A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours.
BACKGROUND
EMD 521873 (Selectikine), an immunocytokine comprising a DNA-targeting antibody, aimed at tumour necrosis, fused with a genetically modified interleukin-2 (IL-2) moiety, was investigated in this first-in-human phase I study.


METHODS
Patients had metastatic or locally advanced solid tumours failing previous standard therapy. Selectikine was administered as a 1-hour intravenous infusion on 3 consecutive days, every 3 weeks. A subgroup of patients also received 300 mg/m(2) cyclophosphamide on day 1 of each cycle. Escalating doses of Selectikine were investigated with the primary objective of determining the maximum tolerated dose (MTD).


RESULTS
Thirty-nine patients were treated with Selectikine alone at dose levels from 0.075 to 0.9 mg/kg, and nine were treated at doses of 0.45 and 0.6 mg/kg in combination with cyclophosphamide. A dose-dependent linear increase of peak serum concentrations and area under curve was found. The dose-limiting toxicity was grade 3 skin rash at the 0.9 mg/kg dose-level; the MTD was 0.6 mg/kg. Rash and flu-like symptoms were the most frequent side-effects. No severe cardiovascular side-effects (hypotension or vascular leak) were observed. At all dose-levels, transient increases in total lymphocyte, eosinophil and monocyte counts were recorded. No objective tumour responses, but long periods of disease stabilisation were observed. Transient and non-neutralising Selectikine antibodies were detected in 69% of patients.


CONCLUSIONS
The MTD of Selectikine with or without cyclophosphamide administered under this schedule was 0.6 mg/kg. The recommended phase II dose was 0.45-0.6 mg/kg. Selectikine had a favourable safety profile and induced biological effects typical for IL-2.
Kantonsspital, St. Gallen, Switzerland.
Silke
S
Gillessen
Ulrike S
US
Gnad-Vogt
Elisa
E
Gallerani
Joachim
J
Beck
Cristiana
C
Sessa
Aurelius
A
Omlin
Maria R
MR
Mattiacci
Bernd
B
Liedert
Daniel
D
Kramer
Julien
J
Laurent
Daniel E
DE
Speiser
Roger
R
Stupp
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
D000970:Antineoplastic Agents; C578499:EMD 521873; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins