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A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours.

Blagden SP, Molife LR, Seebaran A, Payne M, Reid AH, Protheroe AS, Vasist LS, Williams DD, Bowen C, Kathman SJ, Hodge JP, Dar MM, de Bono JS, Middleton MR - Br. J. Cancer (2008)

Bottom Line: The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel.One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease.Preliminary PK data suggest no interaction between ispinesib and docetaxel.

View Article: PubMed Central - PubMed

Affiliation: Royal Marsden Hospital and Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK.

ABSTRACT
The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6-12 mg m(-2)) and docetaxel (50-75 mg m(-2)). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m(-2) with docetaxel 60 mg m(-2). Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (>or=18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.

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Related in: MedlinePlus

Observed and historical docetaxel concentration time profiles. Graph showing concentration time profiles of docetaxel for patients in this study (at 60 and 75 mg m−2) compared to historical controls (at 35, 75 and 100 mg m−2).
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fig2: Observed and historical docetaxel concentration time profiles. Graph showing concentration time profiles of docetaxel for patients in this study (at 60 and 75 mg m−2) compared to historical controls (at 35, 75 and 100 mg m−2).

Mentions: Using this model, ispinesib plasma concentrations in cycle 1 were consistent with those observed in phase I studies, as shown in Figure 1. Docetaxel PK parameters were consistent with those reported historically despite the co-administration of ispinesib (Figure 2; Baker et al, 2003).


A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours.

Blagden SP, Molife LR, Seebaran A, Payne M, Reid AH, Protheroe AS, Vasist LS, Williams DD, Bowen C, Kathman SJ, Hodge JP, Dar MM, de Bono JS, Middleton MR - Br. J. Cancer (2008)

Observed and historical docetaxel concentration time profiles. Graph showing concentration time profiles of docetaxel for patients in this study (at 60 and 75 mg m−2) compared to historical controls (at 35, 75 and 100 mg m−2).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2266864&req=5

fig2: Observed and historical docetaxel concentration time profiles. Graph showing concentration time profiles of docetaxel for patients in this study (at 60 and 75 mg m−2) compared to historical controls (at 35, 75 and 100 mg m−2).
Mentions: Using this model, ispinesib plasma concentrations in cycle 1 were consistent with those observed in phase I studies, as shown in Figure 1. Docetaxel PK parameters were consistent with those reported historically despite the co-administration of ispinesib (Figure 2; Baker et al, 2003).

Bottom Line: The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel.One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease.Preliminary PK data suggest no interaction between ispinesib and docetaxel.

View Article: PubMed Central - PubMed

Affiliation: Royal Marsden Hospital and Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK.

ABSTRACT
The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6-12 mg m(-2)) and docetaxel (50-75 mg m(-2)). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m(-2) with docetaxel 60 mg m(-2). Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (>or=18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.

Show MeSH
Related in: MedlinePlus