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Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma

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Abstract

Purpose: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. Patients and methods: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m2 IV over 1 hour daily × 3 days every 3 weeks. Patients were assessed for response every 2 cycles. Results: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8–9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received ≥90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. Conclusions: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.

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References

  1. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK (eds): SEER Cancer Statistics Review, 1973–1999, National Cancer Institute, Bethesda, MD, 2002. http://seer.cancer.gov/csr/1973_1999

    Google Scholar 

  2. National Cancer Institute of Canada: Canadian Cancer Statistics, Toronto, Canada, 2002. http://www.ncic.cancer.ca

  3. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19: 3635–3648, 2001

    Google Scholar 

  4. Lakhani S, Selby P, Bliss JM, Perren TJ, Gore ME, McElwain TJ: Chemotherapy for malignant melanoma: Combinations and high doses produce more responses without survival benefit. Br J Cancer 61: 330–334, 1990

    CAS  PubMed  Google Scholar 

  5. Kirkwood JM: Melanoma. In: De Vita VT, Hellman S, Rosenberg SA (eds) Biologic Therapy of Cancer. Lippincott, Philadelphia, 1995, pp 388–411

  6. Legha SS, Ring S, Eton O, Bedikian A, Buzaid AC, Plager C, Papadopoulos N: Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 16: 1752–1759, 1998

    CAS  PubMed  Google Scholar 

  7. Tang L, Li G, Tron VA, Trotter MJ, Ho VC: Expression of cell cycle regulators in human cutaneous malignant melanoma. Melanoma Res 9: 148–154, 1999

    CAS  PubMed  Google Scholar 

  8. Rizos H, Darmanian AP, Indsto JO, Shannon JA, Kefford RF, Mann GJ: Multiple abnormalities of the p16INK4a-pRb regulatory pathway in cultured melanoma cells. Melanoma Res 9: 10–19, 1999

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Carlson BA, Pearlstein RA, Naik RG, Sedlacek HH, Sausville EA, Worland PJ: Inhibition of CDK2, CDK4, and CDK7 by flavopiridol and structural analogues (Abstract). Proc Am Assoc Cancer Res 37: 424, 1996

    Google Scholar 

  11. Bible KC, Kaufmann SH: Flavopiridol. A cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells. Cancer Res 56: 4856–4861, 1996

    CAS  PubMed  Google Scholar 

  12. Kaur G, Stetler-Stevenson M, Sebers S, Worland P, Sedlacek H, Myers C, Czech J, Naik R, Sausville E: Growth inhibition with reversible cell-cycle arrest of carcinoma cells by flavone L86-8275. J Natl Cancer Inst 84: 1736–1749, 1992

    CAS  PubMed  Google Scholar 

  13. Investigator’s Brochure, HMR 1275, 1st edition. Hoechst Marion Roussel, Inc., Bridgewater, NJ 1998

  14. Patel V, Senderowicz AM, Pinto D Jr, Igishi T, Raffeld M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS: Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J Clin Invest 102: 1674–1681, 1998

    CAS  PubMed  Google Scholar 

  15. Arguello F, Alexander M, Sterry JA, Tudor G, Smith EM, Kalavar NT, Greene JF Jr, Koss W, Morgan CD, Stinson SF, Siford TJ, Alvord WG, Klabansky RL, Sausville EA: Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts. Blood 91: 2482–2490, 1998

    CAS  PubMed  Google Scholar 

  16. Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, Hill K, Steinberg SM, Figg WD, Tompkins A, Arbuck SG, Sausville EA: Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor in patients with refractory neoplasms. J Clin Oncol 16: 2986–2999, 1998

    CAS  PubMed  Google Scholar 

  17. Stadler WM, Vogelzang NJ, Amato R, Sosman J, Taber D, Liebowitz D, Vokes EE: Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: A University of Chicago Phase II Consortium study. J Clin Oncol 18: 371–375, 2000

