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Publications (5)34.4 Total impact

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    ABSTRACT: Vascular endothelial growth factor (VEGF) signalling plays a key role in tumour angiogenesis. Cediranib (AZD2171) is a small-molecule VEGF signalling inhibitor with potent activity against all three VEGF receptors. In this phase I, open-label, parallel-group study, adults with advanced solid tumours received a single 45 mg dose of cediranib, followed by 30 mg continuous once-daily oral dosing for 21 days after a 7-day washout period (clinicaltrials.gov identifier NCT00621725). The primary objective was to compare the single-dose pharmacokinetics (PK) of cediranib in patients with different levels of hepatic impairment classified according to the bilirubin level. Safety, tolerability, multiple-dose PK and PK stratified according to the Child-Pugh criteria were also assessed. Thirty patients received cediranib: 18 with normal-mild hepatic impairment and 12 with moderate hepatic impairment. Single-dose PK parameters were similar between the group with normal-mild hepatic impairment and the group with moderate hepatic impairment [ratio of geometric least square means: area under the curve (AUC) 1.12, 90% confidence interval (CI) 0.77-1.61; Cmax 0.95, 90% CI 0.69-1.31]. Hepatic impairment did not influence PK results in multiple dosing. After continuous once-daily dosing, the geometric least square means ratio was 0.72 (90% CI 0.51-1.03) for AUCSS and 0.67 (90% CI 0.47-0.94) for CSS,max. Similar results were obtained when patients were classified for hepatic impairment according to the Child-Pugh criteria. There was no clear difference in the incidence or the severity of adverse events between hepatic impairment groups. Moderate hepatic impairment does not appear to affect the PK profile or the tolerability of cediranib. Dose adjustments are not necessary in this patient population.
    Anti-cancer drugs 11/2012; · 2.23 Impact Factor
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    ABSTRACT: Combining different targeted anticancer agents may improve clinical outcomes. This Phase I study investigated cediranib, an oral inhibitor of vascular endothelial growth factor signalling in combination with saracatinib, an oral Src inhibitor. The primary endpoint was safety/tolerability. Secondary assessments included pharmacokinetics and preliminary efficacy. Patients with advanced solid tumours received cediranib 20, 30 or 45 mg/day for 7 days followed by daily treatment with cediranib at the same dose plus saracatinib 175 mg/day. Thirty-nine patients received cediranib (20 mg, n = 6; 30 mg, n = 6; 45 mg, n = 27 [n = 20 in cohort expansion]) plus saracatinib. In the cediranib 45 mg cohort, 59% of patients required dose reduction/pause compared with 33% in each of the other two cohorts. There was one dose-limiting toxicity (hypertension; 45 mg cohort). The most common adverse events were hypertension (67%), diarrhoea (62%), dysphonia (46%) and fatigue (39%). There was no evidence of a clinically significant effect of saracatinib on cediranib pharmacokinetics and vice versa. 22/35 evaluable patients had a best response of stable disease. All cediranib doses were tolerated; however, in patients with advanced solid tumours, for combination with saracatinib 175 mg/day, cediranib 20 or 30 mg/day was more sustainable than 45 mg/day.
    Investigational New Drugs 10/2011; 30(5):1962-71. · 3.50 Impact Factor
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    ABSTRACT: The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer. Patients received continuous, once-daily oral doses of cediranib 20 mg in combination with either cisplatin (60 mg/m(2) iv day 1) plus S-1 (40-60 mg bid, days 1-21) every 5 weeks for a maximum of eight cycles [Arm A]; or cisplatin (80 mg/m(2) iv, day 1) plus capecitabine (1,000 mg/m(2) bid, days 1-14) every 3 weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21 days of cycle 1. Fourteen patients (Arm A, n = 6; Arm B, n = 8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n = 13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n = 1; Arm B, n = 2) partial responses that were ongoing at data cut-off. Cediranib 20 mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.
    Cancer Chemotherapy and Pharmacology 08/2011; 69(2):439-46. · 2.80 Impact Factor
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    ABSTRACT: To determine the toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of cediranib administered orally, once daily, continuously in children and adolescents with solid tumors. Children and adolescents with refractory solid tumors, excluding primary brain tumors, were eligible. DLT at the starting dose of 12 mg/m(2)/d resulted in de-escalation to 8 mg/m(2)/d and subsequent re-escalation to 12 and 17 mg/m(2)/d. Pharmacokinetic and pharmacodynamic studies were performed during cycle 1. Response was evaluated using WHO criteria. Sixteen patients (median age, 15 years; range, 8 to 18 years) were evaluable for toxicity. DLTs (grade 3 nausea, vomiting, fatigue in one; hypertension and prolonged corrected QT interval in another) occurred in patients initially enrolled at 12 mg/m(2)/d. Subsequently, 8 mg/m(2)/d was well tolerated in three patients. An additional seven patients were enrolled at 12 mg/m(2)/d; one had DLT (grade 3 diarrhea). At 17 mg/m(2)/d, two of four patients had DLTs (grade 3 nausea; intolerable grade 2 fatigue). Non-dose-limiting toxicities included left ventricular dysfunction, elevated thyroid stimulating hormone, palmar-plantar erythrodysesthesia, weight loss, and headache. The MTD of cediranib was 12 mg/m(2)/d (adult fixed dose equivalent, 20 mg). At 12 mg/m(2)/d, the median area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) was 900 ng·h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma. The recommended monotherapy dose of cediranib for children with extracranial solid tumors is 12 mg/m(2)/d administered orally, once daily, continuously. A phase II study is in development.
    Journal of Clinical Oncology 11/2010; 28(35):5174-81. · 18.04 Impact Factor
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    ABSTRACT: In part A, the aim was to define the maximum tolerated dose (MTD) of the hydrogen sulfate (Hyd-Sulfate) oral capsule formulation of the mitogen-activated protein kinase kinase inhibitor AZD6244 (ARRY-142886). In part B, the aim was to compare the pharmacokinetic profile of the new Hyd-Sulfate capsule with the initial AZD6244 free-base suspension and further characterize the pharmacodynamic profile and efficacy of the new formulation. In part A, 30 patients received escalating doses of AZD6244 Hyd-Sulfate twice daily. In part B, 29 patients were randomized to a single dose of the Hyd-Sulfate capsule or free-base suspension, followed by a washout, then a single dose of the alternative formulation. Patients received the Hyd-Sulfate capsule twice daily at MTD of part A thereafter. The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events grade 3 acneiform rash and pleural effusion. Fatigue (65.7%) and acneiform dermatitis (60.0%) were the most frequent adverse events at the MTD. Based on area under curve(0-24), exposure of the 75 mg Hyd-Sulfate capsule relative to the 100 mg free-base suspension was 197% (90% confidence interval, 161-242%). Pharmacodynamic analysis showed that inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC(50) of 352 ng/mL and maximum inhibition (E(max)) of approximately 91%, showing target inhibition. A patient with metastatic melanoma bearing a V600E BRAF mutation achieved a complete response persisting after 15 months of therapy. The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials.
    Clinical Cancer Research 02/2010; 16(5):1613-23. · 7.84 Impact Factor