Skip to main content

Advertisement

SpringerLink
Log in

A Phase I/II study of GTI-2040 and capecitabine in patients with renal cell carcinoma

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

Abstract

Background

Fluoropyrimidine based therapy has modest activity in patients with metastatic renal carcinoma and inhibition of ribonucleotide reductase is synergistic in model systems. GTI-2040 is a 20-mer phosphorothioate oligonucleotide complimentary to the R2 component of ribonucleotide reductase that has activity in renal cancer models.

Methods

Metastatic renal carcinoma patients without prior fluoropyrimidine therapy and normal organ function were treated with oral capecitabine 880 mg/m2 twice daily along with continuous infusion GTI-2040 starting at 148 mg/m2/day for 21 days, for each 28-day cycle. After completion of the phase I portion, the phase II study portion sought to rule out a null hypothesized 10% response rate versus an alternative 25% response rate utilizing α and β errors of 0.05 and 0.2, respectively. GTI-2040 pharmacokinetics and effects on ribonucleotide reductase expression in peripheral mononuclear cells were evaluated in a subset of patients.

Results

Based on one dose limiting toxicity in nine patients in the phase I portion, the phase II portion was conducted using the previously recommended 185 mg/m2/day dose of GTI-2040. Twenty-six patients were enrolled in the phase II portion to obtain 18 fully evaluable for response. Only one patient, treated at a GTI 2040 dose of 185 mg/m2/day in the phase I portion of the protocol, responded. Toxicities and GTI-2040 pharmacokinetics were consistent with previously reported results. R2 expression in peripheral mononuclear cells was too variable for accurate interpretation.

Conclusion

Further study of GTI-2040 and capecitabine in metastatic renal cancer at this dose and schedule is not indicated. Further study is necessary to determine whether lack of activity is due to inadequate target inhibition or inadequate effect of appropriate targeting.

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

Fig. 1

Similar content being viewed by others

References

  1. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  PubMed  CAS  Google Scholar 

  2. Motzer R J, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    Article  PubMed  CAS  Google Scholar 

  3. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13:688–696

    PubMed  CAS  Google Scholar 

  4. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB (2005) Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 23:133–141

    Article  PubMed  CAS  Google Scholar 

  5. George CM, Stadler WM (2003) The role of systemic chemotherapy in the treatment of kidney cancer. In: Figlin R (eds) Kidney cancer. Kluwer, Norwell

    Google Scholar 

  6. Heinemann V, Schulz L, Issels RD, Plunkett W (1995) Gemcitabine: a modulator of intracellular nucleotide and deoxynucleotide metabolism. Semin Oncol 22:11–18

    PubMed  CAS  Google Scholar 

  7. Stadler WM, Halabi S, Rini B, Ernstoff MS, Davila E, Picus J, Barrier R, Small EJ (2006) A phase II study of gemcitabine and capecitabine in metastatic renal cancer: a report of cancer and leukemia group B protocol 90008. Cancer 107:1273–1279

    Article  PubMed  CAS  Google Scholar 

  8. Stadler WM, Huo D, George C, Yang X, Ryan CW, Karrison T, Zimmerman TM, Vogelzang NJ (2003) Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimens for metastatic renal cancer. J Urol 170:1141–1145

    Article  PubMed  CAS  Google Scholar 

  9. Lee Y, Vassilakos A, Feng N, Lam V, Xie H, Wang M, Jin H, Xiong K, Liu C, Wright J, Young A (2003) GTI-2040, an antisense agent targeting the small subunit component (R2) of human ribonucleotide reductase, shows potent antitumor activity against a variety of tumors. Cancer Res 63:2802–2811

    PubMed  CAS  Google Scholar 

  10. Nocentini G (1996) Ribonucleotide reductase inhibitors: new strategies for cancer chemotherapy. Crit Rev Oncol Hematol 22:89–126

    Article  PubMed  CAS  Google Scholar 

  11. Huang A, Fan H, Taylor WR, Wright JA (1997) Ribonucleotide reductase R2 gene expression and changes in drug sensitivity and genome stability. Cancer Res 57:4876–4881

    PubMed  CAS  Google Scholar 

  12. Desai AA, Schilsky RL, Young A, Janisch L, Stadler WM, Vogelzang NJ, Cadden S, Wright JA, Ratain MJ (2005) A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors. Ann Oncol 16:958–965

    Article  PubMed  CAS  Google Scholar 

  13. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (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 (see comments). J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  14. Zhang W, Leighl N, Zawisza D, Moore MJ, Chen EX (2005) Determination of GTI-2040, a novel antisense oligonucleotide, in human plasma by using HPLC combined with solid phase and liquid–liquid extractions. J Chromatogr B Analyt Technol Biomed Life Sci 829:45–49

    Article  PubMed  CAS  Google Scholar 

  15. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10

    Article  PubMed  CAS  Google Scholar 

  16. Kish JA, Wolf M, Crawford ED, Leimert JT, Bueschen A, Neefe JR, Flanigan RC (1994) Evaluation of low dose continuous infusion 5-fluorouracil in patients with advanced and recurrent renal cell carcinoma. A Southwest Oncology Group Study. Cancer 74:916–919

    Article  PubMed  CAS  Google Scholar 

  17. Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M (2004) Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454–463

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology and Urology, University of Chicago, 5841 S. Maryland Ave, MC-2115, Chicago, IL, 60637, USA

    Walter M. Stadler

  2. Department of Surgery, Section of Hematology/Oncology and Urology, University of Chicago, 5841 S. Maryland Ave, MC-2115, Chicago, IL, 60637, USA

    Walter M. Stadler

  3. Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Ave, MC-2115, Chicago, IL, 60637, USA

    Apurva A. Desai

  4. Department of Medicine, Section of Hematology/Oncology, University of Southern California, 1441 E Lake Ave, Los Angeles, CA, 90033, USA

    David I. Quinn

  5. Medical Oncology, Cleveland Clinic Taussig Cancer Center, 9500 Euclid Ave, Cleveland, OH, 44195-0001, USA

    Ronald Bukowski

  6. Hematology/Oncology, SUNY Upstate Medical University, 750 East Adams Street Syracuse, New York, 13210, USA

    Bernard Poiesz

  7. Hematology/Oncology, Ochsner Clinic, 1514 Jefferson Hwy, New Orleans, LA, 70121-2483, USA

    Carl G. Kardinal

  8. Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA

    Nancy Lewis

  9. California Hem Onc Medical Group, 6801 Park Terr Ste 130, Los Angeles, CA, 90045, USA

    Alex Makalinao

  10. Clinical Development, Lorus Therapeutics Inc, 2 Meridian Rd, Toronto, Ontario, Canada, M9W 4Z7

    Peter Murray

  11. Hematology/Oncology, Wake Forest Comprehensive Cancer Center, Medical Center Blvd, Winston Salem, NC, 27157-1082, USA

    Frank M. Torti

Authors
  1. Walter M. Stadler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Apurva A. Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David I. Quinn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ronald Bukowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernard Poiesz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carl G. Kardinal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nancy Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alex Makalinao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Frank M. Torti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Walter M. Stadler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stadler, W.M., Desai, A.A., Quinn, D.I. et al. A Phase I/II study of GTI-2040 and capecitabine in patients with renal cell carcinoma. Cancer Chemother Pharmacol 61, 689–694 (2008). https://doi.org/10.1007/s00280-007-0524-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0524-6

Keywords

Search

Navigation