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

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.

SUBMITTER: Blagden SP

PROVIDER: S-EPMC2266864 | biostudies-other | 2008 Mar

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC. METHODS:Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75?mg/m2, with or without sunitinib 12.5?mg daily for 7?days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR?+?PR) and clinical-benefit rate (CBR:CR?+?PR?+?SD); secondary endpoints were toxicity and progression-free-survival (PFS). RESULTS:We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p =?0.432, odds-ratio [OR] 1.10, 95% CI 0.38-3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p =?0.027 OR 0.37, 95% CI 0.14-1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9?months, hazard-ratio [HR] 2.00, 95% CI 1.15-3.48, p =?0.014) overall, as well as in breast (4.2 vs 5.6?months, p =?0.048) and other cancers (2.0 vs 5.3?months, p =?0.009), but not in lung cancers (2.9 vs 4.1?months, p =?0.597). Median OS was similar in both arms overall (9.9 vs 10.5?months, HR 0.92, 95% CI 0.51-1.67, p =?0.789), and in the breast (18.9 vs 25.8?months, p =?0.354), lung (7.0 vs 6.7?months, p =?0.970) and other cancers (4.5 vs 8.8?months, p =?0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p =?0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p =?0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p =?0.792). CONCLUSIONS:The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial. TRIAL REGISTRATION:The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.

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

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