Endostatin plus interferon-α2b therapy for metastatic melanoma: a novel combination of antiangiogenic and immunomodulatory agents

Abstract

In patients with stage IIB-III disease, adjuvant high-dose interferon-alpha2b has shown clinical benefit, although metastatic melanoma is currently without any known survival-prolonging therapy. Angiogenesis has been considered important in melanoma progression, and endostatin is an angiogenesis inhibitor with antitumor activity that has shown promising results in murine model systems, prompting investigation of a formulation of rh-Endostatin (EntreMed, Rockville, Maryland, USA) alone and with interferon in metastatic melanoma. Patients were randomly assigned to receive interferon alpha2b (Schering-Plough) 10 million units/m(2) subcutaneously three times a week plus rh-Endostatin 45 mg/m(2) subcutaneously every 12 h (arm A) vs. rh-Endostatin alone (arm B). Twenty-one patients (age range 31-77 years, median age 54, 12 men and nine women, 17 cutaneous, and four ocular melanomas) were enrolled. No antitumor responses were observed, and no significant differences were noted in time to progression or overall survival. Two patients had stable disease enduring more than 30 weeks on treatment. Serum endostatin levels increased significantly 4 weeks after treatment in both groups. Basic fibroblast growth factor levels in urine were significantly lower following treatment in patients on arm B (P=0.043). The percentage of circulating endothelial cells was increased in five evaluable patients 4 weeks after treatment. Low titer (<or=1:25) IgG antibodies against the rh-Endo formulation were detected in two patients (one per arm) in cycle 4. In conclusion, interferon did not improve response rate of rh-Endo although prolonged disease stability was observed in two patients. Better laboratory correlates of antiangiogenic response are needed, and the predictive value of circulating endothelial cells warrants further evaluation.

ECOG Phase II Trial of Graded-Dose Peginterferon α-2b in Patients with Metastatic Melanoma Overexpressing Basic Fibroblast Growth Factor (E2602)

“…In addition, FGF-2 and VEGF concentrations were not found to change significantly from baseline (26). Similar findings of dissociation between presence of clinical antitumor response and lack of angiogenic response were noted in several phase II trials using daily or intermittent regimens of recombinant non-pegylated interferon in conjunction with bevacizumab and endostatin (28–31). …”

The multiple functions of collagen XVIII in development and disease

“…The efficacy of endostatin has also been tested in some clinical trials. In one phase II study it failed to show any antitumorigenic effect on hypervascular neuroendocrine tumors (Kulke et al, 2006), and no antitumor response, as judged by standard response criteria, was observed in the treatment of melanoma with endostatin alone or in combination with interferon-α2b (Moschos et al, 2007). In China, however, endostatin has been approved as a treatment for non-small-cell lung cancer (Folkman, 2006).…”

Pharmacodynamic (Phase 0) Study Using Etaracizumab in Advanced Melanoma

“…7 However, a v b 3 signaling may induce production of VEGF by tumors 8 and therefore the lack of etaracizumab-induced changes in melanoma cell signal transduction molecules may reflect inability of etaracizumab treatment to suppress VEGF production by melanoma, an important prognostic factor in MM. 34 There are several explanations for these findings, such as insufficient etaracizumab dosing and insufficient interval (3 wk) to detect changes in proliferative VECs. Thus, etaracizumab's mechanism of action may need to be reexamined, as has been previously reported.…”