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

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/m2 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. ©2011 AACR.

[1]  Axel Hoos,et al.  Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. , 2011, The New England journal of medicine.

[2]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[3]  A. Pavlick,et al.  A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma , 2011, Investigational New Drugs.

[4]  F. D. De Braud,et al.  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. , 2010, European journal of cancer.

[5]  H. Pehamberger,et al.  Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  P. Castellani,et al.  Therapy‐induced antitumor vaccination in neuroblastomas by the combined targeting of IL‐2 and TNFα , 2010, International journal of cancer.

[7]  M. Atkins,et al.  Phase II multicenter trial of maintenance biotherapy after induction concurrent Biochemotherapy for patients with metastatic melanoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  M. Atkins,et al.  Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma , 2009, Journal of Translational Medicine.

[9]  John A Thompson,et al.  Treatment of metastatic melanoma: an overview. , 2009, Oncology.

[10]  P. Erba,et al.  Expression of the oncofetal ED-B-containing fibronectin isoform in hematologic tumors enables ED-B-targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients. , 2009, Blood.

[11]  W. Klapper,et al.  Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. , 2009, Blood.

[12]  C. R. Leemans,et al.  124I-L19-SIP for immuno-PET imaging of tumour vasculature and guidance of 131I-L19-SIP radioimmunotherapy , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[13]  S. Steinberg,et al.  Treatment of Metastatic Melanoma Using Interleukin-2 Alone or in Conjunction with Vaccines , 2008, Clinical Cancer Research.

[14]  B. Weber,et al.  Uptake of 18F-Fluorocholine, 18F-FET, and 18F-FDG in C6 Gliomas and Correlation with 131I-SIP(L19), a Marker of Angiogenesis , 2007, Journal of Nuclear Medicine.

[15]  S. Stoeckli,et al.  Immunoscintigraphy of patients with head and neck carcinomas, with an anti-angiogenetic antibody fragment , 2007, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[16]  R. Marais,et al.  Melanoma biology and new targeted therapy , 2007, Nature.

[17]  I. Quirt,et al.  Single-agent interleukin-2 in the treatment of metastatic melanoma , 2007, Current oncology.

[18]  T. Einarson,et al.  Treatments for metastatic melanoma: synthesis of evidence from randomized trials. , 2006, Cancer treatment reviews.

[19]  H. Pehamberger,et al.  Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  U. Ringborg,et al.  Cutaneous Malignant Melanoma , 2006 .

[21]  C. R. Leemans,et al.  Radioimmunotherapy of head and neck cancer xenografts using 131I-labeled antibody L19-SIP for selective targeting of tumor vasculature. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[22]  S. Rosenberg,et al.  IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. , 2006, Blood.

[23]  L. Dinkelborg,et al.  Radioimmunotherapy of Solid Tumors by Targeting Extra Domain B Fibronectin: Identification of the Best-Suited Radioimmunoconjugate , 2005, Clinical Cancer Research.

[24]  H. Kosmehl,et al.  Engineered vascular‐targeting antibody‐interferon‐γ fusion protein for cancer therapy , 2005 .

[25]  Roy Bicknell,et al.  Tumour vascular targeting , 2005, Nature Reviews Cancer.

[26]  A. Menrad,et al.  ED-B fibronectin as a target for antibody-based cancer treatments , 2005, Expert opinion on therapeutic targets.

[27]  T. Warner,et al.  Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  M. Gore,et al.  Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  C. Redfern,et al.  Safety, Pharmacokinetics, and Biological Pharmacodynamics of the Immunocytokine EMD 273066 (huKS-IL2): Results of a Phase I Trial in Patients with Prostate Cancer , 2004, Journal of immunotherapy.

[30]  Dario Neri,et al.  Synergistic therapeutic effects of a tumor targeting antibody fragment, fused to interleukin 12 and to tumor necrosis factor alpha. , 2003, Cancer research.

[31]  Dario Neri,et al.  Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  L. Zardi,et al.  Selective targeting of tumoral vasculature: Comparison of different formats of an antibody (L19) to the ED‐B domain of fibronectin , 2002, International journal of cancer.

[33]  H. Kosmehl,et al.  Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix. , 2002, Blood.

[34]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[35]  M. Atkins,et al.  High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. , 2000, The cancer journal from Scientific American.

[36]  R. Fisher,et al.  High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  L. Zardi,et al.  Increased binding affinity and valence of recombinant antibody fragments lead to improved targeting of tumoral angiogenesis. , 1999, Cancer research.

[38]  R. Spooner,et al.  Applications of monoclonal antibodies in clinical oncology. , 1994, Immunology today.

[39]  G. Mahrle,et al.  Perilumoral injections of interleukin 2 induce tumour regression in metastatic malignant melanoma , 1994 .

[40]  R. Reisfeld,et al.  Monoclonal antibodies in cancer immunotherapy. , 1992, Clinics in laboratory medicine.

[41]  F. Baralle,et al.  Transformed human cells produce a new fibronectin isoform by preferential alternative splicing of a previously unobserved exon. , 1987, The EMBO journal.

[42]  Josep Malvehy,et al.  Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. , 2010, European journal of cancer.

[43]  H. Kosmehl,et al.  Engineered vascular-targeting antibody-interferon-gamma fusion protein for cancer therapy. , 2005, International journal of cancer.

[44]  Cancer Therapy Evaluation Program.  Common Terminology Criteria for Adverse Events v3.0 (CTCAE) , 2003 .

[45]  M Van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. , 2000, Journal of the National Cancer Institute.

[46]  L. Dinkelborg,et al.  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY A High-Affinity Human Antibody That Targets Tumoral Blood Vessels , 1999 .

[47]  S. Gillies,et al.  Recombinant antibody fusion proteins for cancer immunotherapy. , 1996, Current topics in microbiology and immunology.

[48]  R. Reisfeld,et al.  Antibody‐interleukin 2 fusion proteins: A new approach to cancer therapy , 1996, Journal of clinical laboratory analysis.

[49]  G. Mahrle,et al.  Peritumoral injections of interleukin 2 induce tumour regression in metastatic malignant melanoma. , 1994, The British journal of dermatology.