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

Manfred Johannsen, Gianluca Spitaleri, Giuseppe Curigliano, Jan Roigas, Steffen Weikert, Carsten Kempkensteffen, Andreas Roemer, Christian Kloeters, Patrik Rogalla, Gabriele Pecher, Kurt Miller, Alexander Berndt, Hartwig Kosmehl, Eveline Trachsel, Manuela Kaspar, Valeria Lovato, Reinerio González-Iglesias, Leonardo Giovannoni, Hans D. Menssen, Dario NeriFilippo De Braud

Research output: Contribution to journalArticle

Abstract

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. Patients and 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 2-3 h. 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.

Original languageEnglish
Pages (from-to)2926-2935
Number of pages10
JournalEuropean Journal of Cancer
Volume46
Issue number16
DOIs
Publication statusPublished - Nov 2010

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Renal Cell Carcinoma
Interleukin-2
Clinical Trials
Safety
Neoplasms
L19-IL2 immunocytokine
Immunoglobulin Fragments
Tumor Biomarkers
Fibronectins
Intravenous Infusions
Disease-Free Survival
Haplorhini
Half-Life
Therapeutics
Animal Models
Pharmacokinetics

Keywords

  • Immunotherapy
  • Phase I/II study
  • Renal cell carcinoma
  • Solid tumours

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Johannsen, Manfred; Spitaleri, Gianluca; Curigliano, Giuseppe; Roigas, Jan; Weikert, Steffen; Kempkensteffen, Carsten; Roemer, Andreas; Kloeters, Christian; Rogalla, Patrik; Pecher, Gabriele; Miller, Kurt; Berndt, Alexander; Kosmehl, Hartwig; Trachsel, Eveline; Kaspar, Manuela; Lovato, Valeria; González-Iglesias, Reinerio; Giovannoni, Leonardo; Menssen, Hans D.; Neri, Dario; De Braud, Filippo.

In: European Journal of Cancer, Vol. 46, No. 16, 11.2010, p. 2926-2935.

Research output: Contribution to journalArticle

Johannsen, M, Spitaleri, G, Curigliano, G, Roigas, J, Weikert, S, Kempkensteffen, C, Roemer, A, Kloeters, C, Rogalla, P, Pecher, G, Miller, K, Berndt, A, Kosmehl, H, Trachsel, E, Kaspar, M, Lovato, V, González-Iglesias, R, Giovannoni, L, Menssen, HD, Neri, D & De Braud, F 2010, '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', European Journal of Cancer, vol. 46, no. 16, pp. 2926-2935. https://doi.org/10.1016/j.ejca.2010.07.033
Johannsen, Manfred ; Spitaleri, Gianluca ; Curigliano, Giuseppe ; Roigas, Jan ; Weikert, Steffen ; Kempkensteffen, Carsten ; Roemer, Andreas ; Kloeters, Christian ; Rogalla, Patrik ; Pecher, Gabriele ; Miller, Kurt ; Berndt, Alexander ; Kosmehl, Hartwig ; Trachsel, Eveline ; Kaspar, Manuela ; Lovato, Valeria ; González-Iglesias, Reinerio ; Giovannoni, Leonardo ; Menssen, Hans D. ; Neri, Dario ; De Braud, Filippo. / 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. In: European Journal of Cancer. 2010 ; Vol. 46, No. 16. pp. 2926-2935.
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abstract = "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. Patients and 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 2-3 h. 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.",
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T2 - Preclinical safety studies, phase i clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma

AU - Johannsen, Manfred

AU - Spitaleri, Gianluca

AU - Curigliano, Giuseppe

AU - Roigas, Jan

AU - Weikert, Steffen

AU - Kempkensteffen, Carsten

AU - Roemer, Andreas

AU - Kloeters, Christian

AU - Rogalla, Patrik

AU - Pecher, Gabriele

AU - Miller, Kurt

AU - Berndt, Alexander

AU - Kosmehl, Hartwig

AU - Trachsel, Eveline

AU - Kaspar, Manuela

AU - Lovato, Valeria

AU - González-Iglesias, Reinerio

AU - Giovannoni, Leonardo

AU - Menssen, Hans D.

AU - Neri, Dario

AU - De Braud, Filippo

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N2 - 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. Patients and 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 2-3 h. 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.

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KW - Solid tumours

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