Intrathecal Trastuzumab Administration in Metastatic Breast Cancer Patients Developing Carcinomatous Meningitis

Brief Summary

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

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

  • Study Type: Interventional
  • Study Design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
  • Study Primary Completion Date: May 2015

Detailed Clinical Trial 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

Interventions Used in this Clinical Trial

  • 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

Arms, Groups and Cohorts in this Clinical Trial

  • Experimental: Trastuzumab intrathecal

Outcome Measures for this Clinical Trial

Primary Measures

  • Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route.
    • Time Frame: 2 months
      Safety Issue?: Yes

Secondary Measures

  • Phase I : Recommended dose (RD will be used in Phase II)
    • Time Frame: 2 months
      Safety Issue?: Yes
  • Phase I&II : Toxicity during treatment
    • Time Frame: 2 months
      Safety Issue?: Yes
  • Time to neurologic progression
    • Time Frame: 2 years
      Safety Issue?: No
  • Biological response: CSF cellularity and protein concentration
    • Time Frame: 2 years
      Safety Issue?: No
  • Radiological response: cerebrospinal meningitis and neuraxis MRI
    • Time Frame: 2 years
      Safety Issue?: No
  • Impact on quality of life
    • Time Frame: 2 years
      Safety Issue?: No
  • Impact on survival (overall survival, survival without neurological progression, progression-free survival)
    • Time Frame: 2 years
      Safety Issue?: No
  • Pharmacokinetics: dose of trastuzumab in CSF and plasma
    • Time Frame: 2 months
      Safety Issue?: Yes
  • FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer
    • Time Frame: 2 years
      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
      Safety Issue?: No

Criteria for Participation in this Clinical Trial

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)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • Institut Curie
  • Collaborator
    • Hoffmann-La Roche
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Maya Gutierrez, MD, Study Director, Institut Curie – Hopital Rene Huguenin – Saint-Cloud – France
  • Overall Contact(s)
    • Emmanuelle Fourme, MD, +33 1 47 11 16 59, emmanuelle.fourme@curie.net

Source

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The URL of this page is:
http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01373710