Clinical trial NCT01373710: Intrathecal Trastuzumab Administration in Metastatic Breast Cancer Patients Developing Carcinomatous Meningitis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Breast Cancer
Carcinomatous Meningitis
Keywords: Adverse Reaction to Trastuzumab Administered by intrathecal
Lead sponsor: Institut Curie
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
name: Centre Leon Berard
name: Groupe Hospitalier Pitie-Salpetriere
name: Centre Oscar Lambret
name: Centre Francois Baclesse
name: Institut Bergonié
name: University Hospital, Toulouse
name: Institut du Cancer de Montpellier - Val d'Aurelle
name: University Hospital, Grenoble
First posted: 2011-06-15
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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 \< 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)

Primary outcomes:
measure: Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route.
timeFrame: 2 months
Secondary outcomes:
measure: Phase I : Recommended dose (RD will be used in Phase II)
timeFrame: 2 months
measure: Phase I&II : Toxicity during treatment
timeFrame: 2 months
measure: Time to neurologic progression
timeFrame: 2 years
measure: Biological response: CSF cellularity and protein concentration
timeFrame: 2 years
measure: Radiological response: cerebrospinal meningitis and neuraxis MRI
timeFrame: 2 years
measure: Impact on quality of life
timeFrame: 2 years
measure: Impact on survival (overall survival, survival without neurological progression, progression-free survival)
timeFrame: 2 years
measure: Pharmacokinetics: dose of trastuzumab in CSF and plasma
timeFrame: 2 months
measure: FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer
timeFrame: 2 years
measure: Phase II : Determination of antitumor activity trastuzumab when administrated by IT or intra-ventricular in terms of neurological progression free survival at 2 months
timeFrame: 2 month
Other outcomes:
Locations:
city: Caen
country: France
facility: François Baclesse Center
state: Calvados
city: Saint-Cloud
country: France
facility: Rene Huguenin Hospital
state: Haut De Seine
city: Paris
country: France
facility: Institut Curie - Claudius Regaud Hospital
state: Ile De France
city: Paris
country: France
facility: Pitie Salpetriere Hospital
state: Ile De France
city: Lille
country: France
facility: Oscar Lambret Center
state: Nord
city: Lyon
country: France
facility: Léon Bérard Center
state: Rhone
city: Bordeaux
country: France
facility: Institut Bergonié
city: Grenoble
country: France
facility: CHU Grenoble
city: Montpellier
country: France
facility: Institut du Cancer de Montpellier
city: Toulouse
country: France
facility: Institut Univesitaire du Cancer de Toulouse
Study officials:
affiliation: Institut Curie - Hopital Rene Huguenin - Saint-Cloud - France
name: Maya Gutierrez, MD
role: STUDY_DIRECTOR
References:
citation: Bonneau C, Paintaud G, Tredan O, Dubot C, Desvignes C, Dieras V, Taillibert S, Tresca P, Turbiez I, Li J, Passot C, Mefti F, Mouret-Fourme E, Le Rhun E, Gutierrez M. Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis. Eur J Cancer. 2018 May;95:75-84. doi: 10.1016/j.ejca.2018.02.032. Epub 2018 Apr 7.