Improved survival with ipilimumab in patients with metastatic melanoma.

BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

Biological Effects of Anti-Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Antibody Formation in Patients Treated With GM-CSF (Sargramostim) as Adjuvant Therapy of Melanoma.

OBJECTIVES: We investigated the development of binding and neutralizing antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving prolonged therapy with GM-CSF as adjuvant therapy of melanoma and the impact of these antibodies on biological effects. METHODS: Fifty-three patients with high-risk melanoma that had been surgically excised were treated with GM-CSF, 125 µg/m daily for 14 days every 28 days for 1 year after surgical resection of disease. Serum samples for antibodies to GM-CSF were measured before treatment and on study days 155 and 351. Blood draws for testing biological effects were keyed to GM-CSF administration: days 0 (before), 15 (after 14 d on GM-CSF), 29 (after 14 d off GM-CSF), 155, and 351 (after 14 d on GM-CSF in the sixth and 13th cycle of treatment). RESULTS: Of 53 patients enrolled, 43 were evaluable for the development of anti-GM-CSF antibodies. Of these, 93% developed binding antibodies and 42% developed both binding and neutralizing antibodies. The increase in the white blood cell count, percent eosinophils, or neopterin levels engendered by GM-CSF administration was abrogated or markedly decreased in patients with neutralizing antibodies but not in patients who developed only binding antibodies. CONCLUSIONS: Ninety-three percent of patients with melanoma treated with GM-CSF as adjuvant therapy develop antibodies to GM-CSF. In those with neutralizing antibodies, a diminution of the biological effects of GM-CSF was observed. The development of neutralizing antibodies might also abrogate the potential clinical benefit of this treatment and should be considered in the design of future clinical trials.

Low-dose outpatient chemobiotherapy with temozolomide, granulocyte-macrophage colony stimulating factor, interferon-alpha2b, and recombinant interleukin-2 for the treatment of metastatic melanoma.

PURPOSE: The objective of this study was to further investigate the efficacy and safety of low-dose outpatient chemobiotherapy in patients with unresectable metastatic melanoma. PATIENTS AND METHODS: Thirty-one patients with histologically confirmed unresectable measurable metastatic melanoma were enrolled onto an open-label, multicenter phase II study. The treatment regimen consisted of oral temozolomide followed by subcutaneous biotherapy with granulocyte macrophage colony-stimulating factor, interferon-alfa, and recombinant interleukin-2 (rIL-2). RESULTS: Twenty-eight patients (90%) had M1c disease, and 58% had three or more sites of metastasis. Four patients (13%), all with M1c disease, had a complete response, and four patients had a partial response. The median progression-free survival was 4.9 months and the median overall survival was 13.1 months. Two patients (6%) developed CNS metastasis as the first site of disease progression, and 7 (23%) of 30 experienced CNS progression after receiving chemobiotherapy. A total of 112 cycles of therapy were administered. Toxicity occurred in 78% of the cycles and was grade 1 or 2 in the majority of cases and easily managed. Grade 4 toxicity occurred in 3% of the cycles. CONCLUSION: This low-dose chemobiotherapy combination produces clinical responses in patients with metastatic melanoma, even in those with M1c disease, is well tolerated, and allows home dosing. It offers a reasonable alternative to high-dose regimens, such as high-dose biochemotherapy or rIL-2 requiring prolonged periods of hospitalization, or single agent outpatient regimens, such as dacarbazine, which is usually not effective in patients with M1c disease. Furthermore, it may protect against the development of brain metastases.

GM-CSF and ipilimumab therapy in metastatic melanoma: Clinical outcomes and immunologic responses.

We conducted a phase II clinical trial of anti-CTLA-4 antibody (ipilimumab) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 22 patients with metastatic melanoma and determined clinical outcomes and immunologic responses. The treatment consisted of a 3-mo induction with ipilimumab at 10 mg/kg administered every 3 weeks for four doses in combination with GM-CSF at 125 µg/m2 for 14 d beginning on the day of the ipilimumab infusion and then GM-CSF for 3 mo on the same schedule without ipilimumab. This was followed by maintenance therapy with the combination every 3 mo for up to 2 y or until disease progression or unacceptable toxicity. Blood samples for determination of immune subsets were obtained before treatment, at week 3 (end of cycle 1) and at week 6 (end of cycle 2). Blood samples were also obtained from seven subjects who were cancer-free. The immune response disease control (irDC) rate at 24 weeks was 41% and the overall response rate (ORR) was 32%. The median progression free-survival (PFS) was 3.5 mo and the median overall survival (OS) was 21.1 mo. 41% of the patients experienced Grade 3 to 4 adverse events. We conclude that this combination is safe and the results suggest the combination may be more effective than ipilimumab monotherapy. Further, the results suggest that lower levels of CD4+ effector T cells but higher levels of CD8+ T cells expressing PD-1 at pre-treatment could be a potential biomarker for disease control in patients who receive immunotherapy with ipilimumab and GM-CSF. Further trials of this combination are warranted.

