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Intrathecal Trastuzumab Administration in Metastatic Breast Cancer Patients Developing Carcinomatous Meningitis

Information source: Institut Curie
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Metastatic Breast Cancer; Carcinomatous Meningitis

Intervention: Trastuzumab (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Institut Curie

Official(s) and/or principal investigator(s):
Maya Gutierrez, MD, Study Director, Affiliation: Institut Curie - Hopital Rene Huguenin - Saint-Cloud - France

Overall contact:
Emmanuelle Fourme, MD, Phone: +33 1 47 11 16 59, Email: emmanuelle.fourme@curie.net

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

Clinical Details

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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route.

Secondary outcome:

Phase I : Recommended dose (RD will be used in Phase II)

Phase I&II : Toxicity during treatment

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

FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer

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

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

- 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)

Locations and Contacts

Emmanuelle Fourme, MD, Phone: +33 1 47 11 16 59, Email: emmanuelle.fourme@curie.net

François Baclesse Center, Caen, Calvados 14076, France; Recruiting
Gunzer Katharina, MD, Phone: +33231455002, Email: k.gunzer@baclesse.fr
Gunzer Katharina, MD, Principal Investigator

Rene Huguenin Hospital, Saint-Cloud, Haut de Seine 92210, France; Recruiting
Maya Gutierrez, MD, Phone: +33147111515, Email: maya.gutierrez@curie.net
Maya Gutierrez, MD, Principal Investigator

Institut Curie - Claudius Regaud Hospital, Paris, Ile de France 75248, France; Recruiting
DIERAS Veronique, MD, Phone: +33144324675, Email: veronique.dieras@curie.net
Dieras Veronique, MD, Principal Investigator

Pitie Salpetriere Hospital, Paris, Ile de France 75651, France; Recruiting
Taillibert Sophie, MD, Phone: +33142160385, Email: sophie.taillibert@psl.aphp.fr
Taillibert Sophie, MD, Principal Investigator

Oscar Lambret Center, Lille, Nord 59020, France; Recruiting
Le Rhun Emilie, MD, Phone: +33320295935, Email: e-lerhun@o-lambret.fr
Le Rhun Emilie, MD, Principal Investigator

Léon Bérard Center, Lyon, Rhone 69373, France; Recruiting
Tredan Olivier, MD, Phone: +33478782644, Email: tredan@lyon.fnclcc.fr

Additional Information

Starting date: May 2011
Last updated: September 5, 2014

Page last updated: August 23, 2015

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