The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma.
BACKGROUND
L19-IL2, a tumour-targeting immunocytokine composed of the recombinant human antibody fragment L19 (specific to the alternatively-spliced EDB domain of fibronectin, a well characterised marker of tumour neo-vasculature) and of human IL2, has demonstrated strong therapeutic activity in animal cancer models. This phase I/II trial was performed to evaluate safety, tolerability, recommended phase II dose (RD) and early signs of activity of L19-IL2.


METHODS
Five cohorts of patients with progressive solid tumours (n=21) received an intravenous infusion of L19-IL2 (from 5 to 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 3 weeks. This treatment cycle was repeated up to six times. In the following expansion phase, patients with metastatic renal cell carcinoma (RCC) (n=12) were treated at the RD of L19-IL2. Clinical data and laboratory findings were analysed for safety, tolerability and activity.


RESULTS
Preclinical studies in rats and monkeys did not raise any safety concerns. The RD was defined to be 22.5 Mio IU IL2 equivalent. Pharmacokinetics of L19-IL2 was dose proportional over the tested range, with a terminal half-life of 2-3h. Toxicities were manageable and reversible with no treatment-related deaths. We observed stable disease in 17/33 patients (51%) and 15/18 with mRCC (83%) after two cycles. Median progression-free survival of RCC patients in the expansion phase of the study was 8 months (1.5-30.5).


CONCLUSIONS
L19-IL2 can be safely and repeatedly administered at the RD of 22.5 Mio IU IL2 equivalent in advanced solid tumours. Preliminary evaluation suggests clinical activity of L19-IL2 in patients with mRCC.
Johannsen
Manfred
M
Department of Urology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. manfred.johannsen@charite.de
Spitaleri
Gianluca
G
Curigliano
Giuseppe
G
Roigas
Jan
J
Weikert
Steffen
S
Kempkensteffen
Carsten
C
Roemer
Andreas
A
Kloeters
Christian
C
Rogalla
Patrik
P
Pecher
Gabriele
G
Miller
Kurt
K
Berndt
Alexander
A
Kosmehl
Hartwig
H
Trachsel
Eveline
E
Kaspar
Manuela
M
Lovato
Valeria
V
González-Iglesias
Reinerio
R
Giovannoni
Leonardo
L
Menssen
Hans D
HD
Neri
Dario
D
de Braud
Filippo
F
D000328:Adult; D000368:Aged; D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014057:Tomography, X-Ray Computed
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C554817:L19-IL2 immunocytokine; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins