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

S. S. Agarwala, J. Glaspy, S. J. O'Day, M. Mitchell, J. Gutheil, E. Whitman, R. Gonzalez, E. Hersh, L. Feun, R. Belt, F. Meyskens, K. Hellstrand, D. Wood, J. M. Kirkwood, K. R. Gehlsen, P. Naredi

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)125-133
Number of pages9
JournalJournal of Clinical Oncology
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2002

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Histamine
Interleukin-2
Melanoma
Survival
Therapeutics
Population
Interleukin-9
Liver
Phagocytes
Random Allocation
Natural Killer Cells
Disease Progression
Lymphocytes
Cytokines
Neoplasm Metastasis
T-Lymphocytes
Safety
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Agarwala, S. S. ; Glaspy, J. ; O'Day, S. J. ; Mitchell, M. ; Gutheil, J. ; Whitman, E. ; Gonzalez, R. ; Hersh, E. ; Feun, L. ; Belt, R. ; Meyskens, F. ; Hellstrand, K. ; Wood, D. ; Kirkwood, J. M. ; Gehlsen, K. R. ; Naredi, P. / 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. In: Journal of Clinical Oncology. 2002 ; Vol. 20, No. 1. pp. 125-133.
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title = "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",
abstract = "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.",
author = "Agarwala, {S. S.} and J. Glaspy and O'Day, {S. J.} and M. Mitchell and J. Gutheil and E. Whitman and R. Gonzalez and E. Hersh and L. Feun and R. Belt and F. Meyskens and K. Hellstrand and D. Wood and Kirkwood, {J. M.} and Gehlsen, {K. R.} and P. Naredi",
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Agarwala, SS, Glaspy, J, O'Day, SJ, Mitchell, M, Gutheil, J, Whitman, E, Gonzalez, R, Hersh, E, Feun, L, Belt, R, Meyskens, F, Hellstrand, K, Wood, D, Kirkwood, JM, Gehlsen, KR & Naredi, P 2002, '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', Journal of Clinical Oncology, vol. 20, no. 1, pp. 125-133. https://doi.org/10.1200/JCO.20.1.125

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. / Agarwala, S. S.; Glaspy, J.; O'Day, S. J.; Mitchell, M.; Gutheil, J.; Whitman, E.; Gonzalez, R.; Hersh, E.; Feun, L.; Belt, R.; Meyskens, F.; Hellstrand, K.; Wood, D.; Kirkwood, J. M.; Gehlsen, K. R.; Naredi, P.

In: Journal of Clinical Oncology, Vol. 20, No. 1, 01.01.2002, p. 125-133.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Agarwala, S. S.

AU - Glaspy, J.

AU - O'Day, S. J.

AU - Mitchell, M.

AU - Gutheil, J.

AU - Whitman, E.

AU - Gonzalez, R.

AU - Hersh, E.

AU - Feun, L.

AU - Belt, R.

AU - Meyskens, F.

AU - Hellstrand, K.

AU - Wood, D.

AU - Kirkwood, J. M.

AU - Gehlsen, K. R.

AU - Naredi, P.

PY - 2002/1/1

Y1 - 2002/1/1

N2 - 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.

AB - 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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