Phase II study of nab-paclitaxel and bevacizumab as first-line therapy for patients with unresectable stage III and IV melanoma.

OBJECTIVES: This study was an open-label multicenter phase II trial to investigate the efficacy and safety of nab-paclitaxel and bevacizumab as first-line therapy in patients with histologically confirmed unresectable metastatic melanoma. METHODS: The treatment regimen consisted of a 28-day cycle in which patients received nab-paclitaxel, 150 mg/m through intravenous (IV) infusion weekly for 3 weeks and bevacizumab, 10 mg/kg IV every 2 weeks without a rest period. The 28-day cycle was repeated until there was unacceptable toxicity or disease progression. If 1 drug had to be stopped because of toxicity, treatment was continued with the other drug until disease progression or unacceptable toxicity. The primary endpoint was the progression-free survival rate (PFS) at 4 months. RESULTS: Fifty patients were enrolled. The PFS rate at 4 months was 75%. The median PFS was 7.6 months and the median overall survival was 16.8 months with a median duration follow-up of 41.6 months. The overall survival rate was 64% at 1 year and 30% at 2 years. Ten patients (20%) remain alive. The objective response rate was 36%. Common adverse events associated with this regimen were peripheral neuropathy, fatigue, alopecia, and gastrointestinal disorders. CONCLUSIONS: In this phase II multicenter study, this doublet had significant activity in patients with metastatic melanoma, and was well tolerated. These results are promising and follow-up trials to further explore this regimen are warranted.

Biodegradation characteristics of starch-polystyrene loose-fill foams in a composting medium.

The structures and biodegradabilities of loose-fill foams, containing starch and polystyrene at ratios of 70:30 and 80:20, were evaluated using a laboratory composting system. Each formulation was foamed (extrusion expanded) using either 0.2% azodicarbonamide or 0.25% citric acid as the chemical blowing agent. Biodegradability, a measure of the quantity of material mineralized, was expressed as the percentage of CO(2) in the exhaust gas eluted from the individual chambers. The CO(2) generation peaked after about 15 days of composting, and then decreased. The rate and amount of CO(2) eluted depended on the starch content in the foams. Similarly, there were significant differences in the rates and quantities of CO(2) emissions for the foams blown with azodicarbonamide versus citric acid. At the end of the composting tests, the remaining foam material had fibrous and crumbly textures, presumably consisting primarily of polystyrene. FTIR and NMR spectra of the foams, taken after 39days of composting, did not reveal the spectral features of starch, thereby confirming the decomposition of the starch.

Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) administered for 3 years as adjuvant therapy of stages II(T4), III, and IV melanoma.

A hypothesis generating study was conducted to evaluate the safety and efficacy of prolonged (3 y) administration of granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) as surgical adjuvant therapy in patients with melanoma at high risk of recurrence. Ninety-eight evaluable patients with stages II(T4), III, or IV melanoma were given prolonged treatment with GM-CSF after surgical resection of disease. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 microg/m2 was delivered daily for 14 days followed by 14 days rest. Treatment cycles continued for 3 years or until disease recurrence, which could not be surgically excised. Patients were evaluated for toxicity, disease-free survival, and melanoma-specific survival. Prolonged administration of GM-CSF was well tolerated; grade 1 or 2 side effects occurred in 82% of the patients. There were no grade 3 or 4 treatment-related side effects. Two patients developed acute myelogenous leukemia after completion of 3 years of GM-CSF administration. With a median follow-up of 5.3 years, the median melanoma-specific survival has not yet been reached. The 5-year melanoma-specific survival rate was 60%. The current study has expanded the preliminary evidence on GM-CSF as adjuvant therapy of patients with melanoma who are at high risk for recurrence.