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Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies

  • Phase I Clinical Trials
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Summary

Purpose

To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF.

Patients and methods

Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m2 on day 1; GM-CSF (5 Μg/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC).

Results

Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m2/day. Therefore, we conclude the MTD was 37 mg/m2/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) < 500/mm3.

Conclusion

The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.

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References

  1. Schulz G, Frisch J, Greifenberg B, Nicolay U, Oster W: New therapeutic modalities for the clinical use of rhGM-CSF in patients with malignancies. Am J Clin Oncol 14(suppl 1):S19–S26, 1991

    PubMed  Google Scholar 

  2. Lieschke GJ, Burgess AW: Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med 327:28–35, 99–106, 1992

    PubMed  Google Scholar 

  3. Shpall EJ, Jones RB, Holland JF, Bhardwaj S, Paciucci PA, Wilfinger CL, Strashun A: Intensive single-agent mitoxantrone for metastatic breast cancer. J Natl Cancer Inst 80:204–208, 1988

    PubMed  Google Scholar 

  4. LeMaistre CF, Herzig R: Mitoxantrone: potential for use in intensive therapy. Semin Onco 17(suppl 3):43–48, 1990

    Google Scholar 

  5. Lewkow L, Hooker J, Raab M, Morahed A, Chamberlain J, Dainer P, Knupp C, Raab SO: Phase I–II study of dose intensive mitoxantrone and cyclophosphamide with autologous bone marrow transplantation (ABMT) in metastatic breast cancer. Proc Am Soc Clin Oncol 9:38(abstract 145), 1990

    Google Scholar 

  6. Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian cancer. J Clin Oncol 5:756–767, 1987

    PubMed  Google Scholar 

  7. McKenzie RS, Alberts DA, Bishop MR, McCloskey T, Sosman JA, Doran JR, Koch D, Fisher RI, Stiff PJ: Phase I trial of high dose cyclophosphamide (CY), mitoxantrone (MX), and carboplatin (CB) with autologous bone marrow transplantation (ABMT) in female malignancies: pharmacologic levels of mitoxantrone and high response rate in refractory ovarian cancer. Proc Am Soc Clin Oncol 10:186(abstract 605), 1991

    Google Scholar 

  8. Wallerstein R, Spitzer G, Dunphy F, Huan S, Hortogagyi G, Yau J, Buzdar A, Holmes F, Theriault R, Ewer M, LeMaistre CF, Dicke K, Deisseroth A: A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer. J Clin Oncol 8:1782–1788, 1990

    PubMed  Google Scholar 

  9. Mulder POM, Sleijfer DT, Willemse PHB, de Vries EGE, Uges DRA, Mulder NH: High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors. Cancer Res 49:4654–4658, 1989

    PubMed  Google Scholar 

  10. Bronchud MH, Howell A, Crowther D, Hopwood P, Souza L, Dexter TM: The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer 60:121–125, 1989

    PubMed  Google Scholar 

  11. Tourani JM, Levy R, Colonna P, Desablens B, Leprise P-Y, Guilhot F, Brahimi S, Belhani M, Ifrah N, Sensebe L, Lemevel A, Lotz J-P, LeMaignan C, Andrieu J-M: Highdose salvage chemotherapy without bone marrow transplantation for adult patients with refractory Hodgkin's disease. J Clin Oncol 10:1086–1094, 1992

    PubMed  Google Scholar 

  12. Smith IE: Mitoxantrone (NovantroneO): a review of experimental and early clinical studies. Cancer Treat Rev 10:103–115, 1983

    Google Scholar 

  13. Faulds D, Balfour JA, Chrisp P, Langtry HD: Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs 41:400–449, 1991

    PubMed  Google Scholar 

  14. Henderson IC, Allegra JC, Woodcock T, Wolff S, Bryan S, Cartwright K, Dukart G, Henry D: Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J Clin Oncol 7:560–571, 1989

    PubMed  Google Scholar 

  15. Shenkenberg TD, Von Hoff DD: Mitoxantrone: a new anticancer drug with significant clinical activity. Ann Intern Med 105:67–81, 1986

    PubMed  Google Scholar 

  16. Saletan S: Mitoxantrone: an active, new antitumor agent with an improved therapeutic index. Cancer Treat Rep 14:297–303, 1987

    Google Scholar 

  17. Lawton F, Blackledge G, Mould J, Latief T, Watson R, Chetiyawardana AD: Phase II study of mitoxantrone in epithelial ovarian cancer. Cancer Treat Rep 71:627–629, 1987

    PubMed  Google Scholar 

  18. Frasci G, Pacelli R, Scala S: Intraperitoneal mitoxantrone via temporary catheter in patients with ovarian cancer: toxicity and feasibility evaluation. Adv Ther 7:124–135, 1990

    Google Scholar 

  19. Belani CP, Hiponia D, Engstrom C, Fishbein G, Eisenberger M, Aisner J, VanEcho DA: Combination of mitoxantrone (M) and cisplatin (C) for patients (FTS) with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 10:266(abstract 924), 1991

    Google Scholar 

  20. Cartei G, Rosa Bian A, Cendrone R, Collimedaglia P, Kolarich K, DeliaValentina M, Veronesi A, Coletti B, Antoci B: Evaluation of synergy with cis-platinum (DOP) in nonsmall cell lung cancer (NSCLC): interim report from a multicenter study. Proc Am Soc Clin Oncol 7:198(abstract 766), 1988

    Google Scholar 

  21. Von Hoff DD, Coltman CA, Forseth B: Activity of mitoxantrone in a human tumor cloning system. Cancer Res 41:1853–1855, 1981

