Eastern Cooperative Group trial of interferon gamma in metastatic melanoma

An innovative study design

Joan H. Schiller, Marian Pugh, John M. Kirkwood, Daniel Karp, Marilyn Larson, Ernest Borden

Research output: Contribution to journalArticle

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Abstract

IFN-γ is a potent immunomodulator, which has activity against melanoma in vitro and in murine models. However, preclinical data suggests that the optimal therapeutic and immunomodulatory dose may not be the maximally tolerated clinical dose. We conducted a Phase II/III trial in good prognosis patients with metastatic melanoma to determine whether a therapeutic and immunomodulatory dose-response curve of IFN-γ could be identified, and whether the two could be correlated. Ninety-eight patients with metastatic melanoma were randomized to one of seven dose levels of IFN-γ ranging from 0.01 to 0.90 mg/m2. All patients were required to have s.c., skin, soft tissue, or nodal disease, although visceral disease was also allowed, and no more than one prior chemotherapy regimen. Patients received IFN-γ as a 1-h i.v. infusion three times per week for at least 8 weeks or until progressive disease. Ninety-five patients were eligible for toxicity evaluation; 81 were eligible for tumor response. Four patients responded to therapy (response rate, 5%) at three dose levels: two patients at 0.01 mg/m2 and one each at 0.5 and 0.9 mg/m2. The duration of response ranged from 5 to 58 weeks. Toxicities were typical of IFNs and included flu-like constitutional symptoms. No dose-response relationship was identified for efficacy. A dose-response relationship for toxicity was observed only for fever and chills (p = 0.035) and hepatic toxicity (p = 0.034). IFN-γ has minimal activity in metastatic melanoma, and a therapeutic dose-response curve could not be identified. Although potent dose-dependent effects on immunomodulation were identified (J.M. Kirkwood, J. Bryant, J.H. Schiller, M.M. Oken, E.C. Borden, and T.L. Whiteside. Immunomodulatory function of interferon gamma in patients with metastatic melanoma: results of a phase IIB trial in subjects with metastatic melanoma: ECOG Study E4987, submitted for publication), this biological activity does not translate into therapeutic activity in the metastatic disease setting in this trial.

Original languageEnglish (US)
Pages (from-to)29-36
Number of pages8
JournalClinical Cancer Research
Volume2
Issue number1
StatePublished - Jan 1996

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Interferon-gamma
Melanoma
Therapeutics
Chills
Maximum Tolerated Dose
Immunomodulation
Immunologic Factors
Publications
Fever
Drug Therapy
Skin
Liver
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Schiller, J. H., Pugh, M., Kirkwood, J. M., Karp, D., Larson, M., & Borden, E. (1996). Eastern Cooperative Group trial of interferon gamma in metastatic melanoma: An innovative study design. Clinical Cancer Research, 2(1), 29-36.

Eastern Cooperative Group trial of interferon gamma in metastatic melanoma : An innovative study design. / Schiller, Joan H.; Pugh, Marian; Kirkwood, John M.; Karp, Daniel; Larson, Marilyn; Borden, Ernest.

In: Clinical Cancer Research, Vol. 2, No. 1, 01.1996, p. 29-36.

Research output: Contribution to journalArticle

Schiller, JH, Pugh, M, Kirkwood, JM, Karp, D, Larson, M & Borden, E 1996, 'Eastern Cooperative Group trial of interferon gamma in metastatic melanoma: An innovative study design', Clinical Cancer Research, vol. 2, no. 1, pp. 29-36.
Schiller JH, Pugh M, Kirkwood JM, Karp D, Larson M, Borden E. Eastern Cooperative Group trial of interferon gamma in metastatic melanoma: An innovative study design. Clinical Cancer Research. 1996 Jan;2(1):29-36.
Schiller, Joan H. ; Pugh, Marian ; Kirkwood, John M. ; Karp, Daniel ; Larson, Marilyn ; Borden, Ernest. / Eastern Cooperative Group trial of interferon gamma in metastatic melanoma : An innovative study design. In: Clinical Cancer Research. 1996 ; Vol. 2, No. 1. pp. 29-36.
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abstract = "IFN-γ is a potent immunomodulator, which has activity against melanoma in vitro and in murine models. However, preclinical data suggests that the optimal therapeutic and immunomodulatory dose may not be the maximally tolerated clinical dose. We conducted a Phase II/III trial in good prognosis patients with metastatic melanoma to determine whether a therapeutic and immunomodulatory dose-response curve of IFN-γ could be identified, and whether the two could be correlated. Ninety-eight patients with metastatic melanoma were randomized to one of seven dose levels of IFN-γ ranging from 0.01 to 0.90 mg/m2. All patients were required to have s.c., skin, soft tissue, or nodal disease, although visceral disease was also allowed, and no more than one prior chemotherapy regimen. Patients received IFN-γ as a 1-h i.v. infusion three times per week for at least 8 weeks or until progressive disease. Ninety-five patients were eligible for toxicity evaluation; 81 were eligible for tumor response. Four patients responded to therapy (response rate, 5{\%}) at three dose levels: two patients at 0.01 mg/m2 and one each at 0.5 and 0.9 mg/m2. The duration of response ranged from 5 to 58 weeks. Toxicities were typical of IFNs and included flu-like constitutional symptoms. No dose-response relationship was identified for efficacy. A dose-response relationship for toxicity was observed only for fever and chills (p = 0.035) and hepatic toxicity (p = 0.034). IFN-γ has minimal activity in metastatic melanoma, and a therapeutic dose-response curve could not be identified. Although potent dose-dependent effects on immunomodulation were identified (J.M. Kirkwood, J. Bryant, J.H. Schiller, M.M. Oken, E.C. Borden, and T.L. Whiteside. Immunomodulatory function of interferon gamma in patients with metastatic melanoma: results of a phase IIB trial in subjects with metastatic melanoma: ECOG Study E4987, submitted for publication), this biological activity does not translate into therapeutic activity in the metastatic disease setting in this trial.",
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