title: Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma-safety and efficacy in a phase II study.
abstract: Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany. benjamin.weide@med.uni-tuebingen.de.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.|Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Martens
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.|Department of Internal Medicine II, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Wistuba-Hamprecht
authors.affiliation: Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Zelba
authors.affiliation: University Hospital Ulm Pharmacy, University Hospital Ulm, Ulm, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Maier
authors.affiliation: Department of Hospital Pharmacy, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Lipp
authors.affiliation: Department for Diagnostic and Interventional Radiology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Bernhard D
authors.initials: BD
authors.lastname: Klumpp
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Soffel
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Eigentler
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003092:Colitis / Q000209:etiology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D007376:Interleukin-2 / Q000627:therapeutic use*; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D000074324:Ipilimumab
keywords: Clinical trial; Interleukin-2; Ipilimumab; Melanoma