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A phase II study of flavopiridol in patients with advanced renal cell carcinoma: results of Southwest Oncology Group Trial 0109

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Abstract

Purpose

Flavopiridol is a cyclin-dependent kinase inhibitor that prevents cell cycle progression and tumor growth. In initial phase I studies, encouraging responses were seen in advanced renal cell cancer (RCC). In a phase II study of flavopiridol given as a 72-h continuous infusion every 2 weeks in RCC, a response rate of 6% was seen but with considerable grade 3 or 4 asthenia, diarrhea, and thrombosis. Subsequently, an alternative 1-h bolus schedule was reported to have enhanced tolerability in a phase I trial. We therefore conducted a phase II study of this bolus regimen.

Methods

A total of 38 patients with advanced RCC were entered into this multi-institutional phase II study. Flavopiridol (50 mg/m2 per day) was administered by bolus intravenous injection daily for three consecutive days, repeated every 3 weeks.

Results

Out of 34 eligible patients, one complete response and three partial responses were observed, for an overall response rate of 12% (95% CI 3–27%). Of the 34 patients, 14 (41%) had stable disease (SD). The probability of not failing treatment by 6 months was 21% (95% CI 9–35%). Median overall survival time was 9 months (95% CI 8–18 months). The most common grade 3 or 4 toxicities were diarrhea (35%) and tumor pain (12%) along with anemia, dyspnea, and fatigue (9% each).

Conclusions

Flavopiridol at this dose and schedule is feasible with an acceptable toxicity profile. Flavopiridol has some modest biologic activity against advanced RCC, as evidenced by its single-agent objective response and SD rates.

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References

  1. Bible KC, Kaufmann SH (1997) Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res 57(16):3375–3380

    CAS  PubMed  Google Scholar 

  2. Byrd JC, Shinn C, Waselenko JK, et al (1998) Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood 92:3804–3816

    Google Scholar 

  3. Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ (1996) Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res 56:2973–2978

    Google Scholar 

  4. Carlson B, Lahusen T, Singh S, et al (1999) Downregulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res 59:4634–4641

    Google Scholar 

  5. Carlson B, Pearlstein R, Naik R, Sedlacek H, Sausville E, Worland PJ (1996) Inhibition of CDK2, CDK4 and CDK7 by flavopiridol and structural analogs (abstract). Proc Am Assoc Cancer Res 37:424

    Google Scholar 

  6. Couillard DR, deVere White RW (1995) Surgery of renal cell carcinoma. Urol Clin North Am 20:263–275

    Google Scholar 

  7. Flanigan RC, Salmon S, Blumenstein BA, et al (2001) Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345:1655–1659

    Article  CAS  PubMed  Google Scholar 

  8. Innocenti F, Stadler WM, Iyer L, Ramirez J, Vokes EE, Ratain MJ (2000) Flavopiridol metabolism in cancer patients is associated with the occurrence of diarrhea. Clin Cancer Res 6(9):3400–3405

    Google Scholar 

  9. Jung CP, Motwani MV, Schwartz GK (2001) Flavopiridol increases sensitization to gemcitabine in human gastrointestinal cancer cells lines and correlates with down-regulation of ribonucleotide reductase M2 subunit. Clin Cancer Res 7(8):2527–2536

    Google Scholar 

  10. Karp JE, Ross DD, Yang W, Tidwell ML, Wei Y, Greer J, Mann DL, Nakanishi T, Wright JJ, Colevas AD (2003) Timed sequential therapy of acute leukemia with flavopiridol: in vitro model for a phase I clinical trial. Clin Cancer Res 9(1):307–315

    Google Scholar 

  11. Kaur G, Stetler-Stevenson M, Sebers S, et al (1992) Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275. J Natl Cancer Inst 84:1736–1740

    Google Scholar 

  12. Konig A, Schwartz GK, Mohammad RM, Al-Katib A, Gabrilove JL (1997) The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines. Blood 90:4307–4312

    Google Scholar 

  13. Losiewicz MD, Carlson BA, Kaur G, Sausville EA, Worland PJ (1994) Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. Biochem Biophys Res Commun 201:589–595

    Google Scholar 

  14. Melillo G, Sausville EA, Cloud K, Lahusen T, Varesio L, Senderowicz AM (1999) Flavopiridol, a protein kinase inhibitor, down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes. Cancer Res 59:5433–5437

    Google Scholar 

  15. Motwani M, Rizzo C, Sirotnak F, She Y, Schwartz GK (2003) Flavopiridol enhances the effect of docetaxel in vitro and in vivo in human gastric cancer cells. Mol Cancer Ther 2(6):549–555

