title: Safety, pharmacokinetics, and biological pharmacodynamics of the immunocytokine EMD 273066 (huKS-IL2): results of a phase I trial in patients with prostate cancer.
abstract: This phase 1 clinical trial was conducted to evaluate the safety and to determine the maximum tolerated dose (MTD) of the immunocytokine EMD 273066 huKS-IL2 and, secondarily, to assess its pharmacokinetics, immunogenic potential, and immunologic activity in patients with androgen-independent prostate cancer (n = 22). EMD 273066 was administered in 3-day cycles (separated by 4 weeks) of once-daily, 4-hour intravenous infusions at a dose determined by an escalation protocol (0.4, 0.7, 1.4, 2.8, 4.3, 6.4, or 8.5 mg/m/d). Approximately 2/3 of patients received a second cycle of treatment. The results show that the MTD of EMD 273066 [ie, one dose level below that producing dose-limiting toxicity (DLT) in at least 33% of patients in a dosing group] was 6.4 mg/m/d. EMD 273066 was generally well tolerated up to a dose of 4.3 mg/m/d. No DLTs, defined as drug-related toxicities >OR= Grade 3 occurring during the first treatment cycle, were observed among patients in the 0.4-, 0.7-, 1.4-, or 4.3-mg/m/d dosing groups. Four patients treated with 2.8, 6.4, or 8.5 mg/m/d EMD 273066 experienced DLTs. Titers of both antiimmunocytokine and anti-FcIL-2 antibody responses were observed after the first dose cycle and either decreased or remained stable during a second course of treatment. No hypersensitivity reactions were observed. EMD 273066 exhibited immunologic activity as demonstrated by increases in lymphocyte counts, natural killer cell number and specific activity, and antibody-dependent cellular cytotoxicity activity. On average, Cmax, which was dose-dependent, was achieved within 1 hour after infusion. Mean t(1/2) which was independent of dose, ranged from 4.0 to 6.7 hours across doses. A zero-compartment body model with one-order kinetics best described the concentration-time profiles. These data demonstrate that the novel immunocytokine EMD 273066 is well tolerated at doses above a level of observed systemic biologic activity in patients with androgen-independent prostate cancer.
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Yoo-Joung
authors.initials: YJ
authors.lastname: Ko
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Bubley
authors.forename: Robert
authors.initials: R
authors.lastname: Weber
authors.forename: Charles
authors.initials: C
authors.lastname: Redfern
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gold
authors.forename: Lothar
authors.initials: L
authors.lastname: Finke
authors.forename: Andreas
authors.initials: A
authors.lastname: Kovar
authors.forename: Thomas
authors.initials: T
authors.lastname: Dahl
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016207:Cytokines / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000378:metabolism; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013696:Temperature; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D007376:Interleukin-2; C494047:tucotuzumab celmoleukin