Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis.

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).

• Authors: Claire Bonneau, Gilles Paintaud, Olivier Trédan, Coraline Dubot, Céline Desvignes, Véronique Dieras, Sophie Taillibert, Patricia Tresca, Isabelle Turbiez, Jacques Li, Christophe Passot, Fawzia Mefti, Emmanuelle Mouret-Fourme, Emilie Le Rhun, Maya Gutierrez
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 95 Pg. 75-84 (05 2018) ISSN: 1879-0852 [Electronic] England
• PMID: 29635147 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Receptor, ErbB-2
• Trastuzumab

Topics

• Adult
• Aged
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Feasibility Studies
• Female
• Humans
• Injections, Spinal
• Maximum Tolerated Dose
• Meningeal Carcinomatosis (drug therapy, metabolism, secondary)
• Middle Aged
• Receptor, ErbB-2 (genetics, metabolism)
• Trastuzumab (administration & dosage, adverse effects, cerebrospinal fluid, pharmacokinetics)
• Young Adult