    Google Scholar 

  16. Motzer RJ, Bander NH, Nanus DM (1996) Renal cell carcinoma. N Engl J Med 335(12):865–875

    Article  CAS  PubMed  Google Scholar 

  17. Negrier S, Escudier B, Lasset C, et al (1998) Recombinant human interleukin 2, recombinant human interferon alfa-2a, or both in metastatic renal cell carcinoma. N Engl J Med 338:1272–1278

    Article  CAS  PubMed  Google Scholar 

  18. Parker BW, Kaur G, Nieves-Neira W, et al (1998) Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 91:458–465

    Google Scholar 

  19. Schwartz GK, O‘Reilly E, Ilson D, Saltz L, Sharma S, Tong W, Maslak P, Stoltz M, Eden L, Perkins P, Endres S, Baraazzoul J, Spriggs D, Kelsen D (2002) Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol 20(8):2157–2170

    Google Scholar 

  20. Sedlacek HH, Czech J, Naik R, et al (1996) Flavopiridol (L86-8275, NSC-6498980), a new kinase inhibitor for tumor therapy. Int J Oncol 9:1143–1168

    Google Scholar 

  21. Senderowicz AM (1999) Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs 17(3):313–320

    Google Scholar 

  22. Senderowicz AM, Sausville EA (2000) Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 92:376–387

    Article  CAS  PubMed  Google Scholar 

  23. Shapiro GI, Koestner DA, Matranga CB, Rollins B (1999) Flavopiridol induces cell cycle arrest and p53-independent apoptosis in non-small cell lung cancer cell lines. Clin Cancer Res 5:2925–2938

    Google Scholar 

  24. Stadler WM, Vogelzang NJ, Amato R, et al (2000) Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a university of Chicago phase II consortium study. J Clin Oncol 18(2):371–375

    Google Scholar 

  25. Tan AR, Headlee D, Messmann R, et al (2002) Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol 20(19):4074–4082

    Google Scholar 

  26. Therasse P, Arbuck SG, Eisenhauer EA, et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  CAS  PubMed  Google Scholar 

  27. Worland PJ, Kaur G, Stetler-Stevenson M, Sebers S, Sartor O, Sausville EA (1993) Alteration of the phosphorylation state of p34cdc2 kinase by the flavone L86-8275 in breast carcinoma cells. Correlation with decreased H1 kinase activity. Biochem Pharmacol 46:1831–1840

    Google Scholar 

  28. Zhai S, Sausville EA, Senderowicz AM, Ando Y, Headlee D, Messman RA, Arbuck S, Murgo AJ, Melillo G, Fuse E, Figg WD (2003) Clinical pharmacologic and pharmacogenetics of flavopiridol 1-h iv infusion in patients with refractory neoplasms. Anticancer Drugs 14(2):125–135

    Google Scholar 

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Acknowledgements

We thank Dr. Catherine Tangen, PhD, for statistical advice and comments on this manuscript.

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Authors and Affiliations

  1. University of Kansas Medical Center, Kansas City, KS, USA

    Peter J. Van Veldhuizen

  2. Southwest Oncology Group Statistical Center, Seattle, WA, USA

    James R. Faulkner

  3. University of California, Davis, Sacramento, CA, USA

    Primo N. Lara Jr & Paul H. Gumerlock

  4. Ozarks Regional Community Clinical Oncology Program, Springfield, MO, USA

    J. Wendall. Goodwin

  5. Wichita Community Clinical Oncology Program, Wichita, KS, USA

    Shaker R. Dakhil

  6. Dayton Community Clinical Oncology Program, Dayton, OH, USA

    Howard M. Gross

  7. Loyola University Stritch School of Medicine, Maywood, IL, USA

    Robert C. Flanigan

  8. University of Colorado Health Science Center, Denver, CO, USA

    E. David. Crawford

  9. Veterans Affairs Medical Center, 4801 Linwood Blvd, Kansas City, MO, 64128, USA

    Peter J. Van Veldhuizen

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  1. Peter J. Van Veldhuizen
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  2. James R. Faulkner
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  3. Primo N. Lara Jr
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  7. Howard M. Gross
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Correspondence to Peter J. Van Veldhuizen.

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Van Veldhuizen, P.J., Faulkner, J.R., Lara, P.N. et al. A phase II study of flavopiridol in patients with advanced renal cell carcinoma: results of Southwest Oncology Group Trial 0109. Cancer Chemother Pharmacol 56, 39–45 (2005). https://doi.org/10.1007/s00280-004-0969-9

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  • DOI: https://doi.org/10.1007/s00280-004-0969-9

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