Phase II study of irinotecan and temozolomide in breast cancer patients with progressing central nervous system disease

  • Michelle E. MeliskoEmail author
  • Michael Assefa
  • Jimmy Hwang
  • Amy DeLuca
  • John W. Park
  • Hope S. Rugo
Clinical trial



Breast cancer patients with progressing central nervous system (CNS) disease have limited treatment options. Few chemotherapy drugs with activity in breast cancer have well-documented CNS penetration. This phase 2 trial evaluated efficacy and safety of irinotecan 125 mg/m2 on days 1 and 15 with temozolomide 100 mg/m2 days 1–7 and days 15–21 of a 28 day cycle.


Breast cancer patients of any biological subtype and progressing brain metastases and/or leptomeningeal disease (LMD) were eligible. The primary endpoint was CNS response rate. Secondary endpoints were clinical benefit rate (CBR), time to progression (TTP), and overall survival (OS). Imaging studies evaluating intracranial and extracranial response were performed every 8 weeks.


Thirty patients were evaluable for safety and efficacy. The most common hematologic and non-hematologic adverse events were neutropenia, and nausea and fatigue, respectively. There were two confirmed CNS partial responses (PR) and five patients with stable disease in the CNS ≥ 16 weeks, resulting in a 7% PR and 23% CBR. Median TTP was 2.3 months (range 13–444 days), and median OS from treatment initiation until death was 4.9 months (range 20–1023 days). Excluding patients with LMD, median TTP and OS were 3.1 and 5.6 months, respectively. Only one patient progressed systemically before CNS progression.


The combination of irinotecan and temozolomide was well tolerated, demonstrated some clinical activity across multiple breast cancer subtypes with progressing CNS disease, and offers a reasonable option for patients who are not candidates for further radiation or clinical trials.


Breast cancer Brain metastases Chemotherapy Clinical trial Irinotecan Temozolomide 



This research was funded by Pfizer (Grant Number 2005-0811) and Merck & Co. (Grant Number A105089).

Compliance with ethical standards

Conflict of interest

Michelle Melisko has received funding for clinical trials (paid to the UC Regents) from: Genentech, Merck, Astra Zeneca, Novartis, Lilly, Puma, Celldex, Galena, Nektar, and Daewha Pharmaceuticals, and honorarium from Agendia. Hope Rugo has received funding (paid to the UC Regents) from Genentech, Pfizer, Merck, Astra Zeneca, Novartis, Lilly, Nektar, Macrogenics, Immunomedics, Odonate, OBI, Seattle Genetics, Eisai, and Daiichi, and travel funding from Daiichi, Mylan, Pfizer, Amgen, Merck and Puma. John Park has stock ownership in Merrimack Pharmaceuticals and is a member of the speaker’s bureau for Genentech and Pfizer. The remaining authors have no conflicts to disclose.

Ethical approval

This manuscript complies with all current laws of the country in which it was performed. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained by all individual participants included in the study and all procedures were performed after obtaining informed consent.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medicine, Division of Hematology and OncologyUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Wellstar Atlanta Medical CenterAtlantaUSA
  3. 3.Emeritus Professor, Department of Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoUSA

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