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Phase I trial of continuous infusion recombinant human interleukin-4 in patients with cancer

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Abstract

Background: A phase I study using recombinant human interleukin-4 (rhuIL-4) administered as a continuous intravenous infusion was conducted in patients with advanced cancer to study the toxicity profile and to determine the maximum tolerated dose (MTD) of this cytokine. Methods: Twenty-six patients with non-hematologic malignancies were treated with escalating doses of rhuIL-4 administered as 24-hour continuous intravenous infusion on days 1–5 and 15–19 every 28 days. The dose levels of rhuIL-4 were: dose level I—0.25 μg/kg/day (3 patients), dose level II—0.5 μg/kg/day (5 patients), dose level III—1.0 μg/kg/day (3 patients), dose level IV—2.0 μg/kg/day (10 patients) and dose level V—4.0 μg/kg/day (5 patients). Results: Dose limiting toxicity of continuous infusion rhuIL-4 occurred at 4.0 μg/kg/day D1–5 & 15–19, in three of five patients and consisted of hematologic (thrombocytopenia and prolongation of PT) and neurologic (headache and neurocortical toxicity) toxicity. A mild flu-like syndrome characterized by fever, chills, fatigue, headache, anorexia, arthralgias and myalgias was seen almost universally, occurred more commonly and with increasing severity with higher dose levels and resolved completely on discontinuing therapy with rhuIL-4. None of the enrolled patients had an objective response to treatment with continuous infusion rhuIL-4. Conclusions: A five-day continuous infusion of rhuIL-4 given biweekly is well tolerated with a MTD of 2.0 μg/kg/day.

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References

  1. Paul WE: Interleukin-4: A prototypic immunoregulatory lymphokine. Blood 77: 1859–1870, 1990

    Google Scholar 

  2. Howard M, Farrar J, Hilfiker M, Johnson B, Takatsu K, Hamaoka T, Paul WE: Identification of aT-cell derived B-cell growth factor distinct from interleukin 2. J Exp Med 155: 914, 1982

    Google Scholar 

  3. Spits H, Yssel H, Paliard X, Kastelein R, Figdor C, de Vries JE: IL-4 inhibits the IL-2 mediated induction of human lymphokineactivated killer cells, but not the generation of antigen-specific cytotoxic T lymphocytes in mixed leukocyte cultures. J Immunol 141: 29–36, 1998

    Google Scholar 

  4. Kawakami Y, Custer MC, Rosenberg SA, Lotze MT: IL-4 regulates IL-2 induction of lymphokine-activated killer activity from human lymphocytes. J Immunol 142: 3452–3461, 1989

    Google Scholar 

  5. Treisman J, Higuchi CM, Thompson JA, Gillis S, Lindgren CG, Kern DE, Ridell SR, Greenberg PD, Fefer A: Enhancement by interleukin 4 of interleukin 2 or antibody-induced proliferation of lymphocytes from interleukin 2 treated cancer patients. Cancer Res 50: 1160–1164, 1990

    Google Scholar 

  6. Martinez OM, Gibbons RS, Garovoy MR, Aronson FR: IL-4 inhibits IL-2 receptor expression and IL-2 dependent proliferation of human T-cells. J Immunol 144: 2211–2215, 1990

    Google Scholar 

  7. Higuchi CM, Thompson JA, Lindgren CG, Gillis S, Widmer MB, Kern DE, Fefer A: Induction of lymphokine activated killer activity by interleukin 4 in human lymphocytes preactivated by interleukin 2 in vivoor in vitro. Cancer Res 49: 6487–6492, 1989

    Google Scholar 

  8. Rougier N, Schmitt D, Vincent C: IL-4 addition during differentiation of CD34 progenitors delays maturation of dendritic cells while promoting their survival. Eur J Cell Biol 75: 287–293, 1998

    Google Scholar 

  9. Menetrier-Caux C, Thomachot MC, Alberti L, Montmain G, Blay JY: IL-4 prevents the blockade of dendritic cell differentiation induced by tumor cells. Cancer Res 61: 3096–3104, 2001

    Google Scholar 

  10. Hoon DSB, Banez M, Okun E, Morton DL, Irie RF: Modulation of human melanoma cells by interleukin-4 and in combination with ?-interferon or tumor necrosis factor. Cancer Res 51: 2002–2008, 1991

    Google Scholar 

  11. Morisaki T, Yuzuki DH, Lin RT, Foshag LJ, Morton DL, Hood DSB: Interleukin 4 receptor expression and growth inhibition of gastric carcinoma cells by interleukin 4. Cancer Res52: 6059–6065, 1992

    Google Scholar 

  12. Obiri NI, Hillman GG, Haas GP, Sud S, Puri RK: Expression of high affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitroby interleukin 4. J Clin Invest 91: 88–93, 1993

