A phase I-II trial of the kinesin spindle protein (KSP) inhibitor SB-743921 on days 1 and 15 every 28 days in non-Hodgkin or Hodgkin lymphoma

Abstract

8539 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. In the first-in-humans (FIH) trial, the maximum tolerated dose (MTD) was 4 mg/m2 q21 days (d), i.e., 0.2 mg/m2/d. Neutropenia was the major dose-limiting toxicity (DLT). Methods: Phase I of this trial determines the MTD of SB-921 without prophylactic GCSF (pGCSF) in patients (pts) with Non-Hodgkin (NHL) or Hodgkin Lymphoma (HL). Eligible pts with relapsed or refractory lymphoma had at least 1 prior chemotherapy regimen, and had 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 a DLT. Results: To date, 32 pts have received ≤ 7 mg/m2 of SB-921; 14 had HL; 18 had NHL (9 indolent, 9 aggressive). Thirty-one pts had ≥ 2 prior chemotherapy regimens (14 had ≥ 5). Cycle 1 neutropenia ≥ grade 3 occurred in 7 pts. Two DLTs at 6 mg/m2 occurred with ≥ grade 3 neutropenia; one was noted after escalation to 7 mg/m2, a dose tolerated through cycle 1 without DLT by 3 pts. Cycle 1 drug-related non-hematologic toxicities ≥ grade 3 were infection (1), dehydration (1) and dyspnea (1). A HL pt had a partial response (PR) for 4 cycles at 6 mg/m2; a NHL pt begun at 3 mg/m2 and escalated to 5 mg/m2 had stable disease for 13 cycles. Conclusions: SB-921 is well tolerated without pGCSF at < 6 mg/m2 and possibly at ≥ 7 mg/m2 given d1/d15 q28d, an increase from the MTD of 4 mg/m2 q21d in the FIH trial (possibly ≥ 0.5 vs. 0.2 mg/m2/d). The 6 mg/m2 cohort was expanded and may allow re-escalation to > 7 mg/m2. A HL pt had a PR at 6 mg/m2. If the MTD without pGCSF is neutropenia, the MTD will next be determined with pGCSF. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cytokinetics