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

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 Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer; Carcinomatous Meningitis
• Intervention / Treatment: Drug: Trastuzumab

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 Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Institut Bergonié
  • Grenoble, France, 38700
    • Chu Grenoble
  • Montpellier, France, 34298
    • Institut du Cancer de Montpellier
  • Toulouse, France, 31100
    • Institut Univesitaire du Cancer de Toulouse
  • Calvados
    • Caen, Calvados, France, 14076
      • Francois Baclesse Center
  • Haut De Seine
    • Saint-Cloud, Haut De Seine, France, 92210
      • Rene Huguenin Hospital
  • Ile De France
    • Paris, Ile De France, France, 75248
      • Institut Curie - Claudius Regaud Hospital
    • Paris, Ile De France, France, 75651
      • Pitié Salpétrière Hospital
  • Nord
    • Lille, Nord, France, 59020
      • Oscar Lambret Center
  • Rhone
    • Lyon, Rhone, France, 69373
      • Leon Berard Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I : To determine the Trastuzumab maximum tolerated dose (MTD) when weekly administrated by intrathecal or intraventricular route.	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).	2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I : Recommended dose (RD will be used in Phase II)		2 months
Phase I&II : Toxicity during treatment	Issued the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 National Cancer Institute (NCI)	2 months
Time to neurologic progression		2 years
Biological response: CSF cellularity and protein concentration		2 years
Radiological response: cerebrospinal meningitis and neuraxis MRI		2 years
Impact on quality of life		2 years
Impact on survival (overall survival, survival without neurological progression, progression-free survival)		2 years
Pharmacokinetics: dose of trastuzumab in CSF and plasma		2 months
FCGR3A Genetic status influence on efficacy trastuzumab in metastatic breast cancer		2 years
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

Collaborators and Investigators

• Sponsor: Institut Curie
• Collaborators: Centre Leon Berard; Institut Bergonié; Hoffmann-La Roche; University Hospital, Grenoble; University Hospital, Toulouse; Groupe Hospitalier Pitie-Salpetriere; Institut du Cancer de Montpellier - Val d'Aurelle; Centre Oscar Lambret; Centre Francois Baclesse
• Investigators: Study Director: Maya Gutierrez, MD, Institut Curie - Hopital Rene Huguenin - Saint-Cloud - France

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2011
• Primary Completion (Actual): April 1, 2018
• Study Completion (Actual): April 9, 2018

Study Registration Dates

• First Submitted: May 24, 2011
• First Submitted That Met QC Criteria: June 14, 2011
• First Posted (Estimate): June 15, 2011

Study Record Updates

• Last Update Posted (Actual): July 10, 2019
• Last Update Submitted That Met QC Criteria: July 9, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Adverse Reaction to Trastuzumab Administered by intrathecal
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Meningeal Neoplasms; Breast Neoplasms; Meningitis; Meningeal Carcinomatosis; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab
• Other Study ID Numbers: 09/501/M; 2009-017218-63 (EudraCT Number)