Clinical Research Papers:

A Phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer

David M. Jackman _, Leigh Anne Cioffredi, Lorraine Jacobs, Farhana Sharmeen, Linda K. Morse, Joan Lucca, Scott R. Plotkin, Paul J. Marcoux, Michael S. Rabin, Thomas J. Lynch, Bruce E. Johnson and Santosh Kesari

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Oncotarget. 2015; 6:4527-4536. https://doi.org/10.18632/oncotarget.2886

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David M. Jackman1,2,*, Leigh A. Cioffredi4, Lorraine Jacobs5, Farhana Sharmeen1, Linda K. Morse1, Joan Lucca1, Scott R. Plotkin2,6, Paul J. Marcoux1,2, Michael S. Rabin1,2, Thomas J. Lynch7,8, Bruce E. Johnson1,2, Santosh Kesari3,*

1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

2Harvard Medical School, Boston, MA, USA

3Department of Neurosciences, Translational Neuro-Oncology Laboratories, Moores UCSD Cancer Center, University of California, San Diego, La Jolla CA, USA

4Georgetown University School of Medicine, Washington, DC, USA

5Eurofins Medinet B.V., Breda, The Netherlands

6Stephen E. & Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA

7Smilow Cancer Hospital at Yale-New Haven, Yale Cancer Center, New Haven, CT, USA

8Yale University, New Haven, CT, USA

*These authors have contributed equally to this work

Correspondence to:

David M. Jackman, e-mail: [email protected]

Santosh Kesari, e-mail: [email protected]

Keywords: non-small cell lung carcinoma, epidermal growth factor receptor, meningeal carcinomatosis, kinase inhibitors

Received: September 20, 2014     Accepted: December 09, 2014     Published: February 25, 2015


Introduction: There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI.

Methods: This phase I open-label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR-TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF).

Results: Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3months (range 1.6–4.0 months); median OS was 3.5months (range 1.6–5.1months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF.

Conclusion: Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high-dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation.

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