    PubMed  Google Scholar 

  22. Alberts DS, Young L, Mason N, Salmon SE:In vitro evaluation of anticancer drugs against ovarian cancer at concentrations achievable by intraperitoneal administration. Semin Oncol 12(suppl 4):38–42, 1985

    Google Scholar 

  23. Groopman JE, Molina JM, Scadden DT: Hematopoietic growth factors. N Engl J Med 321:1449–1459, 1989

    PubMed  Google Scholar 

  24. Antman KS, Griffin JD, Elias A, Socinski MA, Ryan L, Cannistra SA, Oetta D, Whitley M, Frei E 3rd, Schnipper LE: Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy induced myelosuppression. N Engl J Med 319:593–598, 1988

    PubMed  Google Scholar 

  25. Ho AD, DelValle F, Haas R: Role of mitoxantrone, highdose cytosine arabinoside, and recombinant human GMCSF in aggressive non-Hodgkin's lymphoma. Hematol Blood Transfusion 34:656–660, 1992

    Google Scholar 

  26. Taylor KK, Jagannath S, Spitzer G, Spinolo JA, Tucker SL, Fogel B, Cabanillas FF, Hagemeister FB, Souza LM: Recombinant human granulocyte colony-stimulating factor hastens granulocyte recovery after high-dose chemotherapy and autologous bone marrow transplantation in Hodgkin's disease. J Clin Oncol 7:1791–1799, 1989

    PubMed  Google Scholar 

  27. Van Belle SJP, Schoemaker TJ, Verwey SL, Paalman ACA, McVie JG: Ion-paired high-performance liquid chromatographic determination of mitoxantrone in physiological fluids. J Chrom 337:73–80, 1985

    Google Scholar 

  28. Macpherson JS, Smyth JF, Clements JA, Ramsay MW, Wartington PS, Leonard RCF, Wolf CR: Pharmacokinetics and metabolism of mitoxantrone. Br J Cancer 50:252–253, 1984

    Google Scholar 

  29. Rstrip User Handbook. MicroMath Scientific Software, Salt Lake City, Utah, 1991

  30. Gibaldi M, Perrier D: Pharmacokinetics, 2nd ed. pp. 84–111. Marcel Dekker, New York, 1982

    Google Scholar 

  31. Dukart G, Barone JS: An overview of cardiac episodes following mitoxantrone administration. Cancer Treat Symn 3:35–41, 1984

    Google Scholar 

  32. Crossley RJ: Clinical safety and tolerance of mitoxantrone. Semin Oncol 11:54–58, 1984

    PubMed  Google Scholar 

  33. Posner LE, Dukart G, Goldberg J, Bernstein T, Cartwright K: Mitoxantrone: an overview of safety and toxicity. Invest New Drugs 3:123–132, 1985

    PubMed  Google Scholar 

  34. Clark GM, Tokaz LK, Von Hoff DD, Thoi LL, Coltman Jr CA: Cardiotoxicity in patients treated with mitoxantrone on Southwest Oncology Group Phase II protocols. Cancer Treat Symp 3:25–30, 1984

    Google Scholar 

  35. Dukart G, Iatropoulos MJ, Yacobi A: Comment on mitoxantrone. Drug Intelligence and Clin Pharm 19:216–218, 1985

    Google Scholar 

  36. Allen A: The cardiotoxicity of chemotherapeutic drugs. Semin Oncol 19:529–542, 1992

    PubMed  Google Scholar 

  37. Neidhart JA, Gochnour D, Roach R, Hoth D, Young D: A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol 4:672–677, 1986

    PubMed  Google Scholar 

  38. Cowan JD, Neidhart J, McClure S, Coltman CA, Gumbart C, Martini S, Hutchins LF, Stephens RL, Vaughn CB, Osborne CK: Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst 83:1077–1084, 1991

    PubMed  Google Scholar 

  39. Hainsworth JD, Andrews MB, Johnson DH, Greco FA: Mitoxantrone, fluorouracil, and high-dose leucovorin: an effective, well-tolerated regimen for metastatic breast cancer. J Clin Oncol 9:1731–1735, 1991

    PubMed  Google Scholar 

  40. Bennett JM, Muss MB, Doroshow JH, Wolf S, Krementz ET, Cartwright K, Dukart G, Reisman A, Schoch I: A randomized trial comparing mitoxantrone, cyclophosphamide, and with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast cancer. J Clin Oncol 6:1611–1620, 1988

    PubMed  Google Scholar 

  41. Dunphy F, Hortobagyi G, Buzdar A, Horwitz L, Yau J, Spinolo J, Jagannth S, Dicke K, Spitzer G: High response rate following chemotherapy failure in metastatic breast cancer using high-dose mitoxantrone/etoposide/thiotepa and autologous bone marrow support. Abstract 998. Proc Amer Ass Cancer Res 30:251, 1989

    Google Scholar 

  42. Ehninger G, Schuler U, Proksch B, Zeller KP, Blanz J: Pharmacokinetics and metabolism of mitoxantrone, a review. Clin Pharmacokinet 18:365–380, 1990

    PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue, 53792, Madison, WI

    Joan H. Schiller, Barry Storer, Rhoda Arzoomanian, Kendra Tutsch, Dona Alberti & David Spriggs

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  1. Joan H. Schiller
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Schiller, J.H., Storer, B., Arzoomanian, R. et al. Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies. Invest New Drugs 11, 291–300 (1993). https://doi.org/10.1007/BF00874427

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