Abstract #5059: A phase I dose-escalation study with the modified IL-2/anti-DNA immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumors: Preliminary results of safety, pharmacokinetics, immunogenicity, and biological effects
Authors: Silke Gillessen, Elisa Gallerani, Joachim Beck, Julien Laurent, Veit Erpenbeck, Daniel Speiser, Arnoud Templeton, Ulrike Gnad-Vogt, Cristiana Sessa, Roger Stupp
Journal: Cancer Research (2009)

Background: EMD 521873(Selectikine) is an immunocytokine consisting of a de-immunized, aglycosylated human antibody fused to genetically modified human interleukin-2 (IL-2). By binding to free DNA in micronecrotic areas of tumors, EMD 521873 delivers modified IL-2 to the tumor microenvironment, triggering an antitumor immune response in preclinical models. Selectivity of EMD 521873 for the high-affinity IL-2 receptor expressed on activated T cells may reduce acute vascular toxicity observed with normal IL-2. Methods: Patients with advanced solid tumors refractory to standard treatment were eligible. EMD 521873 was given as a 1-h intravenous infusion on days 1-3 q21d until tumor progression or unacceptable toxicity. Seven dose levels were explored in cohorts of 3-6 patients: 0.075 mg/kg, 0.15 mg/kg, 0.225 mg/kg, 0.3 mg/kg, 0.45 mg/kg, 0.6 mg/kg, and 0.9 mg/kg. The primary endpoint was occurrence of dose-limiting toxicities (DLTs) during cycle 1, defined as grade \#8805;3 (G3) adverse drug reactions. Secondary endpoints included pharmacokinetic (PK) parameters, immunogenicity, and changes in leukocyte subsets.The maximum tolerated dose (MTD) was defined as the dose level where \#8804;1 of 6 patients experienced DLTs. Preliminary results are reported. Results: Twenty-eight patients were enrolled in the first part of the trial receiving 67 cycles (median 2, range 1-10). Skin rash was the DLT observed in 2/6 patients treated at 0.9 mg/kg (and also 1/6 patients treated at 0.6 mg/kg). Other G\#8805;3 toxicities were: lymphopenia (G3, n=6), pulmonary embolism (G4, n=1), asymptomatic lipase increase (G3, n=1), partial thromboplastin time increase (G3, n=1), anorexia (G3, n=1), dyspnea (G3, n=1), and angioedema (G3, n=1). The most frequent attributable G1/G2 toxicities were skin rash, dry skin, erythema, hypotension, pyrexia, asthenia, anorexia, diarrhea, stomatitis, nausea, rhinorrhea, and conjunctivitis. PK analyses revealed a dose-dependent increase in maximum concentration and area under the concentration-time curve (AUC). Median serum half-life was 9.6 h (range 6.2-15.6 h). At the MTD, the AUC reached >2 x 104 IU*h/mL when based on IL-2 activity. Antibody responses occurred in 23/26 patients in cycle 1 but declined during treatment. The number of activated and effector CD4+ and CD8+ T cells in the peripheral blood increased in cycle 1 and cycle 2, while NK cells were only modestly increased, and only in cycle 1. Conclusion: EMD 521873 induced an IL-2-like cellular response in CD4+ and CD8+ T cells with less pronounced effects on NK cells. The DLT was skin rash; the MTD is 0.6 mg/kg. At the doses studied, severe hypotension or vascular leak were not observed. Updated results will be presented.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5059.