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Results From a Randomized Phase III Study Comparing Combined Treatment With Histamine Dihydrochloride Plus Interleukin-2 Versus Interleukin-2 Alone in Patients With Metastatic Melanoma

From the Melanoma Center of the University of Pittsburgh Cancer Institute, Pittsburgh, PA; Bowyer Oncology Center, University of California at Los Angeles, Los Angeles; John Wayne Cancer Institute, Santa Monica; Sidney Kimmel Cancer Center, and Maxim Pharmaceuticals, San Diego; and University of California, Irvine Comprehensive Cancer Center, Orange, CA; Karmanos Cancer Institute, Detroit, MI; Washington University and The Melanoma Center of St. Louis, St Louis; and Oncology/Hematology Associates of Kansas City, Kansas City, MO; University of Colorado, Denver, CO; Arizona Cancer Center, Tucson, AZ; University of Miami Sylvester Cancer Research Center, Miami, FL; Department of Virology, University of Göteborg, Göteborg; and Department of Surgery, Umea University, Umea, Sweden.

Address reprint requests to Sanjiv S. Agarwala, MD, Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop St, Pittsburgh, PA 15213-2582; email: agarwalass{at}msx.upmc.edu

PURPOSE: Reactive oxidative species (ROS) produced by phagocytic cells have been ascribed a role in the localized suppression of lymphocyte function within malignant tumors. Histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients.

PATIENTS AND METHODS: A phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m² bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m² bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat–overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate.

RESULTS: Combined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P = .004) and showed a trend for improved survival in the ITT population (P = .125). Grade 3 and 4 adverse events were comparable in the two arms.

CONCLUSION: Use of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement. Further trials to confirm and understand the role of histamine in this combination treatment are underway.

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