Adjuvant Therapy of Stage III and IV Malignant Melanoma Using Granulocyte-Macrophage Colony-Stimulating Factor

S̄pitler, Lynn E.; Grossbard, Michael L.; Ernstoff, Marc S.; Silver, G.; Jacobs, Mark; Hayes, F. Ann; Soong, Seng Jaw

doi:10.1200/jco.2000.18.8.1614

Cited by 232 publications

(150 citation statements)

References 30 publications

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“…Other possible contributors to this lack of significant benefit include lack of efficacy, pre-existing immune status of patients, immunologic response to GM-CSF, development of neutralizing antibodies to GM-CSF, effects of GM-CSF on suppressor elements (such as myeloid-derived suppressor cells), and possible suboptimal dose and/or duration of treatment. 6,7,9 The greater effect on OS than on RFS seen in other studies [6][7][8] was not seen in this study. In HLA-A2-positive patients, the median RFS was 1.7 months longer in patients who received PV versus PV placebo (11.5 v 9.8 months; 17.3% improvement), which was less than the expected improvement (3 months; 33% improvement) and not statistically significant.…”

Section: Discussioncontrasting

confidence: 52%

“…5 Early clinical trials support the possible benefit of GM-CSF as adjuvant therapy for melanoma. Spitler et al 6 reported longer overall survival (OS) of 48 patients with stage III to IV melanoma treated for 1 year with adjuvant GM-CSF compared with historical controls (median OS, 37.5 v 12.2 months; 2-year survival, 64% v 15%). A subsequent single-arm trial in 98 patients with stage II, III, or IV melanoma evaluated GM-CSF for 3 years and demonstrated 5-year melanomaspecific survival rates of 67% and 40% among patients with resected stage III and IV disease, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (E4697)

Lawson

Lee

Zhao

et al. 2015

JCO

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102

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Purpose We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. Patients and Methods Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2–positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2–negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. Results A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF–treated patients with resected visceral metastases. When survival in HLA-A2–positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. Conclusion Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation.

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Section: Discussioncontrasting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (E4697)

Lawson

Lee

Zhao

et al. 2015

JCO

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102

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“…The strong induction of GM-CSF production by CC-5013 in all nine patients is further evidence of immune activation and is likely to lead to the stimulation and increased functional capacity of monocytes/ macrophages and dendritic cells (Armitage, 1998), thereby potentially boosting the presentation of tumour antigens. The clinical use of recombinant GM-CSF as a cancer immunotherapy has led to reports demonstrating its benefits in the treatment of patients with melanoma (Armitage, 1998;Spitler et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers

et al. 2004

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We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMIDt), in the treatment of patients with metastatic malignant melanoma and other advanced cancers. A total of 20 heavily pretreated patients received a dose-escalating regimen of oral CC-5013. Maximal tolerated dose, toxicity and clinical responses were evaluated and analysis of peripheral T-cell surface markers and serum for cytokines and proangiogenic factors were performed. CC-5013 was well tolerated. In all, 87% of adverse effects were classified as grade 1 or grade 2 according to Common Toxicity Criteria and there were no serious adverse events attributable to CC-5013 treatment. Six patients failed to complete the study, three because of disease progression, two withdrew consent and one was entered inappropriately and withdrawn from the study. The remaining 14 patients completed treatment without dose reduction, with one patient achieving partial remission. Evidence of T-cell activation was indicated by significantly increased serum levels of sIL-2 receptor, granulocyte -macrophage colony-stimulating factor, interleukin-12 (IL-12), tumour necrosis factor-a and IL-8 in nine patients from whom serum was available. However, levels of proangiogenic factors vascular endothelial growth factor and basic foetal growth factor were not consistently affected. This study demonstrates the safety, tolerability and suggests the clinical activity of CC-5013 in the treatment of refractory malignant melanoma. Furthermore, this is the first report demonstrating T-cell stimulatory activity of this class of compound in patients with advanced cancer.

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“…Recombinant human GM-CSF is used clinically to treat a variety of hematopoietic disorders, including reducing the severity of chemotherapy-induced neutropenia, accelerating hematopoietic recovery following bone marrow transplantation and mobilizing blood progenitor cells for transplantation (1,2). Recombinant GM-CSF also has shown promise as a treatment for Crohn's disease and as an adjuvant therapy for melanoma (3,4). A limitation of current GM-CSF products is the fact that GM-CSF has a short circulating half-life (1,2) and must be administered to patients by daily injection for optimal effectiveness.…”

Section: Introductionmentioning

confidence: 99%

Site-Specific PEGylation of Engineered Cysteine Analogues of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

et al. 2005

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Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) stimulates proliferation of hematopoietic cells of the macrophage and granulocyte lineages and is used clinically to treat neutropenia and other myeloid disorders. Because of its short circulating half-life GM-CSF is administered to patients by daily injection. We describe here the engineering of highly potent, long acting human GM-CSF proteins through site-specific modification of GM-CSF cysteine analogs with a cysteine-reactive polyethylene glycol (PEG) reagent. Thirteen cysteine analogs of GM-CSF were constructed, primarily in non-helical regions of the protein believed to lie away from the major receptor binding sites. The GM-CSF cysteine analogs were properly processed, but insoluble following secretion into the Escherichia coli periplasm. The proteins were refolded and purified by column chromatography. Ten of the cysteine analogs could be modified with a 5 kDa-maleimide PEG and seven of the mono-PEGylated proteins were purified by ion-exchange column chromatography. Biological activities of the 13 cysteine analogs and seven PEGylated cysteine analogs were comparable to that of wild type GM-CSF in an in vitro cell proliferation assay using human TF-1 cells. One cysteine analog was modified with larger 10 kDa-, 20 kDa-and 40 kDaPEGs, with only minimal loss of in vitro bioactivity. Pharmacokinetic experiments in rats demonstrated that the PEGylated proteins had up to 47-fold longer circulating half-lives than wild type GM-CSF. These data demonstrate the utility of site-specific PEGylation for creating highly potent, long-acting GM-CSF analogs, and provide further evidence that the non-helical regions of human GM-CSF examined are largely non-essential for biological activity of the protein.

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Adjuvant Therapy of Stage III and IV Malignant Melanoma Using Granulocyte-Macrophage Colony-Stimulating Factor

Cited by 232 publications

References 30 publications

Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers

Site-Specific PEGylation of Engineered Cysteine Analogues of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

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