A Dose-Escalation and Signal-Generating Study of the Immunocytokine L19-IL2 in Combination with Dacarbazine for the Therapy of Patients with Metastatic Melanoma

被引：125

作者：

Eigentler, Thomas K. ^{[1
]}

Weide, Benjamin ^{[1
]}

de Braud, Filippo ^{[2
]}

Spitaleri, Gianluca ^{[2
]}

Romanini, Antonella ^{[3
]}

Pflugfelder, Annette ^{[1
]}

Gonzalez-Iglesias, Reinerio ^{[4
]}

Tasciotti, Annaelisa ^{[4
]}

Giovannoni, Leonardo ^{[4
]}

Schwager, Kathrin ^{[5
]}

Lovato, Valeria ^{[5
]}

Kaspar, Manuela ^{[5
]}

Trachsel, Eveline ^{[5
]}

Menssen, Hans D. ^{[4
]}

Neri, Dario ^{[6
]}

Garbe, Claus ^{[1
]}

机构：

[1] Univ Med Ctr, Dept Dermatol, D-72076 Tubingen, Germany

[2] European Inst Oncol, Clin Pharmacol & New Drugs Dev Unit, Milan, Italy

[3] Santa Chiara Hosp, Dept Oncol, Div Med Oncol, Pisa, Italy

[4] Philogen SpA, Siena, Italy

[5] Philochem AG, Otelfingen, Switzerland

[6] Swiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, Zurich, Switzerland

来源：

CLINICAL CANCER RESEARCH | 2011年 / 17卷 / 24期

基金：

瑞士国家科学基金会;

关键词：

RECOMBINANT INTERLEUKIN-2 THERAPY; I CLINICAL-TRIAL; ED-B DOMAIN; MONOCLONAL-ANTIBODIES; FIBRONECTIN ISOFORM; PLUS DACARBAZINE; FUSION PROTEINS; AFFINITY; MARKER; SAFETY;

D O I：

10.1158/1078-0432.CCR-11-1203

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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. Clin Cancer Res; 17(24); 7732-42. (C) 2011 AACR.

引用

页码：7732 / 7742

页数：11

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