A phase II study of the heparanase inhibitor PI-88 in patients with advanced melanoma

Abstract

Treatment options for advanced melanoma are limited. PI-88, a potent inhibitor of heparanase, demonstrates anitangiogenic properties and has shown activity against melanoma in phase I studies. This was an open-label, multicenter, phase II study of PI-88 in patients with advanced melanoma. Patients received a fixed-dose of 250 mg/day given subcutaneously for four consecutive days followed by three drug-free days per week in a 28-day cycle. A total of 44 patients were enrolled in the intent to treat population, with 59.1% having received previous therapy. The median time to progression and overall survival was 1.7 months and 9 months, respectively. Forty-one patients are included in the efficacy analysis. One (2.4%) patient achieved a partial response, six (14.6%) patients had stable disease as best response, and 30 (73.2%) had progressive disease. At the end of six cycles of treatment, three of the 41 evaluable patients had non-progressive disease. Treatment was generally well tolerated. Injection site bruising occurred in 45% of patients. Serious bleeding did occur in two patients and three patients developed a positive anti-platelet antibody test during the study. One of these four patients experienced an associated thrombosis. In patients with advanced melanoma, PI-88 demonstrates an overall survival and time to progression similar to standard chemotherapy. Although the current study did not meet the primary end-point of progression free survival of >or=20%, there is some evidence of activity and further investigation is warranted.

Role of Angiogenesis and Microenvironment in Melanoma Progression

“…PI-88, a potent inhibitor of heparanase, demonstrates an overall survival and time to progression similar to standard chemotherapy (Basche et al, 2006). In a phase II trial (Lewis et al, 2008) a total of 44 patients were enrolled with about 60% of them previously treated. The median time to progression and overall survival was 1.7 months and 9 months, respectively.…”

Alternatively splicedSpalaxheparanase inhibits extracellular matrix degradation, tumor growth, and metastasis

“…Hence, heparanase is a highly specific target for anticancer therapy; if successfully suppressed, inhibition of tumor growth, metastasis, and angiogenesis is expected to ensue (29,30). Several inhibitors of heparanase were developed mainly through screening of sulfated compounds, of which PI-88 is being tested in clinical trials (31). A glycol-split N-acetylated heparin (32) has been demonstrated to be highly effective in myeloma tumors (33) and will soon enter clinical trials.…”

Carbohydrate drugs: current status and development prospect

“…On the other hand, PI-88 which is primarily composed of highly sulfated oligomannose generated from yeast turns to be the most potential novel antitumor pharmaceutical exhibiting excellent antiangiogenic and anti-metastatic activities (33). PI-88 was initially developed by Progen while the Phase III clinical trial of PI-88 in hepatocellular carcinoma patients has been conducted all around the world by Taiwan Medigen Biotechnology Corporation since 2011 (34)(35)(36). Medigen reported that the treatment of patients was nearly completed and desirable results were expected.…”