Phase I trial of the diphtheria toxin/interleukin-2 fusion protein DAB486IL-2: efficacy in mycosis fungoides and other non-Hodgkin's lymphomas.

The purpose of this study was to investigate the biologic activity of DAB486IL-2 when administered three times daily, in terms of toxicity, pharmacokinetics, and anti-tumor effects in patients with IL-2R expressing hematologic malignancies, especially mycosis fungoides. 20 patients were enrolled in this dose escalation phase I trial. Patient cohorts were treated at levels of 0.03 mg/kg, 0.05 mg/kg, 0.07 mg/kg and 0.09 mg/kg every 8 hours for a total of 12 doses, every 21 days as toxicity and response warranted. Eight patients experienced transient fevers associated with DAB486IL-2 administration. One patient experienced grade 3 hypotension, and a second developed fluid retention manifested as weight gain/pedal edema. Dose limiting toxicity consisted of one episode of transient grade 4 hepatic transaminase elevation, and 8 episodes of transient asymptomatic grade 3 hepatic transaminase elevation. At the maximum tolerated dose DAB486IL-2 exhibited biphasic clearance kinetics; transient receptor saturation may be one mechanism for this observation. Initial serum concentration and apparent steady state level (plateau) directly correlated with the dose administered, but no difference in area under the concentration curve with greater dose was observed. Biologic activity was noted in patients with mycosis fungoides with skin lesion clearing and relief of pruritus. One patient with mycosis fungoides, and one patient with a relapsed intermediate grade non-Hodgkin's lymphoma achieved partial responses. The novel mechanism of action, toxicity profile, and evidence of biologic activity in refractory cancer patients, support development of more active constructs of this agent; such trials are underway.

[1]  J. Reuben,et al.  Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor. , 1992, Blood.

[2]  T. Waldmann,et al.  The Multichain Interleukin-2 Receptor: A Target for Immunotherapy , 1988, Annals of Internal Medicine.

[3]  Kendall A. Smith,et al.  Interleukin 2 receptor‐targeted cytotoxicity. Receptor binding requirements for entry of a diphtheria toxin‐related interleukin 2 fusion protein into cells , 1990, European journal of immunology.

[4]  A. M. Zimmer,et al.  Monoclonal antibody therapy of lymphoproliferative disorders. , 1990, Oncology.

[5]  T. Chisesi,et al.  Evaluation of serum levels of soluble interleukin‐2 receptor in patients with chronic lymphoproliferative disorders of T‐lymphocytes , 1989, Cancer.

[6]  K. Yamaguchi,et al.  Elevated serum levels of soluble interleukin-2 receptors in HTLV-I--associated myelopathy. , 1989, The Journal of laboratory and clinical medicine.

[7]  F. Menestrina,et al.  Serum levels of soluble interleukin‐2 receptor in hairy cell leukaemia: a reliable marker of neoplastic bulk , 1989, British journal of haematology.

[8]  T. Uchiyama,et al.  Elevated serum-soluble interleukin-2 receptor (Tac antigen) levels in chronic myelogenous leukemia patients with blastic crisis. , 1989, Blood.

[9]  T. Strom,et al.  Cytotoxicity of interleukin 2-toxin toward lymphocytes from patients with adult T-cell leukemia. , 1989, Cancer research.

[10]  D. Longo,et al.  Elevated serum levels of soluble Tac peptide in adult T-cell leukemia: correlation with clinical status during chemotherapy. , 1988, Annals of internal medicine.

[11]  N. Kay,et al.  The malignant B cells from B-chronic lymphocytic leukemia patients release TAC-soluble interleukin-2 receptors. , 1988, Blood.

[12]  Jeffrey W. Clark,et al.  Serum soluble IL-2 receptor as a tumor marker in patients with hairy cell leukemia , 1988 .

[13]  T. Strom,et al.  Interleukin 2 receptor-targeted cytotoxicity. Interleukin 2 receptor- mediated action of a diphtheria toxin-related interleukin 2 fusion protein , 1988, The Journal of experimental medicine.

[14]  R. Foà,et al.  High serum levels of soluble interleukin 2 receptor in patients with B chronic lymphocytic leukemia. , 1987, Blood.

[15]  W. Bishai,et al.  Diphtheria toxin receptor binding domain substitution with interleukin-2: genetic construction and properties of a diphtheria toxin-related interleukin-2 fusion protein. , 1987, Protein engineering.

[16]  D. Nelson,et al.  Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. , 1985, Journal of immunology.

[17]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity , 1975, Nature.