intrathecal trastuzumab administration in metastatic breast cancer patients developing carcinomatous meningitis

Conditions: Metastatic Breast Cancer; Carcinomatous Meningitis

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

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

Eligibility criteria:
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 \ 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)

Keywords: adverse reaction to trastuzumab administered by intrathecal