treatment | Issued the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 National Cancer Institute (NCI) | 2 months | 
| Time to neurologic progression |  | 2 years | 
| Biological response: CSF cellularity and protein concentration |  | 2 years | 
| Radiological response: cerebrospinal meningitis and neuraxis MRI |  | 2 years | 
| Impact on quality of life |  | 2 years | 
| Impact on survival (overall survival, survival without neurological progression, progression-free survival) |  | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adverse Reaction to Trastuzumab Administered by intrathecal