Pilot study of vitaxin?an angiogenesis inhibitor?in patients with advanced leiomyosarcomas

Leiomyosarcomas comprise one of the common histologic subsets of a rare and heterogenous group of tumors called soft tissue sarcomas. Leiomyosarcomas have a variable biologic behavior depending on their site of origin. Tumors originating in the gastrointestinal (GI) tract belong to a broader class of tumors called GI stromal tumors and are refractory to standard chemotherapeutic agents such as doxorubicin and ifosfamide. Those originating outside the GI tract, especially the ones arising from the uterus, conversely are indeed sensitive to these standard chemotherapeutic agents.1 Unfortunately, the options for salvage chemotherapy after failure of initial therapy with standard agents are very limited, and therefore newer strategies need to be investigated aggressively. Angiogenesis is critical for the growth and development of tumor. It is a complicated process initiated by the expression of several proteases and growth factors acting as angiogenic molecules. The migration of endothelial cells is dependent on their adhesion to extracellular matrix proteins, such as vitronectin, through a variety of cell adhesion receptors known as integrins. The role of the integrin αvβ3 in the angiogenic process has been established.2-5 Blocking neoangiogenesis by inhibiting the ανβ3 integrin therefore can result in antitumor activity. We tested Vitaxin, a humanized monoclonal antibody targeted against the endothelial cell ανβ3 integrin in a group of patients with advanced leiomyosarcomas with an intent to test feasibility and safety and to better estimate the antitumor activity that was observed in one patient with liver metastases from a leiomyosarcoma in the Phase I study of Vitaxin performed at the Sidney Kimmel Cancer Center in San Diego, California.6 Vitaxin was administered intravenously as an outpatient at a fixed dose of 0.25 mg/kg over 90 minutes every week. Therapy was continued until maximal response or significant tumor progression or Grade 3–4 toxicity occurred or up to a maximum of 6 months. This protocol was approved by our institutional review board. In total, 15 patients with advanced, previously progressing, measurable or evaluable disease were entered on the study between January and April 1999, after informed consent was obtained. (Table 1) The median age of the group was 55 years (range, 34–77 years). There were 10 males and 5 females. Fourteen of 15 patients had a Zubrod performance status of 0–1. Nine patients had leiomyosarcomas of GI origin. Eleven patients had received prior systemic therapy (median, 2 regimens), 1 had prior immunotherapy, 14 had prior surgery, and 4 had prior radiation therapy. No concurrent therapy was allowed. Patients received Vitaxin for a median of 6 months (range, 1–8 months). No objective response or significant stabilization of disease was noted. One patient had resection of an increasingly necrotic chest wall mass that showed greater than 90% tumor necrosis; however, his liver metastases progressed simultaneously. Grade 3 headache, fatigue, vomiting, edema, and myalgia were noted in one patient each, and one patient had Grade 4 nausea. In general, the treatment was well tolerated. This study has shown feasibility and an acceptable toxicity profile of Vitaxin administered over several months. It failed to show any evidence of antitumor activity in patients with advanced leiomyosarcomas. Possible explanations may include suboptimal dose and schedule that is an inherent problem with many biologic agents or the advanced nature of the disease in these patients. It is possible that the most appropriate setting for the use of antiangiogenic agents may be as adjuvant therapy in patients at a high risk for recurrence evaluating time to progression as an endpoint or in combination with cytotoxic agents when used for patients with advanced disease. Further studies addressing these issues are warranted for this group of drugs.