    CAS  PubMed  Google Scholar 

  18. Schwartz GK, Ilson D, Saltz L, O’Reilly E, Tong W, Maslak P, Werner J, Perkins P, Stoltz M, Kelsen D: Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 19: 1985–1992, 2001

    CAS  PubMed  Google Scholar 

  19. Shapiro GI, Supko JG, Patterson A, Lynch C, Lucca J, Zacarola PF, Muzikansky A, Wright JJ, Lynch TJ Jr, Rollins BJ: A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. Clinical Cancer Research 7: 1590–1599, 2001

    CAS  PubMed  Google Scholar 

  20. Tan AR, Headlee D, Messmann R, Sausville EA, Arbuck SG, Murgo AJ, Melillo G, Zhai S, Figg WD, Swain SM, Senderowicz AM: Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol 20: 4074–4082, 2002.

    CAS  PubMed  Google Scholar 

  21. National Cancer Institute Clinical Trials Evaluation Program Common Toxicity Criteria Version 2.0, 6/99 update. http://ctep.cancer.gov/forms/CTCManual_v4_10-4-99.pdf

  22. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatments in solid tumors (RECIST guidelines). J Natl Cancer Inst 92: 205–216, 2000

    Article  CAS  PubMed  Google Scholar 

  23. Li Y, Chinni SR, Senderowicz AM, Sarkar FH: Induction of growth inhibition and apoptosis in prostate cancer cells by flavopiridol. Int J Oncol 17: 755–759, 2000

    CAS  PubMed  Google Scholar 

  24. Robey RW, Medina-Perez WY, Nishiyama K, Lahusen T, Miyake K, Litman T, Senderowicz AM, Ross DD, Bates SE: Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cell lines. Clinical Cancer Research 7: 145–152, 2001

    CAS  PubMed  Google Scholar 

  25. Smith V, Raynaud F, Workman P, Kelland LR: Characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol. Molecular Pharmacology 60: 885–893, 2001

    CAS  PubMed  Google Scholar 

  26. Kahn ME, Senderowicz A, Sausville EA, Barrett KE: Possible mechanisms of diarrheal side effects associated with the use of a novel chemotherapeutic agent, flavopiridol. Clinical Cancer Research 7: 343–349, 2001

    CAS  PubMed  Google Scholar 

  27. Bernhard J, Thurlimann B, Schmitz SF, Castiglione-Gertsch M, Cavalli F, Morant R, Fey MF, Bonnefoi H, Goldhirsch A, Hurny C: Defining clinical benefit in postmenopausal patients with breast cancer under second-line endocrine treatment: does quality of life matter? J Clin Oncol 17: 1651–1653, 1999

    PubMed  Google Scholar 

  28. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15: 2403–2413, 1997

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. McGill University, Montreal, Quebec, Canada

    Susan Burdette-Radoux

  2. Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada

    Richard G. Tozer

  3. London Regional Cancer Centre, London, Ontario, Canada

    Reinhard C. Lohmann

  4. Princess Margaret Hospital, Toronto, Ontario, Canada

    Ian Quirt

  5. Tom Baker Cancer Centre, Calgary, Alberta, Canada

    D. Scott Ernst

  6. NCIC Clinical Trials Group, Kingston, Ontario, Canada

    Wendy Walsh, Nancy Wainman & Elizabeth A. Eisenhauer

  7. NCI/CTEP, Rockville, MD, USA

    A. Dimitrios Colevas

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  1. Susan Burdette-Radoux
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  2. Richard G. Tozer
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  3. Reinhard C. Lohmann
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  4. Ian Quirt
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  5. D. Scott Ernst
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  6. Wendy Walsh
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  7. Nancy Wainman
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  8. A. Dimitrios Colevas
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  9. Elizabeth A. Eisenhauer
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Burdette-Radoux, S., Tozer, R.G., Lohmann, R.C. et al. Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma. Invest New Drugs 22, 315–322 (2004). https://doi.org/10.1023/B:DRUG.0000026258.02846.1c

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  • DOI: https://doi.org/10.1023/B:DRUG.0000026258.02846.1c

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