Abstract 1673
Poster Board I-699
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.
ABT-263 is a novel, orally bioavailable BH3 mimetic that binds with high affinity (Ki ≤1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays potent mechanism-based activity ...(EC50 ≤ 1μM) against human lymphoid and small cell lung cancer cell-lines. Mechanistic toxicities observed preclinically include inhibition of spermatogenesis, reduction in circulating lymphocytes and decreased survival of circulating platelets, presumably mediated by inhibition of Bcl-w, Bcl-2 and Bcl-XL, respectively. Study M06-814, a phase 1 dose-escalation study is employing a modified Fibonaci 3 + 3 design to assess ABT-263 safety, pharmacokinetics and anti-tumor activity of two dosing schedules in patients with relapsed or refractory lymphoid malignancies. Enrollment continues with 42 patients (39 on a 14/21 day and 3 on a 21/21 day dosing schedule) enrolled. ABT-263 given on a 14/21 day dosing schedule began at 10 mg and continued escalation to 440 mg, with 315 mg defined as tolerable. The pharmacokinetic profile of ABT-263 on the 14/21 day schedule was linear from 10 – 440 mg with a t1/2 of 14 – 20 h. Consistent with preclinical models, a dose-dependent reduction in circulating platelets was observed. Typically, platelet nadirs were transient, occurring on days 3–5 with subsequent recovery during continued dosing, consistent with accelerated platelet apoptosis and compensatory increased bone marrow release and production. Thrombocytopenia was predictable and manageable. A one week lead-in dosing period at 150mg ABT-263 and a 21/21 day dosing schedule beginning at 200 mg, are being evaluated as measures to ameliorate the platelet nadir. Dose limiting toxicities on cycle 1 in the 14/21 day dosing schedule occurred at 160 mg (bronchitis), 315 mg (elevated ALT and gr 4 thrombocytopenia), and 440 mg (dyspnea). Responses were observed in 3 patients including a 75% and 99% reduction of bulky masses in 2 CLL/SLL and a 75% reduction in a NK/T cell lymphoma. Minor nodal responses occurred in 4 patients with follicular lymphoma and 3 patients with CLL/SLL. Additionally, 2 patients with CLL/SLL had ≥50% decreases in leukemic cells for at least 2 months. ABT-263 is a well tolerated oral small molecular inhibitor of Bcl-2 family proteins with a linear PK, toxicity profile indicative of on-target activity and anti-tumor activity in patients with relapsed or refractory lymphoid malignancies. Accrual continues.
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