A dose-escalation study of aerosolized sargramostim in the treatment of metastatic melanoma: An NCCTG study

Svetomir Nenad Markovic, Vera Jean Suman, Wendy K. Nevala, Louis Geeraerts, Edward T. Creagan, Lori A. Erickson, Kendrith M. Rowland, Roscoe F. Morton, William L. Horvath, Mark R. Pittelkow

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Objectives: Early testing of aerosolized sargramostim therapy demonstrated anecdotal clinical responses in patients with metastatic melanoma associated with emergence of systemic antitumor immunity. To improve the clinical and immunologic efficacy of therapy without compromising patient safety, we performed a further dose escalation trial in patients with metastatic melanoma. Methods: We conducted a dose-escalation clinical trial of HLA-A2+ patients with metastatic melanoma to the lung treated with aerosolized granulocyte macrophage colony stimulating factor (GM-CSF) (500-2000 μg/dose, with increments of 250 μg/dose/cohort) twice/d on days 1 to 7 and 15 to 21 every 28 days until progression or severe toxicity to find a dose where a majority of patients develop antitumor immunity. Five patients were treated per each dose level. Clinical, immune, and safety parameters were examined. Results: The study accrued 40 patients. Toxicity was acceptable. All doses levels were exhausted without identifying a dose of GM-CSF at which a majority of patients (≤3 of 5) demonstrated significant up-regulation of antitumor immunity. Three of 16 patients who were tetramer positive for at least one melanoma antigen (eg, MART-1) pretreatment developed an immune response (IR) to different tumor antigens. Two of 9 patients who were tetramer negative to all melanoma antigens pretreatment developed an IR against gp100. The greatest changes in antitumor immunity occurred at the highest dose levels. Conclusions: A dose of aerosolized GM-CSF capable of inducing antitumor immunity in the majority of patients was not reached. All tested doses were well tolerated. The greatest increase in antitumor T cell IRs was achieved at the highest doses of GM-CSF.

Original languageEnglish (US)
Pages (from-to)573-579
Number of pages7
JournalAmerican Journal of Clinical Oncology: Cancer Clinical Trials
Volume31
Issue number6
DOIs
StatePublished - Dec 2008

Fingerprint

Melanoma
Immunity
Granulocyte-Macrophage Colony-Stimulating Factor
Melanoma-Specific Antigens
Therapeutics
sargramostim
HLA-A2 Antigen
Neoplasm Antigens
Patient Safety
Up-Regulation
Clinical Trials
T-Lymphocytes
Safety
Lung

Keywords

  • Aerosol
  • Granulocyte macrophage colony stimulating factor
  • Immunotherapy
  • Melanoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A dose-escalation study of aerosolized sargramostim in the treatment of metastatic melanoma : An NCCTG study. / Markovic, Svetomir Nenad; Suman, Vera Jean; Nevala, Wendy K.; Geeraerts, Louis; Creagan, Edward T.; Erickson, Lori A.; Rowland, Kendrith M.; Morton, Roscoe F.; Horvath, William L.; Pittelkow, Mark R.

In: American Journal of Clinical Oncology: Cancer Clinical Trials, Vol. 31, No. 6, 12.2008, p. 573-579.

Research output: Contribution to journalArticle

Markovic, Svetomir Nenad ; Suman, Vera Jean ; Nevala, Wendy K. ; Geeraerts, Louis ; Creagan, Edward T. ; Erickson, Lori A. ; Rowland, Kendrith M. ; Morton, Roscoe F. ; Horvath, William L. ; Pittelkow, Mark R. / A dose-escalation study of aerosolized sargramostim in the treatment of metastatic melanoma : An NCCTG study. In: American Journal of Clinical Oncology: Cancer Clinical Trials. 2008 ; Vol. 31, No. 6. pp. 573-579.
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abstract = "Objectives: Early testing of aerosolized sargramostim therapy demonstrated anecdotal clinical responses in patients with metastatic melanoma associated with emergence of systemic antitumor immunity. To improve the clinical and immunologic efficacy of therapy without compromising patient safety, we performed a further dose escalation trial in patients with metastatic melanoma. Methods: We conducted a dose-escalation clinical trial of HLA-A2+ patients with metastatic melanoma to the lung treated with aerosolized granulocyte macrophage colony stimulating factor (GM-CSF) (500-2000 μg/dose, with increments of 250 μg/dose/cohort) twice/d on days 1 to 7 and 15 to 21 every 28 days until progression or severe toxicity to find a dose where a majority of patients develop antitumor immunity. Five patients were treated per each dose level. Clinical, immune, and safety parameters were examined. Results: The study accrued 40 patients. Toxicity was acceptable. All doses levels were exhausted without identifying a dose of GM-CSF at which a majority of patients (≤3 of 5) demonstrated significant up-regulation of antitumor immunity. Three of 16 patients who were tetramer positive for at least one melanoma antigen (eg, MART-1) pretreatment developed an immune response (IR) to different tumor antigens. Two of 9 patients who were tetramer negative to all melanoma antigens pretreatment developed an IR against gp100. The greatest changes in antitumor immunity occurred at the highest dose levels. Conclusions: A dose of aerosolized GM-CSF capable of inducing antitumor immunity in the majority of patients was not reached. All tested doses were well tolerated. The greatest increase in antitumor T cell IRs was achieved at the highest doses of GM-CSF.",
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T1 - A dose-escalation study of aerosolized sargramostim in the treatment of metastatic melanoma

T2 - An NCCTG study

AU - Markovic, Svetomir Nenad

AU - Suman, Vera Jean

AU - Nevala, Wendy K.

AU - Geeraerts, Louis

AU - Creagan, Edward T.

AU - Erickson, Lori A.

AU - Rowland, Kendrith M.

AU - Morton, Roscoe F.

AU - Horvath, William L.

AU - Pittelkow, Mark R.

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N2 - Objectives: Early testing of aerosolized sargramostim therapy demonstrated anecdotal clinical responses in patients with metastatic melanoma associated with emergence of systemic antitumor immunity. To improve the clinical and immunologic efficacy of therapy without compromising patient safety, we performed a further dose escalation trial in patients with metastatic melanoma. Methods: We conducted a dose-escalation clinical trial of HLA-A2+ patients with metastatic melanoma to the lung treated with aerosolized granulocyte macrophage colony stimulating factor (GM-CSF) (500-2000 μg/dose, with increments of 250 μg/dose/cohort) twice/d on days 1 to 7 and 15 to 21 every 28 days until progression or severe toxicity to find a dose where a majority of patients develop antitumor immunity. Five patients were treated per each dose level. Clinical, immune, and safety parameters were examined. Results: The study accrued 40 patients. Toxicity was acceptable. All doses levels were exhausted without identifying a dose of GM-CSF at which a majority of patients (≤3 of 5) demonstrated significant up-regulation of antitumor immunity. Three of 16 patients who were tetramer positive for at least one melanoma antigen (eg, MART-1) pretreatment developed an immune response (IR) to different tumor antigens. Two of 9 patients who were tetramer negative to all melanoma antigens pretreatment developed an IR against gp100. The greatest changes in antitumor immunity occurred at the highest dose levels. Conclusions: A dose of aerosolized GM-CSF capable of inducing antitumor immunity in the majority of patients was not reached. All tested doses were well tolerated. The greatest increase in antitumor T cell IRs was achieved at the highest doses of GM-CSF.

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