A phase II study of ispinesib (SB-715992) in patients with metastatic or recurrent malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group trial

Abstract

To assess the response rate and toxicity of the kinesin spindle protein (KSP) inhibitor, ispinesib, in malignant melanoma. Seventeen patients were enrolled from April to November 2005. Ispinesib was administered as a 1-hour infusion at a dose of 18 mg/m2 once every 3 weeks until disease progression. No objective responses were seen. Six patients (35%) had a best response of stable disease for a median duration of 2.8 months. Disease progression was documented in 9 (53%) after 1 or 2 cycles. Eighty-eight percent of patients received > or =90% of planned dose intensity. Grade 3 non-hematologic toxicities included dizziness (1) and blurred vision (1). There was one episode of febrile neutropenia, but no grade 3 or 4 biochemical adverse events. Pharmacokinetics was consistent with prior studies. KSP immunoreactivity was seen in 14 of 16 available archival tissue samples (88%). Ispinesib can be safely administered using the dose and schedule employed, with mild hematologic and non-hematologic toxicity. No objective responses were observed, and further development of single-agent ispinesib in malignant melanoma is not recommended. Although KSP expression appears to be common in melanoma, KSP may not be a suitable target for its treatment.

Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications

“…In this study, no conclusive evidence of benefit was seen with ispinesib monotherapy. Similar results were obtained from the phase II study in patients with metastatic or recurrent malignant melanoma (44). Although KSP expression seems to be common in melanoma and KSP would be an appropriate target for inhibition, no significant responses were observed in response to ispinesib and further development in malignant melanoma is not recommended.…”

Mitotic drivers—inhibitors of the Aurora B Kinase

“…In mousebased xenograft models, Ispinesib inhibits tumour growth, and encouragingly, monopolar spindles were evident in tumour biopsies, indicating that KSP was targeted in vivo. Importantly, in Phase I clinical trials with Ispinesib and two other KSP inhibitors, namely SB-743921 and MK-0731, neuropathy was not reported as a major side effect; as expected for a cytotoxin, the dose limiting toxicities were neutropenia [16][17][18]. Thus, the KSP inhibitors appear to have achieved one major goal, namely the elimination of neurotoxicities.…”

Functional Genetic Screens Identify Genes Essential for Tumor Cell Survival in Head and Neck and Lung Cancer

“…Multiple clinical studies on the antitumor activity of ispinesib confirmed the absence of significant neuro-and gastrointestinal toxicities, which makes ispinesib favorable over other mitotic spindle interfering drugs. Several phase I clinical trials (30)(31)(32) and at least 4 phase II trials (33)(34)(35)(36) on the application of ispinesib in cancer treatment have been described in literature. The studies were conducted with a variety of dose and treatment schedules in multiple tumor types, making a good comparison between the trials difficult.…”