A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma

Authors

  • Ahmad A. Tarhini MD,

    1. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
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  • Michael Millward MD,

    1. Department of Medical Oncology, Sir Charles Gairdner Hospital & University of Western Australia, Nedlands, Western Australia, Australia
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  • Paul Mainwaring MD,

    1. Department of Medical Oncology, Mater Adult Hospital, South Brisbane, Australia
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  • Richard Kefford MD,

    1. Westmead Institute for Cancer Research, University of Sydney at Westmead Hospital & Westmead Millennium Institute, Westmead, New South Wales, Australia
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  • Ted Logan MD,

    1. Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana
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  • Anna Pavlick MD,

    1. Departments of Medicine and Dermatology, New York University Medical Center, New York, New York
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  • Steven J. Kathman MD,

    1. Clinical Pharmacokinetics-Modelling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina
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  • Kevin H. Laubscher MD,

    1. Clinical Sciences and Study Operations, GlaxoSmithKline, Research Triangle Park, Raleigh, North Carolina
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  • Mohammed M. Dar MD,

    1. Clinical Pharmacology/Discovery Medicine-Oncology, GlaxoSmithKline, Research Triangle Park, Raleigh, North Carolina
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  • John M. Kirkwood MD

    Corresponding author
    1. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
    • University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Suite 1.32c, 5117 Centre Avenue, Pittsburgh, PA 15213-2584
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    • Fax: (412) 623-7704


Abstract

BACKGROUND:

Phase 1 studies demonstrated evidence of recombinant human IL-18 (rhIL-18)-mediated immunomodulatory and clinical activity, and defined a biologically active dose range.

METHODS:

A phase 2 study of rhIL-18 was conducted in untreated AJCC stage IV melanoma. Patients were randomized to 1 of 3 dose groups (0.01, 0.1, and 1.0 mg/kg/d) of rhIL-18 administered as 5 daily intravenous infusions repeated every 28 days. A 2-stage design with a stopping rule was used.

RESULTS:

A total of 64 patients (median age, 57.5 years) with metastatic melanoma (M1a/b (30), M1c (34)) were accrued to stage I, and randomized to 3 groups (21 [0.01 mg/kg/d], 21 [0.1 mg/kg/d], 22 [1.0 mg/kg/d]). Five patients experienced 10 grade 3 drug-related adverse events (AEs): polyarthritis (1 subject: 0.01 mg/kg); deep vein thrombosis, pulmonary embolism (1:0.01 mg/kg); cognitive disorder (1:0.1 mg/kg); fatigue, dyspnea, pleural effusion, lymphopenia (1:1.0 mg/kg); fatigue, lymphopenia (1:1.0 mg/kg). One patient experienced a grade 4 AE of increased lipase (0.1 mg/kg) that led to permanent discontinuation from the study. Among 63 subjects evaluable for response, 1 (M1c; 0.01 mg/kg) achieved a partial response after 4 cycles. Four subjects (3 at 0.01 mg/kg and 1 at 1.0 mg/kg) had stable disease maintained for 6 months or longer. Due to the low apparent level of clinical efficacy using RECIST criteria, the study was terminated at the end of stage 1. The median progression free survival for the 3 groups was 7.5 (0.01), 7.4 (0.1), and 7.3 (1.0) weeks.

CONCLUSIONS:

rIL-18 as tested in this trial was well tolerated, but had limited activity as a single agent in patients with metastatic melanoma. Cancer 2009. © 2009 American Cancer Society.

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