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Phase I/IIa study of sequential chemotherapy regimen of bendamustine/irinotecan followed by etoposide/carboplatin in untreated patients with extensive disease small cell lung cancer (EDSCLC)

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Abstract

Purpose

The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS.

Methods

This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome.

Results

The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis.

Conclusions

B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.

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Funding

This study was supported by NCI 5P30 CA 13148. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Cephalon, Inc. d/b/a Teva Pharmaceuticals.

Author information

Authors and Affiliations

  1. Alabama Oncology, Shelby County, AL, USA

    Daniel J. Allendorf

  2. Georgia Cancer Specialists/Northside Hospital Cancer Institute, Atlanta, GA, USA

    Rodolfo E. Bordoni

  3. Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA

    Stefan C. Grant

  4. Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, WTI 210B, Birmingham, AL, 35294-3300, USA

    Mansoor N. Saleh & Francisco Robert

  5. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    Vishnu B. Reddy

  6. Clinical Studies Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Mary L. Jerome & Deborah K. Miley

  7. Clinical Trials Network Office, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Pamela M. Dixon

  8. Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Karan P. Singh

Authors
  1. Daniel J. Allendorf
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  2. Rodolfo E. Bordoni
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  3. Stefan C. Grant
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  4. Mansoor N. Saleh
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  5. Vishnu B. Reddy
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  6. Mary L. Jerome
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  7. Pamela M. Dixon
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  8. Deborah K. Miley
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  9. Karan P. Singh
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  10. Francisco Robert
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Corresponding author

Correspondence to Francisco Robert.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the UAB Institutional Review Board for Human Use, our Institution’s (UAB) Scientific Review Committee, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Allendorf, D.J., Bordoni, R.E., Grant, S.C. et al. Phase I/IIa study of sequential chemotherapy regimen of bendamustine/irinotecan followed by etoposide/carboplatin in untreated patients with extensive disease small cell lung cancer (EDSCLC). Cancer Chemother Pharmacol 76, 949–955 (2015). https://doi.org/10.1007/s00280-015-2869-6

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  • DOI: https://doi.org/10.1007/s00280-015-2869-6

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