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).
Authors: O'Connor Owen A , Gerecitano J. , Van Deventer H. , Afanasyev B. , Hainsworth J. , Chen M. , Saikali K. , Seroogy J. , Escandon R. , Wolff A. , Conlan MG. 
Published: October 2019

Abstract
Abstract 1673
Poster Board I-699

Background
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.

Methods
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).

Results
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.

Conclusions
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.

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