Carcinomatous Meningitis, Metastatic Breast Cancer
Conditions
Keywords
Adverse Reaction to Trastuzumab Administered by intrathecal
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
Interventions
DRUGTrastuzumab
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
Sponsors
Hoffmann-La Roche
Centre Leon Berard
Groupe Hospitalier Pitie-Salpetriere
Centre Oscar Lambret
Centre Francois Baclesse
Institut Bergonié
University Hospital, Toulouse
Institut du Cancer de Montpellier - Val d'Aurelle
University Hospital, Grenoble
Institut Curie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Phase I&II : Toxicity during treatment | 2 months | Issued the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 National Cancer Institute (NCI) |
| Time to neurologic progression | 2 years | — |
| Biological response: CSF cellularity and protein concentration | 2 years | — |
| Radiological response: cerebrospinal meningitis and neuraxis MRI | 2 years | — |
| Phase I : Recommended dose (RD will be used in Phase II) | 2 months | — |
| 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 | — |
| Impact on quality of life | 2 years | — |
Countries
France
Outcome results
None listed