A Phase I/II Trial of the Kinesin Spindle Protein (KSP) Inhibitor SB- 743921 Administered on Days 1 and 15 Every 28 Days without and with Prophylactic G-CSF in Non-Hodgkin or Hodgkin Lymphoma.

Background: KSP is a mitotic kinesin essential for cell cycle progression. SB-743921 (SB-921), a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and cell death. Since neurons lack a mitotic spindle, neurotoxicty, common with anti-tubulins, is not expected. In the first-in-humans (FIH) trial, the maximum tolerated dose (MTD) was 4 mg/m² q21 days (d), a dose density of 0.2 mg/m²/d. Since neutropenia was the major dose-limiting toxicity (DLT), with nadir at ~d8 and recovery by ~d15, a q14d schedule without (−GCSF) and with prophylactic G-CSF (+GCSF) is being explored in this trial.

Methods: In Phase I of this Phase I/II trial, the MTD of SB-921 (−GCSF) and (+GCSF) will be determined. In Phase II, efficacy and safety of the MTD will be further explored. Eligible patients (pts) have relapsed or refractory Hodgkin (HL) or non-Hodgkin (NHL) lymphoma, aggressive (a) or indolent (i), have had at least 1 prior chemotherapy (CT) regimen, and have relapsed after or were not candidates for autologous stem cell transplant. SB-921 is given to cohorts of 3 on d1/d15 q28d, starting at 2 mg/m² and escalating by 1 mg/m². Cohorts expand to 6 if 1/3 pts have DLT. Once DLT (−GCSF) is identified, (+GCSF) dosing begins at the (−GCSF) MTD, escalating in 1 mg/m² increments until (+GCSF) DLT is identified.

Results: The (−GCSF) cohort included 39 pts treated at 6 dose levels (2–7 mg/m²) of SB-921. DLT was reported in 4 pts: 2/10 at 6 mg/m² (both neutropenia with sepsis) and 2/7 at 7 mg/m² (both Grade 4 neutropenia lasting >5d). MTD (−GCSF) was 6 mg/m². Ten pts have been treated with SB-921 (+GCSF) at 6 (n=4), 7 (n=3) and 8 (n=3) mg/m², with no DLT. Enrollment at 9 mg/m² is ongoing. Among the first 39 pts treated with SB-921 (−GCSF), mean age was 47 yr, 49% were male, histology was 46% HL, 28% aNHL, and 26% iNHL, 67% had ≥3 prior CT regimens. The most common Grade 3/4 adverse event (AE) was neutropenia (42% of pts treated at or above MTD). Other Grade 3/4 AEs were uncommon. No neuropathy or alopecia >Grade 1 was reported. Demographics and AEs in the (+GCSF) cohort are similar with less Grade 3/4 neutropenia. Two partial responses (PRs) have been reported, both in elderly pts with HL, 1 at 6 mg/m² (−GCSF) after 2 cycles and 1 at 8 mg/m² (+GCSF) after 2 cycles.

Conclusions: The MTD of SB-921 (−GCSF) on a d1/d15 q28d schedule was 6 mg/m² (dose density = 0.42 mg/m²/d). The current MTD (+GCSF) is ≥8 mg/m² and dose escalation is continuing. This dose density (0.57 mg/m²/d) is nearly 3-fold higher than observed in the FIH trial with a q21d schedule (0.2 mg/m²/d). SB-921 is well tolerated with few Grade 3/4 AEs other than hematologic. Activity has been observed in HL, with 2 PRs at doses ≥ the (−GCSF) MTD.