    Google Scholar 

  13. Topp MS, Papadimitriou CA, Eitelbach F, Oelmann E, Koehler B, Oberberg D, Von Marschall Z, Reufi B, Stein H, Thiel E: Recombinant human interleukin 4 has anti-proliferative activity on human tumor cell lines derived from epithelial and nonepithelial histologies. Cancer Res 55: 2173–2176, 1995

    Google Scholar 

  14. Tepper RI, Pattengale PK, Leder P: Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell 57: 503–512, 1989

    Google Scholar 

  15. Bosco M, Giovarelli M, Forni M, Modesti A, Scarpa S, Masuelli L, Forni G: Low doses of IL-4 injected perilymphatically in tumor-bearing mice inhibited the growth of poorly and apparently non-immunogenic tumors and induced a tumor-specific immune memory. J Immunol 145: 3136–3143, 1990

    Google Scholar 

  16. Whitehead RP, Unger JM, Goodwin JW, Walker MJ, Thompson JA, Flaherty LE, Sondak VK: Phase II trial of recombinant human interleukin-4 in patients with disseminated malignant melanoma: A southwest oncology group study. J Immunother 21: 440–446, 1998

    Google Scholar 

  17. Whitehead RP, Lew D, Flanigan RC, Geoffrey RW, Roy V, Glode WM, Dakhil SR, Crawford ED: Phase II trial of recombinant human interleukin-4 in patients with advanced renal cell carcinoma: A southwest oncology group study. J Immunother 25: 352–358, 2002

    Google Scholar 

  18. Stadler WM, Rybak ME, Vogelzang NJ: A phase II study of subcutaneous recombinant human interlieukin-4 in metastatic renal cell carcinoma. Cancer 76: 1629–1633, 1995

    Google Scholar 

  19. Vokes EE, Figlin R, Hochster H, Lotze M, Rybak ME. A phase II study of recombinant interleukin-4 for advanced or recurrent non-small cell lung cancer. Cancer J Sci Am 4: 46–51, 1998

    Google Scholar 

  20. Taylor CW, LeBlanc M, Fisher RI, Moore DF, Roach RW, Elias L, Miller TP: Phase II evaluation of interleukin-4 in patients with non-Hodgkin's lymphoma: A southwest oncology group trial. Anticancer Drugs 11: 695–700, 2000

    Google Scholar 

  21. Gilleece MH, Scarrfe JH, Ghosh A, Heyworth CM, Bonnem E, Testa N, Stern P, Dexter TM: Recombinant human interleukin 4 (IL-4) given as daily subcutaneous injections: A phase I dose toxicity trial. Br J Cancer 66: 204–210, 1992

    Google Scholar 

  22. Whitehead RP, Friedman KD, Clark DA, Pagani K, Rapp L: Phase I trial of simultaneous administration of interleukin 2 and interleukin 4 subcutaneously. Clin Cancer Res 1: 1145–1152, 1995

    Google Scholar 

  23. Olencki T, Finke J, Tubbs R, Tuason L, Greene T, McLain D, Swanson SJ, Herzog P, Stanley J, Edinger M, Budd GT, Bukowski RM: Immunomodulatory effects of interlukin-2 and interleukin-4 in patients with malignancy. J Immunother Emphasis Tumor Immunol 19: 69–80, 1996

    Google Scholar 

  24. Lundin J, Kimby E, Bergmann L, Karakas T, Mellstedt H, Osterborg A: Interleukin 4 therapy for patients with chronic lymphocytic leukemia: A phase I/II study. Br J Hematol 112: 155–160, 2001

    Google Scholar 

  25. Sosman JA, Fisher SG, Kefer C, Fisher RI, Ellis TM: A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients. Ann Oncol5: 447–452, 1994

    Google Scholar 

  26. Prendville J, Thatcher N, Lind M, McIntosh R, Ghosh A, Stern P, Crowther D: Recombinant human interleukin-4 (rhuIL-4) administered by the intravenous and subcutaneous routes in patients with advanced cancer-Aphase I toxicity study and pharmacokinetic analysis. Eur J Cancer 29: 1700–1707, 1993

    Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA

    Navneet S. Majhail

  2. Multiple Myeloma Research Program, Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA

    Mohamad Hussein

  3. Experimental Therapeutics Program, Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA

    Thomas E. Olencki, George T. Budd, Laura Wood & Ronald M. Bukowski

  4. Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, OH, USA

    Paul Elson

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  1. Navneet S. Majhail
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  2. Mohamad Hussein
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  3. Thomas E. Olencki
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  4. George T. Budd
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  5. Laura Wood
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  6. Paul Elson
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  7. Ronald M. Bukowski
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Majhail, N.S., Hussein, M., Olencki, T.E. et al. Phase I trial of continuous infusion recombinant human interleukin-4 in patients with cancer. Invest New Drugs 22, 421–426 (2004). https://doi.org/10.1023/B:DRUG.0000036684.67675.fe

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  • DOI: https://doi.org/10.1023/B:DRUG.0000036684.67675.fe

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