A phase I-II study to assess the safety, pharmacokinetics, and potential efficacy of intravenous SB-743921 on days 1 and 15 of a 28-day cycle in patients with non-Hodgkin lymphoma

Abstract

18516 Background: Kinesin spindle protein (KSP) is required for mitotic spindle bipolarity and cell cycle progression. SB-743921 (SB- 921), a selective KSP inhibitor, blocks mitotic spindle assembly, causing cell cycle arrest in mitosis and subsequent cell death. Neutropenia was the dose-limiting toxicity (DLT) in the first-in-humans study of SB-921 given Q21 days. Methods: Cohort 1 of the Phase I portion of a study determining the safety, pharmacokinetics and MTD of SB-921 without prophylactic GCSF in patients (pts) with Non-Hodgkin’s Lymphoma (NHL) or Hodgkin’s Disease is reported. Pts with relapsed or refractory disease were eligible if they had received at least one prior chemotherapy regimen, had failed high-dose therapy with autologous stem cell transplant (ASCT), or were not candidates for ASCT. SB-921 is given to dose-escalating cohorts of 3 pts as a 1 hr IV infusion, Q14 days. Dosing began at 2 mg/m2 and escalated in 1 mg/m2 increments after 3 pts tolerated 1 cycle. Pts without dose-limiting toxicity (DLT) not completing Cycle 1 are replaced. Cohort expansion to 6 pts occurs if 1/3 pts experiences DLT, defined as any drug-related toxicity = grade 3 or drug-related grade 4 hematologic toxicity. Results: Cohort 1 (2 mg/m2) enrolled 6 NHL pts (5 indolent, 1 aggressive). 4 were female; median age = 59 (52–73); 5 Caucasian, 1 African-American; median no. of cycles = 2 (1–6). 5/6 pts were evaluable; 1 dropped out before dosing. The most common Grade 1–2 AEs, in decreasing order, were fatigue, dysgeusia, paresthesia, leukopenia, and diarrhea. Grade 3 AEs of note were 1 each of hemolytic anemia, leukopenia, thrombocytopenia and dyspnea; 1 Grade 4 anemia was reported. Conclusions: SB-921 was well tolerated without prophylactic GCSF in Cohort 1 of the Phase I portion of this study, which continues to dose-escalate. If neutropenia is the DLT, dose escalation will continue with prophylactic GCSF. No significant financial relationships to disclose.