Claire Bonneau1, Gilles Paintaud2, Olivier Trédan3, Coraline Dubot4, Céline Desvignes2, Véronique Dieras5, Sophie Taillibert6, Patricia Tresca7, Isabelle Turbiez7, Jacques Li8, Christophe Passot2, Fawzia Mefti9, Emmanuelle Mouret-Fourme8, Emilie Le Rhun10, Maya Gutierrez11. 1. Department of Surgery, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France. 2. Université François-Rabelais de Tours, CNRS, GICC UMR 7292, CHRU de Tours, Service de Pharmacologie-Toxicologie, Tours, France. 3. Department of Oncology, Centre Leon Berard, 28 Prom. Léa et Napoléon Bullukian, 69008, Lyon, France. 4. Department of Oncology, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France. 5. Department of Oncology, Institut Curie, Hôpital Claudius Regaud, 26 Rue d'Ulm, 75005, Paris, France. 6. Department of Neurology Mazarin, Groupe Hospitalier Pitié Salpétrière, 47 bd del'hôpital, 75013, Paris, France; Assistance Publique des Hôpitaux de Paris, Paris, France; Université Pierre et Marie Curie, Paris VI, Paris, France. 7. Department of Clinical Research, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France. 8. Department of Epidemiology, Institut Curie, 26 Rue d'Ulm, 75005, Paris, France. 9. Department of Oncology, Clinique de La Porte Verte, 6 Avenue Maréchal Franchet D'Esperey, 78004, Versailles, France. 10. Lille University, Inserm U1192 PRISM, Villeneuve d'Ascq, France; Breast unit, Department of Medical Oncology, Oscar Lambret Center, 3 Rue Frédéric Combemale, 59000, Lille, France; Neuro-oncology, Department of Neurosurgery, University Hospital, Lille, France. 11. Department of Oncology, Institut Curie, Hôpital René Huguenin, 35 Rue Dailly, 92210, Saint Cloud, France. Electronic address: maya.gutierrez@curie.fr.
Abstract
PURPOSE: Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT). METHODS: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics. RESULTS: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease. CONCLUSIONS: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing. REGISTRATION IDENTIFICATION: ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1).
PURPOSE:Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT). METHODS: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics. RESULTS: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease. CONCLUSIONS: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing. REGISTRATION IDENTIFICATION: ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1).
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