A dose-escalation and signal-generating study of the immunocytokine L19-IL2 in combination with dacarbazine for the therapy of patients with metastatic melanoma.

Abstract

PURPOSE:

L19-IL2 is an immunocytokine composed of an antibody fragment specific to the EDB domain of fibronectin, a tumor angiogenesis marker, and of human interleukin-2 (IL2). L19-IL2 delivers IL2 to the tumor site exploiting the selective expression of EDB on newly formed blood vessels. Previously, the recommended dose of L19-IL2 monotherapy was defined as 22.5 million international units (Mio IU) IL2 equivalents. In this study, safety and clinical activity of L19-IL2 in combination with dacarbazine were assessed in patients with metastatic melanoma.

EXPERIMENTAL DESIGN:

The first 10 studied patients received escalating doses of L19-IL2 on days 1, 3, and 5 in combination with 1 g/m(2) of dacarbazine on day 1 of a 3-weekly therapy cycle. Subsequently, 22 patients received L19-IL2 at recommended dose plus dacarbazine. Up to six treatment cycles were given, followed by a maintenance regimen with biweekly L19-IL2.

RESULTS:

The recommended dose of L19-IL2 in combination with dacarbazine was defined as 22.5 Mio IU. Toxicity was manageable and reversible, with no treatment-related deaths. Twenty-nine patients were evaluable for efficacy according to Response Evaluation Criteria in Solid Tumors (RECIST). In a centralized radiology analysis, eight of 29 (28%) patients achieved a RECIST-confirmed objective response, including a complete response still ongoing 21 months after treatment beginning. The 12-month survival rate and median overall survival of the recommended dose-treated patients (n = 26) were 61.5% and 14.1 months, respectively.

CONCLUSIONS:

The repeated administration of L19-IL2 in combination with dacarbazine is safe and shows encouraging signs of clinical activity in patients with metastatic melanoma. This combination therapy is currently evaluated in a randomized phase II trial with patients with metastatic melanoma.

• Authors: Thomas K Eigentler, Benjamin Weide, Filippo de Braud, Gianluca Spitaleri, Antonella Romanini, Annette Pflugfelder, Reinerio González-Iglesias, Annaelisa Tasciotti, Leonardo Giovannoni, Kathrin Schwager, Valeria Lovato, Manuela Kaspar, Eveline Trachsel, Hans D Menssen, Dario Neri, Claus Garbe
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 24 Pg. 7732-42 (Dec 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 22028492 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• L19-IL2 immunocytokine
• Recombinant Fusion Proteins
• Dacarbazine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Cohort Studies
• Dacarbazine (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Fatigue (chemically induced)
• Female
• Fever (chemically induced)
• Humans
• Male
• Melanoma (drug therapy, metabolism, mortality)
• Metabolic Clearance Rate
• Middle Aged
• Neoplasm Metastasis
• Recombinant Fusion Proteins (administration & dosage, adverse effects, pharmacokinetics)
• Survival Analysis
• Survival Rate
• Treatment Outcome