Skip to main content

Advertisement

SpringerLink
Log in

A drug interaction study evaluating the pharmacokinetics and toxicity of sorafenib in combination with capecitabine

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To address tolerability and a possible pharmacologic interaction of capecitabine with sorafenib.

Methods

Patients with advanced solid tumors (ECOG PS 0-1) were included. Cohort A received capecitabine 750 mg/m2 BID and Cohort B received capecitabine 1,000 mg/m2 BID, both for 14 days of a 21-day cycle. Steady-state PK was obtained for capecitabine alone, sorafenib alone, and in combination. Cohort C explored an alternate schedule of 7-day on/7-day off flat dose capecitabine 1,000 mg BID with continuous dosing of sorafenib 400 mg BID.

Results

A total of 32 patients were enrolled between February 08 and April 09. Hand-foot skin reaction (HFSR) was the primary toxicity with 16 (50%) of the 32 patients experiencing grade 3 events (75% occurring during cycles 1–2). Grade 3 HFSR defined the maximum tolerated dose (MTD) of Cohort C at 1,000 mg BID flat dose of capecitabine. Other grade 3/4 toxicities were rare (diarrhea 6%, mucositis 3%, and fatigue 3%). Capecitabine did not change the C max or AUC(0-12) of sorafenib. Co-administration of sorafenib with capecitabine 750 mg/m2 (n = 6 patients) increased capecitabine AUC(0–12) 15% and produced no change in the 5FU AUC(0–12). At the capecitabine 1,000 mg/m2 dose level (n = 12 pts), there was a 16% increase in capecitabine AUC(0–12) and an 8% increase in 5FU AUC(0–12). However, these trends were not statistically significant.

Conclusions

Co-administration of sorafenib resulted in a mild increase in capecitabine AUC, although not statistically significant. Capecitabine did not affect the exposure of sorafenib. The rate of grade 3 HFSR is concerning and limits the feasibility of prolonged dosing of sorafenib with capecitabine 1,000 mg/m2 on the 21-day schedule.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  PubMed  CAS  Google Scholar 

  2. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  PubMed  CAS  Google Scholar 

  3. Jemal A, Murray T, Ward E et al (2005) Cancer statistics, 2005. CA Cancer J Clin 55:10–30

    Article  PubMed  Google Scholar 

  4. Wilhelm SM, Carter C, Tang L et al (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109

    Article  PubMed  CAS  Google Scholar 

  5. Xeloda® Tablets package insert. New Jersey Roche Laboratories, Inc.:April 2006

  6. Bajetta E, Procopio G, Celio L et al (2005) Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 23:2155–2161

    Article  PubMed  CAS  Google Scholar 

  7. Theodoulou M, Dugan U, Feigin K et al (2008) A novel capecitabine dosing schedule combined with bevacizumab is safe and active in patients with metastatic breast cancer: a phase II study. J Clin Oncol 26:66s Abstract #1101

    Article  Google Scholar 

  8. Baselga J, Segalla JGM, Roche H et al (2009) SOLTI-0701: a double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with capecitabine (CAP) in patients with locally advanced breast cancer. Eur J Cancer (ECCO-EMSO) 7:3–4

    Google Scholar 

  9. Awada A, Gil T, Whenham N et al (2009) Phase I dose escalation trial evaluating the safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors. Eur J Cancer (EORTC-NCI-AACR) 4:33 (Abstract #98)

    Google Scholar 

  10. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, National cancer institute of the United States, National cancer institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  11. Lacouture ME, Wu S, Robert C et al (2008) Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 13:1001–1011

    Article  PubMed  CAS  Google Scholar 

  12. Gressett SM, Stanford BL, Hardwicke F (2006) Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract 12:131–141

    Article  PubMed  CAS  Google Scholar 

  13. Haller DG, Cassidy J, Clarke SJ et al (2008) Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 26:2118–2123

    Article  PubMed  CAS  Google Scholar 

  14. Chiorean EG, Sweeney CJ, Verschraegen CF et al (2007) Tolerability/safety of sunitinib (SU) on schedule 2/1 in combination with capecitabine (C) in patients (pts) with advanced solid tumors (STs): a phase I dose-finding study. ASCO Meeting Abstracts 26:3562

    Google Scholar 

  15. Nexavar® Tablets Package Insert. New Jersey Bayer HealthCare Pharmaceuticals, Inc.:2009

  16. Sweeney C, Verschraegen C, Chiorean G et al (2007) A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors. J Clin Oncol 25(18):3592

    Google Scholar 

  17. Miller KD, Chap LI, Holmes FA et al (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799

    Article  PubMed  CAS  Google Scholar 

  18. Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019

    Article  PubMed  CAS  Google Scholar 

  19. Hochster HS, Hart LL, Ramanathan RK et al (2008) Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 26:3523–3529

    Article  PubMed  CAS  Google Scholar 

  20. Bhargava P, Esteves B, Nosov DA et al (2009) Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC). J Clin Oncol (ASCO Meeting Abstracts) 27:5032

    Google Scholar 

  21. Sharma S, Abhyankar V, Burgess RE et al (2009) A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Ann Oncol

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA

    Jeffrey R. Infante, Suzanne F. Jones, Johanna C. Bendell, F. Anthony Greco, Denise A. Yardley, Cassie M. Lane, David R. Spigel, John D. Hainsworth & Howard A. Burris III

  2. Tennessee Oncology, PLLC, Nashville, TN, USA

    Jeffrey R. Infante, Suzanne F. Jones, Johanna C. Bendell, F. Anthony Greco, Denise A. Yardley, David R. Spigel, John D. Hainsworth & Howard A. Burris III

Authors
  1. Jeffrey R. Infante
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suzanne F. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johanna C. Bendell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. Anthony Greco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Denise A. Yardley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cassie M. Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David R. Spigel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John D. Hainsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Howard A. Burris III
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey R. Infante.

Additional information

This study was supported by a grant from Bayer Healthcare and Onyx Pharmaceuticals.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 31 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Infante, J.R., Jones, S.F., Bendell, J.C. et al. A drug interaction study evaluating the pharmacokinetics and toxicity of sorafenib in combination with capecitabine. Cancer Chemother Pharmacol 69, 137–144 (2012). https://doi.org/10.1007/s00280-011-1674-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-011-1674-0

Keywords

Search

Navigation