Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days

Chu, Qiuming; Holen, Kyle D.; Rowinsky, Eric K.; Wilding, George; Volkman, Jennifer; Orr, J. B.; Williams, D.; Hodge, Jeffrey; Sabry, James H.

doi:10.1200/jco.2004.22.90140.2078

Cited by 13 publications

(10 citation statements)

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“…Similar to adult trials, (9, 12-14) we observed a high degree of interpatient variability in the drug disposition (Table V, Figure 1). The estimated median (range) terminal t 1/2 of 16 hours (8-44 hours) in children appeared to be independent of dose (5-12 mg/m 2 ).…”

Section: Discussionsupporting

confidence: 78%

“…The estimated median (range) terminal t 1/2 of 16 hours (8-44 hours) in children appeared to be independent of dose (5-12 mg/m 2 ). This high degree of interpatient variation is similar to that observed in adult trials, with reports of terminal half-lives ranging from 17 to 56 hours with doses of 1-21 mg/m 2 ,(9) 20 to 53 hours with doses of 1-21 mg/m 2 ,(15) and 13 to 96 hours with doses of 1-8 mg/m 2 . (14) Thus the lower median terminal half-life observed in children should be interpreted with caution, as the small number of subjects studied and limited duration of sampling in both adult and pediatric subjects cannot allow us to conclude that true differences exist in drug disposition.…”

Section: Discussionsupporting

confidence: 77%

“…Four dosing regimens have been explored in adult patients with solid tumors: once every 21 days found the maximum tolerated dose (MTD) to be 18 mg/m 2 /dose (9), on a weekly × 3 every 28 days schedule the MTD was 7 mg/m 2 /dose (10), on a day 1, 2 and 3 every 21 days schedule the MTD was 6 mg/m 2 (24), and on a day 1 and day 15 every 28 days schedule in patients with breast cancer the MTD was 12 mg/m 2 (25). Neutropenia was dose-limiting on the first three schedules; liver transaminase elevations were dose-limiting on the every 14 day schedule.…”

Section: Introductionmentioning

confidence: 99%

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A pediatric phase I trial and pharmacokinetic study of ispinesib: A Children's Oncology Group phase I consortium study

Souid

Dubowy

Ingle

et al. 2010

Pediatric Blood & Cancer

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Purpose To determine the maximum-tolerated dose, dose-limiting toxicities and pharmacokinetics of the kinesin spindle protein inhibitor ispinesib in pediatric patients with recurrent or refractory solid tumors. Subjects and Methods Ispinesib was administered as 1-hour intravenous infusion weekly × 3, every 28 days. Cohorts of 3-6 patients were enrolled at 5, 7, 9 and 12 mg/m2/dose. Serial plasma samples for pharmacokinetic analyses were obtained after the first dose. Results Twenty-four (13 females) patients with a median (range) age of 10 years (1-19) were enrolled on the study. At the 12 mg/m2 dose level dose-limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients, while at the 9 mg/m2 dose level 1/6 patients had dose-limiting neutropenia. There were no objective responses, but 3 patients (diagnoses of anaplastic astrocytoma, alveolar soft part sarcoma and ependymoblastoma) had stable disease for 4 to 7 courses. There was substantial inter-patient variation in drug disposition. The median (range) terminal elimination half-life was 16 hours (8-44) and the plasma drug clearance was 5 L/hr/m2 (1-14). Conclusions The maximum tolerated and recommended phase II dose for ispinesib administered weekly × 3 every 28 days for children with solid tumors is 9 mg/m2/dose. Plans for a phase II trial in select pediatric solid tumors are in development.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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A pediatric phase I trial and pharmacokinetic study of ispinesib: A Children's Oncology Group phase I consortium study

Souid

Dubowy

Ingle

et al. 2010

Pediatric Blood & Cancer

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show abstract

“…This dose (150 nmol/L) is also comparable with the estimated free fraction of ispinesib at C max at doses producing detectable antitumor activity in clinical studies (~120 nmol/L; refs. 16, 20). In the absence of drug, the proportion of cells within G 2 or M phases of the cell cycle in MDA-MB-468 was twice that of BT-474.…”

Section: Resultsmentioning

confidence: 99%

Activity of the Kinesin Spindle Protein Inhibitor Ispinesib (SB-715992) in Models of Breast Cancer

Purcell

Davis

Reddy

et al. 2010

Clinical Cancer Research

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Purpose: Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer.Experimental Design: We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies.Results: In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone.Conclusions: These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer. Clin Cancer Res; 16(2); 566-76. ©2010 AACR.

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“…Four dosing regimens have been explored in adult patients with solid tumors: once every 21 days found the maximum‐tolerated dose (MTD) to be 18 mg/m 2 /dose 10, on a weekly × 3 of every 28 days schedule the MTD was 7 mg/m 2 /dose 11, on days 1, 2, and 3 of every 21 days schedule the MTD was 6 mg/m 2 12, and on days 1 and 15 of every 28 days schedule in patients with breast cancer the MTD was 12 mg/m 2 13. Neutropenia was dose‐limiting on the first three schedules; liver transaminase elevations were dose‐limiting on the every 14‐day schedule.…”

Section: Introductionmentioning

confidence: 99%

Study of the flexural modulus of natural fiber/polypropylene composites by injection molding

Shibata¹,

Cao²,

Fukumoto³

2006

J of Applied Polymer Sci

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Effect of fiber compression on flexural modulus of the natural fiber composites was examined. The kenaf, bagasse, and polypropylene were mixed into pellets, and composites were fabricated by injection molding. To predict flexural modulus of the composites, the Young's modulus of kenaf and bagasse fiber were measured. Using the obtained Young's modulus, the flexural modulus of the composites was predicted by Cox's model that incorporates the effect of fiber compression. It was found that those fibers with high Young's modulus were more compressed than that with low Young's modulus. Moreover, the distribution of fiber length and orientation in the composites were also investigated. To calculate the orientation factor for the prediction model, the distribution function of fiber orientation was determined to a triangular function. The flexural modulus of the composites increased with increase of volume fraction. The predicted values were in good agreement with the experimental values. Furthermore, it was revealed by SEM that the porous structure of the natural fibers was compressed. The fiber compression ratio (3.6) in bagasse was higher than that in kenaf (1.4) due to the difference in porous structure.

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Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days

Cited by 13 publications

References 0 publications

A pediatric phase I trial and pharmacokinetic study of ispinesib: A Children's Oncology Group phase I consortium study

A pediatric phase I trial and pharmacokinetic study of ispinesib: A Children's Oncology Group phase I consortium study

Activity of the Kinesin Spindle Protein Inhibitor Ispinesib (SB-715992) in Models of Breast Cancer

Study of the flexural modulus of natural fiber/polypropylene composites by injection molding

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