Phase II clinical trial evaluating docetaxel, vinorelbine and GM-CSF in stage IV melanoma

PurposeMetastatic melanoma patients have a poor prognosis. No chemotherapy regimen has improved overall survival. More effective treatments are needed. Docetaxel has clinical activity in melanoma and may be more active when combined with vinorelbine. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown activity as an adjuvant melanoma therapy. We carried out a phase II study of these agents in patients with stage IV melanoma.MethodsPatients had documented stage IV melanoma and may have had prior immuno or chemotherapy. Previously treated brain metastases were allowed. Docetaxel (40 mg/m(2) IV) and vinorelbine (30 mg/m(2) IV) were administered every 14 days, followed by GM-CSF (250 mg/m2 SC on days 2 to 12). The primary endpoint of the study was 1-year overall survival (OS). Secondary objectives were median overall survival, response rate (per RECIST criteria), and the toxicity profiles.ResultsFifty-two patients were enrolled; 80% had stage M1c disease. Brain metastases were present in 21%. Fifty-two percent of patients had received prior chemotherapy, including 35% who received prior biochemotherapy. Toxicity was manageable. Grade III/IV toxicities included neutropenia (31%), anemia (14%), febrile neutropenia (11.5%), and thrombocytopenia (9%). DVS chemotherapy demonstrated clinical activity, with a partial response in 15%, and disease stabilization in 37%. Six-month PFS was 37%. Median OS was 11.4 months and 1-year OS rate was 48.1%.ConclusionsThe DVS regimen was active in patients with advanced, previously treated melanoma, with manageable toxicity. The favorable 1-year overall survival and median survival rates suggest that further evaluation of the DVS regimen is warranted

Malignant Cystosarcoma Phyllodes Metastatic to the Maxilla.

A case of malignant cystosarcoma phyllodes metastatic to the maxilla is reported, representing the only known case with a maxillary metastasis

Phase II clinical trial evaluating docetaxel, vinorelbine and GM-CSF in stage IV melanoma.

PurposeMetastatic melanoma patients have a poor prognosis. No chemotherapy regimen has improved overall survival. More effective treatments are needed. Docetaxel has clinical activity in melanoma and may be more active when combined with vinorelbine. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown activity as an adjuvant melanoma therapy. We carried out a phase II study of these agents in patients with stage IV melanoma.MethodsPatients had documented stage IV melanoma and may have had prior immuno or chemotherapy. Previously treated brain metastases were allowed. Docetaxel (40 mg/m(2) IV) and vinorelbine (30 mg/m(2) IV) were administered every 14 days, followed by GM-CSF (250 mg/m2 SC on days 2 to 12). The primary endpoint of the study was 1-year overall survival (OS). Secondary objectives were median overall survival, response rate (per RECIST criteria), and the toxicity profiles.ResultsFifty-two patients were enrolled; 80% had stage M1c disease. Brain metastases were present in 21%. Fifty-two percent of patients had received prior chemotherapy, including 35% who received prior biochemotherapy. Toxicity was manageable. Grade III/IV toxicities included neutropenia (31%), anemia (14%), febrile neutropenia (11.5%), and thrombocytopenia (9%). DVS chemotherapy demonstrated clinical activity, with a partial response in 15%, and disease stabilization in 37%. Six-month PFS was 37%. Median OS was 11.4 months and 1-year OS rate was 48.1%.ConclusionsThe DVS regimen was active in patients with advanced, previously treated melanoma, with manageable toxicity. The favorable 1-year overall survival and median survival rates suggest that further evaluation of the DVS regimen is warranted

Phase II study of pazopanib in combination with paclitaxel in patients with metastatic melanoma.

PURPOSE:This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and β, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma. EXPERIMENTAL DESIGN:Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m2 weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted. RESULTS:The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response. CONCLUSIONS:The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted

Intra-arterial administration of TNF-alpha followed by arterial ablation is an effective therapy for a regionally confined TNF-resistant rat mammary adenocarcinoma.

Tumor necrosis factor-alpha (TNF-alpha) is an immunomodulatory cytokine that has exhibited anti-tumor activity in a variety of experimental systems. However, the toxicities associated with systemic administration of TNF-alpha have limited its clinical utility and have led to the investigation of targeted delivery techniques with the ability to present the TNF-alpha dose directly to the vascular bed of the tumor. The intra-arterial (IA) administration of TNF-alpha to patients with liver metastases represents one such approach, and recent work suggests that subsequent ablation of the tumor's arterial supply via embolization may enhance the efficacy of intra-arterial treatments (hepatic chemoembolization). The present study was undertaken to test the hypothesis that IA administration of TNF-alpha is superior to the intravenous (IV) route for inhibition of tumor growth in a regionally confined rat mammary adenocarcinoma model that provides for ablation of the arterial supply to the tumor following cytokine therapy. Rats bearing hind limb mammary adenocarcinomas received single IA or IV infusions of 8 x 10(5), 1 x 10(6), and 1.5 x 10(6) units of TNF-alpha via the common femoral artery (CFA) followed 1 h later by ligation of the artery. Control animals received either no treatment or IA infusion of 2% normal rat serum (NRS) followed by ipsilateral CFA ligation. Tumor size was measured every other day after treatment. Tumor growth inhibition occurred in the first 5 to 10 days after treatment. IV administration of TNF-alpha did not result in visual tumor necrosis or significant reduction in the rate of tumor growth. IA administration of TNF-alpha resulted in statistically significant diminution of tumor size as compared to untreated controls and animals receiving IA 2% normal rat serum (NRS; P<0.05 at days 6, 8 and 10), regardless of the dose employed. The maximum growth inhibition with IA TNF-alpha was a 91% reduction in tumor volume that was achieved with a dose of 1 x 10(6) U TNF-alpha. These results demonstrate improved anti-tumor activity with the IA administration of TNF-alpha over the IV route in a regionally confined mammary adenocarcinoma. IA administration of biologic response modifiers like TNF-alpha may therefore be a useful approach for the hepatic chemoembolization of breast adenocarcinomas metastatic to the liver