Intrathecal Trastuzumab Administration in Metastatic Breast Cancer Patients Developing Carcinomatous Meningitis

• Status: Completed
• Trial end date: 2018-04-09
• Target enrollment: 0
• Participant gender: All

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: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Institut Curie
• Collaborators: Centre Francois Baclesse; Centre Leon Berard; Centre Oscar Lambret; Groupe Hospitalier Pitie-Salpetriere; Hoffmann-La Roche; Institut Bergonié; Institut du Cancer de Montpellier - Val d'Aurelle; University Hospital, Grenoble; University Hospital, Toulouse
• Treatments: Trastuzumab

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 < 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 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)