A Phase I/II Trial of the Kinesin Spindle Protein (KSP) Inhibitor SB-743921 Dosed Q14D without and with Prophylactic G-CSF in Non-Hodgkin (NHL) or Hodgkin Lymphoma (HL).

KSP is a mitotic kinesin essential for cell cycle progression. SB-743921, a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and cell death. In the first-in-humans (FIH) trial, the maximum tolerated dose (MTD) was 4 mg/m² q21d. Since neutropenia was the major dose-limiting toxicity (DLT), with recovery by ∼d15, a q14d schedule without (-GCSF) and with prophylactic G-CSF (+GCSF) is being explored.

In Phase I of this Phase I/II trial, DLT and MTD of SB-921 given on d1 and d15 q28d (-GCSF) and (+GCSF) were determined. Eligible patients (pts) had relapsed or refractory HL or NHL, aggressive (a) or indolent (i), had at least 1 prior chemotherapy (CT) regimen, and had relapsed after or were not candidates for stem cell transplant. This was a standard 3+3 dose escalation trial design, starting at 2 mg/m² and escalating by 1 mg/m². Once DLT (-GCSF) was identified, (+GCSF) dosing started at the (-GCSF) MTD, escalating until (+GCSF) DLT was identified. MTD was defined as one dose level below maximum administered dose (MAD). Response was assessed with IWG criteria (2007).

39 pts were treated (-GCSF) at 6 dose levels (2-7 mg/m²). Five pts had DLT: 1/3 at 4 (grade 3 hepatic enzyme elevation; found retrospectively); 2/10 at 6 (both sepsis with neutropenia), and 2/7 DLT-evaluable at 7 (both grade 4 neutropenia lasting >5d) mg/m². MTD (-GCSF) was 6 mg/m². 17 pts were treated with SB-743921 (+GCSF) at 6 (n=4), 7 (n=3), 8 (n=3) and 9 (n=7) mg/m², with 1 DLT of neutropenia lasting >5d at 9 mg/m². For all 56 pts treated at these dose levels, mean age was 51 yr; 54% were male; 39% HL, 30% aNHL, and 30% iNHL; 79% had ≥3 prior CT regimens. The most frequent grade 3/4 toxicity in Cycle 1 was neutropenia: 47% at ≥MTD (-GCSF) and 41% (+GCSF). Other grade 3/4 AEs (all cohorts combined, Cycle 1) were: thrombocytopenia 14% and anemia 5%; other grade 3/4 AEs were <5%. Nausea and diarrhea occurred in 13-14% of pts, all grade 1/2. There was no neuropathy or alopecia >grade 1. Seven pts were treated at 10 mg/m² (+GCSF): 2 were not DLT-evaluable; 2/5 DLT-evaluable pts had DLT of grade 4 thrombocytopenia. The SB-743921 (+GCSF) MAD was 10 mg/m² and the MTD was 9 mg/m². There were 4 partial responses (PR), 3 in HL (1 at 6; 1 at 8; and 1 at 9 mg/m²) and 1 in marginal zone NHL (at 9 mg/m²); duration of response was 8-28+ weeks. One pt with diffuse large B cell NHL remains on study with stable disease for >17 months.

The MTD of SB-743921 on a q14d schedule (-GCSF) was 6 mg/m² and (+GCSF) was 9 mg/m². These dose densities (0.43 and 0.64 mg/m²/d) are >2- and 3-fold higher, respectively, than in the FIH trial with a q21d schedule (0.19 mg/m²/d). SB-743921 is well tolerated with minimal toxicity other than hematologic. Activity has been observed in heavily pre-treated HL and NHL, with 4 PRs at doses ≥6 mg/m². SB-743921 warrants further investigation in lymphoma.

Chen:Cytokinetics: Employment. Saikali:Cytokinetics: Employment. Seroogy:Cytokinetics: Employment. Escandon:Cytokinetics: Employment. Wolff:Cytokinetics: Employment. Conlan:Cytokinetics: Employment.