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

Sponsor
Institut Curie (Other)
Overall Status
Completed
CT.gov ID
NCT01373710
Collaborator
Hoffmann-La Roche (Industry), Centre Leon Berard (Other), Groupe Hospitalier Pitie-Salpetriere (Other), Centre Oscar Lambret (Other), Centre Francois Baclesse (Other), Institut Bergonié (Other), University Hospital, Toulouse (Other), Institut du Cancer de Montpellier - Val d'Aurelle (Other), University Hospital, Grenoble (Other)
34
Enrollment
10
Locations
1
Arm
82.7
Actual Duration (Months)
3.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

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

Study Design

Study Type:
Interventional
Actual Enrollment :
34 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (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
Actual Study Start Date :
May 19, 2011
Actual Primary Completion Date :
Apr 1, 2018
Actual Study Completion Date :
Apr 9, 2018

Arms and Interventions

Arm Intervention/Treatment
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 Names:
  • Herceptin

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route. [2 months]

      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

    1. Phase I : Recommended dose (RD will be used in Phase II) [2 months]

    2. Phase I&II : Toxicity during treatment [2 months]

      Issued the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 National Cancer Institute (NCI)

    3. Time to neurologic progression [2 years]

    4. Biological response: CSF cellularity and protein concentration [2 years]

    5. Radiological response: cerebrospinal meningitis and neuraxis MRI [2 years]

    6. Impact on quality of life [2 years]

    7. Impact on survival (overall survival, survival without neurological progression, progression-free survival) [2 years]

    8. Pharmacokinetics: dose of trastuzumab in CSF and plasma [2 months]

    9. FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer [2 years]

    10. Phase II : Determination of antitumor activity trastuzumab when administrated by IT or intra-ventricular in terms of neurological progression free survival at 2 months [2 month]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Locations

    Site City State Country Postal Code
    1 François Baclesse Center Caen Calvados France 14076
    2 Rene Huguenin Hospital Saint-Cloud Haut De Seine France 92210
    3 Institut Curie - Claudius Regaud Hospital Paris Ile De France France 75248
    4 Pitie Salpetriere Hospital Paris Ile De France France 75651
    5 Oscar Lambret Center Lille Nord France 59020
    6 Léon Bérard Center Lyon Rhone France 69373
    7 Institut Bergonié Bordeaux France 33076
    8 CHU Grenoble Grenoble France 38700
    9 Institut du Cancer de Montpellier Montpellier France 34298
    10 Institut Univesitaire du Cancer de Toulouse Toulouse France 31100

    Sponsors and Collaborators

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

    Investigators

    • Study Director: Maya Gutierrez, MD, Institut Curie - Hopital Rene Huguenin - Saint-Cloud - France

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Institut Curie
    ClinicalTrials.gov Identifier:
    NCT01373710
    Other Study ID Numbers:
    • 09/501/M
    • 2009-017218-63
    First Posted:
    Jun 15, 2011
    Last Update Posted:
    Jul 10, 2019
    Last Verified:
    Jul 1, 2019
    Keywords provided by Institut Curie
    Adverse Reaction to Trastuzumab Administered by intrathecal
    Additional relevant MeSH terms:
    Breast Neoplasms
    Meningeal Carcinomatosis
    Meningitis
    Trastuzumab

    Study Results

    No Results Posted as of Jul 10, 2019