Phase I study of ispinesib in combination with carboplatin in patients with advanced solid tumors

Abstract

2027 Background: Kinesin spindle protein (KSP) is required for establishment of mitotic spindle bipolarity and cell cycle progression. Ispinesib (SB-715992), a KSP inhibitor, blocks assembly of a functional mitotic spindle leading to G2/M arrest. Carboplatin is a platinum compound that produces predominantly interstrand DNA cross-links. In vivo combination of a platinum-containing agent (cisplatin) and ispinesib resulted in synergistic activity and an increase in maximum tolerated dose (MTD) of ispinesib. In a phase I study of single agent ispinesib on a once every 21-day schedule, the MTD was 18 mg/m2 with prolonged gr 4 neutropenia and febrile neutropenia as DLTs. Methods: Patients (pts) with advanced solid tumors, PS ≤ 1, and ≤ 3 prior chemotherapy regimens were eligible for this study. Escalating doses of carboplatin (AUC 4-6) were administered over 30 minutes followed by a 1-hour infusion of escalating doses of ispinesib (9– 21 mg/m2) on a 21-day schedule. At least 3 pts were treated at each dose level. The primary objectives of this study included characterizing safety and tolerability and defining the optimally tolerated regimen (OTR). Limited pharmacokinetic (PK) samples were obtained. Clinical response assessments per RECIST criteria were performed every 2 cycles. Results: 24 pts [15 M/9 F; median age 63yrs, ECOG PS 1], were treated at 6 dose levels. The most common tumor types were prostate (7) and breast (4). A median of 3 cycles were administered (range 1–7; total 75 cycles). In 17 pts, the most common toxicities were (# pts, [grade]): nausea (10, Gr 1–2), vomiting (8, Gr 1–3), fatigue (8, Gr 1–2), neutropenia (8, Gr 2–4), anemia (7, Gr 1–3), and thrombocytopenia (7, Gr 1–4). Gr 4 thrombocytopenia was the observed DLT in 2 pts [ispinesib (mg/m2)/carboplatin (mg/ml·min) (# pts): 15/6 (1); 18/6 (1). PK assessment of ispinesib and carboplatin will be completed when the OTR has been defined. Unconfirmed minor responses have been observed in 3 pts (breast, prostate, NSCLC) starting at doses of 18/6. Conclusions: Determination of an OTR is ongoing. Ispinesib doses ≥ single agent MTD when combined with carboplatin AUC 6 have an acceptable tolerability profile and demonstrate preliminary evidence of anti-tumor activity. [Table: see text]

Second-Generation Antimitotics in Cancer Clinical Trials

“…In the phase I study in combination with Docetaxel, the MTD was established as 10 mg/m 2 of Ispinesib and 60 mg/m 2 of Docetaxel; prolonged neutropenia and febrile neutropenia were the DLTs observed, although the safety profile was considered acceptable and manageable [ 187 ]. Similar results were obtained with Carboplatin and Capecitabine, in which the best response was SD, and the DLTs observed were thrombocytopenia and neutropenia, respectively [ 188 , 189 ]. The efficacy outcomes with Ispinesib as monotherapy in patients with liver cancer (NCT00095992), metastatic prostate cancer (NCT00096499), recurrent or metastatic squamous cell carcinoma of the head and neck (NCT00095628), melanoma (NCT00095953), and metastatic kidney cancer (NCT00354250) were also disappointing, with SD being the best response [ 190 , 191 , 192 , 193 , 194 ].…”

“…Ispinesib, developed by Cytokinetics and GlaxoSmithKline, was the first Eg-5 inhibitor to enter clinical trials. Thirteen studies have been completed or terminated as monotherapy against solid and hematological tumors, and three phase I/II trials in combination with Docetaxel (NCT00169520), Capecitabine (NCT00119171), and Carboplatin (NCT00136578) against solid tumors have also been completed [ 187 , 188 , 189 ]. In the phase I study in combination with Docetaxel, the MTD was established as 10 mg/m 2 of Ispinesib and 60 mg/m 2 of Docetaxel; prolonged neutropenia and febrile neutropenia were the DLTs observed, although the safety profile was considered acceptable and manageable [ 187 ].…”

Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity

“…While the monotherapy generally failed, the combination therapy approach led to some promising results, 25 with the best responses achieved for ispinesib with capecitabine 26 and carboplatin. 27 The success of platinum-based drugs in cancer therapy 28 inspired scientists to evaluate other metal-based drug candidates. Recent progress in bioorganometallic chemistry led to the discovery of highly active compounds bearing organometallic moieties.…”

“…While the monotherapy generally failed, the combination therapy approach led to some promising results, 25 with the best responses achieved for ispinesib with capecitabine 26 and carboplatin. 27…”