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Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies

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Summary

Background. Sorafenib (a VEGFR and multi-targeted kinase inhibitor) and Bortezomib (a proteasome inhibitor) have clinical antineoplastic activities as single agents, and combine synergistically in preclinical models. Methods. This Phase I study was undertaken to define the toxicity and the maximum tolerated doses (MTD) of the combination in patients with advanced solid tumors. Patients with cytologic or histologic proof of unresectable solid tumors were treated with escalating doses of sorafenib (twice daily) and bortezomib (days 1, 4, 8 and 11 intravenously) with 21-day cycles. Results. Fourteen patients (7 males, median age 65, range 24–74), with renal (3), lung (3), pancreas (2), and breast, adrenal gland, melanoma, spindle cell tumor, chronic lymphocytic leukemia and multiple myeloma (1 each) were enrolled. All patients are off treatment, 10 due to disease progression. DLT was seen in two patients (one grade 3 abdominal pain and grade 4 lipase elevation; one with grade 3 vomiting) at sorafenib 200 mg twice daily and bortezomib 1.3 mg/m2, establishing the MTD. No grade 4 hematologic or grade 5 toxicities were seen. One patient with renal cell cancer had a partial response and 5 patients attained stable disease. Conclusions. The combination of sorafenib and bortezomib was tolerated well. The recommended phase 2 doses are sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m2 on days 1, 4, 8, 11 (21 day cycles). The combination shows preliminary signs of efficacy, supporting phase 2 studies.

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Acknowledgments

We are indebted to patients participating in this trial and to the enrolling investigators for their interest in and dedication to this study. We also thank the clinical research associates and research protocol specialists at the Mayo Clinic Cancer Center for commitment to the completion of this trial and for administrative assistance.

Funding

This work was supported by National Cancer Institute; CA69912.

Clinicaltrials.gov identifier: NCT00303797

Conflict of Interest

SKK has research funding for clinical trials from Millennium Pharmaceuticals and Onyx Pharmaceuticals, and has participated in advisory boards with Millennium Pharmaceuticals and Onyx Pharmaceuticals.

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Authors and Affiliations

  1. Divisions of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA

    Shaji K. Kumar, Svetomir N. Markovic & Scott H. Kaufmann

  2. Division of Medical Oncology and Department of Oncology, Mayo Clinic, Rochester, MN, USA

    James Jett, Randolph Marks, Ronald Richardson, Fernando Quevedo, Timothy Moynihan, Gary Croghan, Svetomir N. Markovic, Keith C. Bible, Angelina Tan, Julian Molina & Charles Erlichman

  3. Division of Biostatistical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    Rui Qin & Angelina Tan

  4. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    Alex A. Adjei

  5. Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Shaji K. Kumar

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  1. Shaji K. Kumar
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  2. James Jett
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Correspondence to Shaji K. Kumar.

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Kumar, S.K., Jett, J., Marks, R. et al. Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies. Invest New Drugs 31, 1201–1206 (2013). https://doi.org/10.1007/s10637-013-0004-2

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  • DOI: https://doi.org/10.1007/s10637-013-0004-2

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