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A phase I evaluation of the combination of vinflunine and erlotinib in patients with refractory solid tumors

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Summary

Purpose. Epidermal growth factor receptor (EGFR) inhibition may overcome chemotherapy resistance by inhibiting important anti-apoptotic signals that are constitutively activated by an overstimulated EGFR pathway. Methods. This phase I dose escalation trial assessed the safety and efficacy of vinflunine, a novel vinca alkaloid microtubule inhibitor, with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with refractory solid tumors. Results. Seventeen patients were treated, 10 with continuous erlotinib, and 7 with intermittent erlotinib. At dose level 1, vinflunine 280 mg/m2 IV day 1 and erlotinib 75 mg PO days 2–21 (“continuous erlotinib”) in 21 day cycles, two of four patients experienced DLTs. At dose level −1 (vinflunine 250 mg/m2 every 21 days and erlotinib 75 mg/day), two of six patients experienced DLTs. The study was amended to enroll to “intermittent erlotinib” dosing: vinflunine day 1 and erlotinib days 2–15 of a 21 day cycle. Two of seven experienced DLTs and the study was terminated. One patient with breast cancer had a partial response; three had stable disease ≥6 cycles. All were treated in the continuous erlotinib group. Conclusions. Given the marked toxicity in our patient population, the combination of vinflunine and erlotinib cannot be recommended for further study with these dosing schemas.

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Funding

This work was supported by Bristol-Myers Squibb; Genentech; General Clinical Research Centers Program of Division of Research Resources, National Institutes of Health (RR00046); and K12 (RR025746 to H.K.S.); Alberta Heritage Foundation for Medical Research Clinical Fellowship (JMD); and Canadian Association of Medical Oncology Fellowship (JMD).

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology-Oncology, School of Medicine, University of North Carolina at Chapel Hill, 170 Manning Drive, 3rd Floor POB, CB 7305, Chapel Hill, NC, 27599-7305, USA

    Hanna K. Sanoff, Janine M. Davies, William Irvin, Bert H. O’Neil, Thomas E. Stinchcombe & E. Claire Dees

  2. Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Hanna K. Sanoff, Janine M. Davies, Christine Walko, William Irvin, Kimberly Keller, Anastasia Ivanova, Wing-Keung Chiu, Bert H. O’Neil, Thomas E. Stinchcombe & E. Claire Dees

  3. School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Christine Walko

  4. Department of Pharmacy, University of North Carolina Hospitals, Chapel Hill, NC, USA

    Larry Buie

Authors
  1. Hanna K. Sanoff
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  2. Janine M. Davies
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  3. Christine Walko
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  4. William Irvin
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  5. Larry Buie
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  6. Kimberly Keller
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  7. Anastasia Ivanova
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  8. Wing-Keung Chiu
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  9. Bert H. O’Neil
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  10. Thomas E. Stinchcombe
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  11. E. Claire Dees
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Correspondence to E. Claire Dees.

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Sanoff, H.K., Davies, J.M., Walko, C. et al. A phase I evaluation of the combination of vinflunine and erlotinib in patients with refractory solid tumors. Invest New Drugs 29, 978–983 (2011). https://doi.org/10.1007/s10637-010-9427-1

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  • DOI: https://doi.org/10.1007/s10637-010-9427-1

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