Intrathecal Trastuzumab Administration in Metastatic Breast Cancer Patients Developing Carcinomatous Meningitis (HIT)

Institut Curie

Status and phase

Completed

Phase 2

Phase 1

Conditions

Carcinomatous Meningitis

Metastatic Breast Cancer

Treatments

Drug: Trastuzumab

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT01373710

2009-017218-63 (EudraCT Number)

09/501/M

Details and patient eligibility

About

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

Full 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

Enrollment

34 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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)