A Phase I-II Study To Determine the Safety, Pharmacokinetics and Potential Efficacy of the Kinesin Spindle Protein (KSP) Inhibitor SB-743921 on Days 1 and 15 of a 28 Day Schedule in Patients with Non-Hodgkin’s or Hodgkin’s Lymphoma.

Background: KSP is required for mitotic spindle bipolarity and cell cycle progression. SB-743921 (SB-921) is a selective KSP inhibitor blocking assembly of the mitotic spindle, causing cell cycle arrest in mitosis and subsequent cell death. Neutropenia was the dose-limiting toxicity (DLT) in the first-in-human study of SB-921 and the maximum tolerated dose (MTD) was 4 mg/m² when given on a Q21 day dosing schedule.

Methods: Data from the Phase I portion of this 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 (HD) are reported. Pts with relapsed or refractory lymphoma were eligible if they had received at least 1 prior chemotherapy regimen, had relapsed after high-dose therapy with autologous stem cell transplant (ASCT), or were not candidates for ASCT. SB-921 was given in cohorts of 3–6 pts as a 1 hour IV infusion on day 1 and 15 of a Q28 day dosing schedule (cycle). Dosing began at 2 mg/m² and escalated in 1 mg/m² increments. Pts without DLT not completing Cycle 1 were replaced. Cohort expansion to 6 pts occurred if 1/3 pts experienced a DLT, defined as any drug-related non-hematologic toxicity ≥ grade 3 or grade 4 neutropenia ≥ 5 days or neutropenic fever/sepsis.

Results: Twenty four pts were treated to date, with the highest dose studied being 6 mg/m². Twenty three patients had > 2 prior regimens and 10 had > 5 prior regimens. The median age was 48 yrs (24–78); Of the 24 patients receiving one dose, 9 pts had HD and 15 had NHL (7 indolent, 8 aggressive); 14 were female, 21 were Caucasian and 3 were African-American. The median number of cycles was 2 (1–9). Two septic DLTs were reported at 6 mg/m² associated with grade 4 neutropenia. Overall, dose related grade 3 (3 pts) and grade 4 (3 pts) neutropenia was reported in 6 patients. Grade 4 neutropenia resolved in all pts in < 5 days. There was 1 grade 3 and no grade 4 anemia. Two pts had grade 3 thrombocytopenia. Two pts had lymphopenia, 1 grade 3 and the other grade 4. There was 1 report of grade 3 nausea and vomiting but most other non-hematologic adverse events were grade 1–2. There was 1 report each of grade 1 neuropathy and alopecia. A 78 yr old woman with HD in second relapse (after receiving ABVD and ICE) had a partial response at 6 mg/m² and a 24 year old with small cleaved cell, follicular lymphoma (progressed after R-CHOP chemotherapy, R-ICE and APSCT) initially treated at 3 mg/m² (subsequently escalated to 5 mg/m²) had stable disease for 9 cycles.

Conclusions: These data suggest that SB-921 was well tolerated without prophylactic GCSF in doses < 6 mg/m² in this Phase I study. The septic DLTs were associated with neutropenia of < 5 days. The cohort at 5 mg/m² has been expanded and pending data review, dose escalation will continue. A partial response was seen in a patient with refractory HD at 6 mg/m². Future directions of the study are to try and mitigate the DLT of neutropenia with concurrent growth factor support.