Ispinesib, a novel small molecule inhibitor of kinesin spindle protein (KSP) has been the subject of nine Phase II clinical trials and eight Phase I or Ib clinical trials evaluating ispinesib in a variety of both solid and hematologic cancers. To date, we believe clinical activity for ispinesib has been observed in non-small cell lung, ovarian and breast cancers, with the most clinical activity observed in a Phase II clinical trial evaluating in the treatment of patients with locally advanced or metastatic breast cancer that had failed treatment with taxanes and anthracyclines. In addition, preclinical and Phase Ib clinical data on ispinesib indicate that it may have an additive effect when combined with existing chemotherapeutic agents. We retain all development and commercialization rights to ispinesib.
Breast Cancer: In June 2009, at the American Society of Clinical Oncology meeting, Cytokinetics presented data interim data from the Phase I portion of a Phase I/II clinical trial evaluating ispinesib in patients with advanced breast cancer. The primary objectives of the Phase I portion of this clinical trial are to determine the dose-limiting toxicities (DLTs) and maximum-tolerated dose and to assess the safety and tolerability of ispinesib administered as a 1-hour intravenous infusion on days 1 and 15 of a 28-day cycle. The secondary objectives are to characterize the pharmacokinetics of ispinesib on this schedule and to evaluate the potential effect of ispinesib on biomarkers of cell proliferation in patients with accessible tumors. The authors concluded that one Response Evaluation Criteria in Solid Tumors (RECIST)-confirmed partial response (PR) with a duration of 6 months has been reported. Also, two additional patients had a best response of PR (unconfirmed), and 10 additional patients have had stable disease not reaching PR criteria, four of which had a duration of 4 or more months. The authors also noted that protocol-defined DLTs of Grade 3 ALT/AST increases with questionable relationship to study drug were observed in two out of seven patients treated at the 14 mg/m2 dose level. The 12 mg/m2 cohort has been expanded to six patients with no observed DLTs. The protocol has been amended to further evaluate the 14 mg/m2 dose level.
Previously, in December 2008, at the San Antonio Breast Cancer Symposium, Cytokinetics presented interim results from the Phase I portion of its Phase I/II clinical trial of ispinesib. Interim data demonstrated that this drug candidate was well-tolerated when administered as a 1-hour intravenous infusion on days 1 and 15 of a 28-day cycle, with the most frequent adverse event being neutropenia. The best responses observed to date were investigator-reported tumor reductions of 30% or greater in the sum of the target lesion diameter, reported in 3 patients. One of these patients had an investigator-reported PR according to the RECIST. Cytokinetics continues to enroll and dose-escalate patients in the Phase I portion of this trial.
In June 2007, Cytokinetics reported final results of a Phase II clinical trial conducted previously designed to evaluate the safety and efficacy of ispinesib in patients with locally advanced or metastatic breast cancer whose disease had recurred or progressed despite treatment with anthracyclines and taxanes. In that trial, patients received ispinesib as monotherapy at 18 mg/m2 as a 1-hour intravenous infusion every 21 days. The primary endpoint of the trial was objective response by RECIST. Partial responses, observed in 4 of 45 evaluable patients, were confirmed by independent radiology review and were seen in liver, lung and lymph node metastases. The duration of these responses, also independently reviewed, ranged from 6.9 weeks to 19.1 weeks. The median time to progression in the treated population was 5.9 weeks. The adverse events were manageable, predictable and consistent with those seen in the Phase I trials of ispinesib. The most common grade 3/4 adverse events observed in the 50 patients evaluable for safety were neutropenia (21 patients), febrile neutropenia (4 patients) and neutropenic sepsis (1 patient).