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A Phase I Multi-Institutional Study of Systemic Sorafenib in Conjunction with Regional Melphalan for In-Transit Melanoma of the Extremity

  • Melanomas
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Isolated limb infusion with melphalan (ILI-M) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies.

Methods

A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months.

Results

A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics.

Conclusion

This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.

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Acknowledgment

Bayer provided drug only (sorafenib, Nexavar) for the phase I trial of systemic sorafenib and regional melphalan. This paper was supported in part by Duke University’s CTSA grant TL1RR024126 from NCRR/NIH (Coleman/Raymond), T32 grant CA093245-10 from NIH (Beasley), and the Duke Melanoma Research Fund (Tyler).

Author information

Authors and Affiliations

  1. Department of Surgery, Duke University, Durham, NC, USA

    G. M. Beasley MD, A. P. Coleman MD, A. Raymond MD, G. Sanders BS, C. Augustine PhD & D. S. Tyler MD

  2. Department of Pathology, Duke University, Durham, NC, USA

    M. A. Selim MD

  3. Cancer Center Biostatistics, Duke University, Durham, NC, USA

    B. L. Peterson PhD

  4. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA

    M. S. Brady MD

  5. Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA

    M. A. Davies MD, PhD

  6. Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas, USA

    M. A. Davies MD, PhD

  7. VA Medical Center, Durham, NC, USA

    C. Augustine PhD & D. S. Tyler MD

Authors
  1. G. M. Beasley MD
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  2. A. P. Coleman MD
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  5. M. A. Selim MD
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  8. M. A. Davies MD, PhD
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  9. C. Augustine PhD
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  10. D. S. Tyler MD
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Correspondence to G. M. Beasley MD.

Additional information

G.M. Beasley and A.P. Coleman contributed equally to this work.

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Beasley, G.M., Coleman, A.P., Raymond, A. et al. A Phase I Multi-Institutional Study of Systemic Sorafenib in Conjunction with Regional Melphalan for In-Transit Melanoma of the Extremity. Ann Surg Oncol 19, 3896–3905 (2012). https://doi.org/10.1245/s10434-012-2373-8

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  • DOI: https://doi.org/10.1245/s10434-012-2373-8

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