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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Institut Curie
Sponsor:
Collaborators:
Hoffmann-La Roche
Gustave Roussy, Cancer Campus, Grand Paris
Centre Leon Berard
Groupe Hospitalier Pitie-Salpetriere
Centre Oscar Lambret
Centre Francois Baclesse
Institut Bergonié
ICO Paul Papin
Information provided by (Responsible Party):
Institut Curie
ClinicalTrials.gov Identifier:
NCT01373710
First received: May 24, 2011
Last updated: September 5, 2014
Last verified: September 2014
  Purpose

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


Condition Intervention Phase
Metastatic Breast Cancer
Carcinomatous Meningitis
Drug: Trastuzumab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1-2 Study of Safety and Efficacy of Intrathecal Trastuzumab Administration in Metastatic HER2 Positive Breast Cancer Patients Developing Carcinomatous Meningitis

Resource links provided by NLM:


Further study details as provided by Institut Curie:

Primary Outcome Measures:
  • Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route. [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
    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 Outcome Measures:
  • Phase I : Recommended dose (RD will be used in Phase II) [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
  • Phase I&II : Toxicity during treatment [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
    Issued the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 National Cancer Institute (NCI)

  • Time to neurologic progression [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Biological response: CSF cellularity and protein concentration [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Radiological response: cerebrospinal meningitis and neuraxis MRI [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Impact on quality of life [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Impact on survival (overall survival, survival without neurological progression, progression-free survival) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Pharmacokinetics: dose of trastuzumab in CSF and plasma [ Time Frame: 2 months ] [ Designated as safety issue: Yes ]
  • FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Phase II : Determination of antitumor activity trastuzumab when administrated by IT or intra-ventricular in terms of neurological progression free survival at 2 months [ Time Frame: 2 month ] [ Designated as safety issue: No ]

Estimated Enrollment: 37
Study Start Date: May 2011
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Trastuzumab intrathecal Drug: Trastuzumab
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
Other Name: Herceptin

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01373710

Contacts
Contact: Emmanuelle Fourme, MD +33 1 47 11 16 59 emmanuelle.fourme@curie.net
Contact: Isabelle Turbiez, CRA + 33 11 47 11 16 59 isabelle.turbiez@curie.net

Locations
France
François Baclesse Center Recruiting
Caen, Calvados, France, 14076
Contact: Gunzer Katharina, MD    +33231455002    k.gunzer@baclesse.fr   
Principal Investigator: Gunzer Katharina, MD         
Rene Huguenin Hospital Recruiting
Saint-Cloud, Haut de Seine, France, 92210
Contact: Maya Gutierrez, MD    +33147111515    maya.gutierrez@curie.net   
Principal Investigator: Maya Gutierrez, MD         
Institut Curie - Claudius Regaud Hospital Recruiting
Paris, Ile de France, France, 75248
Contact: DIERAS Veronique, MD    +33144324675    veronique.dieras@curie.net   
Principal Investigator: Dieras Veronique, MD         
Pitie Salpetriere Hospital Recruiting
Paris, Ile de France, France, 75651
Contact: Taillibert Sophie, MD    +33142160385    sophie.taillibert@psl.aphp.fr   
Principal Investigator: Taillibert Sophie, MD         
Oscar Lambret Center Recruiting
Lille, Nord, France, 59020
Contact: Le Rhun Emilie, MD    +33320295935    e-lerhun@o-lambret.fr   
Principal Investigator: Le Rhun Emilie, MD         
Léon Bérard Center Recruiting
Lyon, Rhone, France, 69373
Contact: Tredan Olivier, MD    +33478782644    tredan@lyon.fnclcc.fr   
Sponsors and Collaborators
Institut Curie
Hoffmann-La Roche
Gustave Roussy, Cancer Campus, Grand Paris
Centre Leon Berard
Groupe Hospitalier Pitie-Salpetriere
Centre Oscar Lambret
Centre Francois Baclesse
Institut Bergonié
ICO Paul Papin
Investigators
Study Director: Maya Gutierrez, MD Institut Curie - Hopital Rene Huguenin - Saint-Cloud - France
  More Information

No publications provided

Responsible Party: Institut Curie
ClinicalTrials.gov Identifier: NCT01373710     History of Changes
Other Study ID Numbers: 09/501/M, 2009-017218-63
Study First Received: May 24, 2011
Last Updated: September 5, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Institut Curie:
Adverse Reaction to Trastuzumab Administered by intrathecal

Additional relevant MeSH terms:
Meningitis
Breast Neoplasms
Meningeal Carcinomatosis
Central Nervous System Infections
Central Nervous System Diseases
Nervous System Diseases
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Trastuzumab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 16, 2014