西地尼布（Cediranib）相关信息

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本帖最后由老马于 2013-9-18 16:48 编辑

西地尼布（Cediranib）是阿斯利康公司的新药，又叫AZD2171，商品名recentin。
4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-[3-(吡咯烷-1-基)丙氧基]喹唑啉(288383-20-0)，分子量：450.51
西地尼布临床形态是马来酸盐，参见专利：
用作抗血管发生剂的喹唑啉衍生物的马来酸盐 WO2005/061488
用于制备吲哚-5-氧基喹唑啉衍生物及中间体的方法申请号：200780040437.6
西地尼布马来酸盐，分子式：C25H27FN4O3. C4H4O4 分子量：566.58
盐与碱的质量换算比例是1.26：1，用普通胃溶胶囊。
空腹服用（饭前1小时或者饭后2小时），服药后3小时到过血药峰值，中国病人的平均半衰期是20小时（国外病人是22小时），平均表观清除率是28.2 L/h，连续服药7天后到达稳态血药浓度，约1.6倍初始值。
最低剂量20mg（盐25.2mg）每天，一天一次；标准剂量是30mg（盐37.8mg）每天，一天一次；
最大剂量是45mg（盐56.7mg）每天，一天一次。

主要的副作用是腹泻、高血压、疲劳、肌肉酸痛、食欲降低、味觉改变等。
其它副作用有口腔溃疡、蛋白尿、甲状腺功能减退、手足综合征、肝功能改变、头痛，呕吐等。
小概率的严重副作用是低蛋白血症，极少数人有不严重的骨髓抑制。

用于制备吲哚-5-氧基喹唑啉衍生物方法(西地尼布).part1.rar (1.39 MB, 下载次数: 131)

用于制备吲哚-5-氧基喹唑啉衍生物方法(西地尼布).part2.rar (1.15 MB, 下载次数: 82)

西地尼布马来酸盐中文专利.pdf (1.79 MB, 下载次数: 214)

老马 · 发表于 2013-9-18 14:36:51

老马 · 发表于 2013-9-18 14:37:06

本帖最后由老马于 2013-9-18 14:39 编辑

相关临床试验结果
Cancer Chemother Pharmacol. 2011 Sep;68(3):631-41. doi: 10.1007/s00280-010-1534-3. Epub 2010 Dec 1.
A two-part phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics.
Mitchell CL, O'Connor JP, Roberts C, Watson Y, Jackson A, Cheung S, Evans J, Spicer J, Harris A, Kelly C, Rudman S, Middleton M, Fielding A, Tessier J, Young H, Parker GJ, Jayson GC.
Source
Department of Medical Oncology, Christie Hospital NHS Trust, Withington, Manchester, UK. Claire.Mitchell@christie.nhs.uk

Abstract
BACKGROUND:
Cediranib (RECENTIN™) is an oral, highly potent VEGF inhibitor. This study evaluated the effect of food on the pharmacokinetics of cediranib and compared the administration of continual cediranib via two dosing strategies using this as a platform to investigate pharmacodynamic imaging biomarkers.
METHODS:
Sixty patients were randomised to receive two single doses of cediranib in either fed/fasted or fasted/fed state (Part A). In continual dosage phase (Part B), patients were randomised to a fixed-dose or dose-escalation arm. Exploratory pharmacodynamic assessments were performed using DCE-MRI and CT enhancing fraction (EnF).
RESULTS:
In part A, plasma AUC and C (max) of cediranib were lower in the presence of food by a mean of 24 and 33%, respectively (94% CI: AUC, 12-34% and C (max), 20-43%), indicating food reduces cediranib plasma exposure. In part B, cediranib 30 mg/day appeared to be the most sustainable for chronic dosing. Continuous cediranib therapy was associated with sustained antivascular effects up to 16 weeks, with significant reductions in DCE-MRI parameters and CT EnF.
CONCLUSIONS:
It is recommended that cediranib be administered at least 1 h before or 2 h after food. Evidence of antitumour activity was observed, with significant sustained effects upon imaging vascular parameters.

the effect of food about Cediranib.pdf (248.99 KB, 下载次数: 41)

老马 · 发表于 2013-9-18 14:40:30

J Clin Oncol. 2007 Jul 20;25(21):3045-54.
Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors.
Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, Harder J, Blum H, Robertson J, Jürgensmeier JM, Puchalski TA, Young H, Saunders O, Unger C.
Source
Tumor Biology Center, MR Development and Application Center, Albert Ludwigs University, Freiburg, Germany. drevs@sanafontis.com

Abstract
PURPOSE:
AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy.
PATIENTS AND METHODS:
In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed.
RESULTS:
Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related.
CONCLUSION:
Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.

老马 · 发表于 2013-9-18 14:41:27

J Clin Oncol. 2008 Apr 10;26(11):1871-8. doi: 10.1200/JCO.2007.14.4741.
Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group.
Laurie SA, Gauthier I, Arnold A, Shepherd FA, Ellis PM, Chen E, Goss G, Powers J, Walsh W, Tu D, Robertson J, Puchalski TA, Seymour L.
Source
The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa ON K1H 8L6, Canada. slaurie@ottawahospital.on.ca

Abstract
PURPOSE:
AZD2171 is a potent inhibitor of vascular endothelial growth factor receptors that showed broad antitumor activity in preclinical models. Doses of up to 45 mg/d of AZD2171 are tolerable when administered alone. This study evaluated escalating doses of AZD2171 in combination with standard chemotherapy in patients with advanced non-small-cell lung cancer.
PATIENTS AND METHODS:
Eligible patients received carboplatin targeted to an area under the concentration time curve of 6 mg . min/mL and paclitaxel 200 mg/m(2), both on day 1 of a 3-week cycle; daily oral AZD2171 at either 30 mg or 45 mg commenced day 2 of cycle 1. Pharmacokinetics of all drugs were performed, and tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST).
RESULTS:
Twenty patients were enrolled. No dose-limiting toxicities were observed during cycle 1 at either dose. Fatigue, diarrhea, anorexia, and granulocytopenia were common; hypertension was manageable with a treatment algorithm designed for this protocol. No clinically significant drug-related bleeding was observed. At 45 mg/d, fatigue and diarrhea were increased, and headache and hoarseness were observed. Paclitaxel clearance decreased during cycle 2, but no other significant pharmacokinetic interactions were observed. After radiology review, confirmed responses were observed in nine patients (response rate, 45%; 95% CI, 23% to 68%); all but one enrolled patient showed evidence of tumor shrinkage, some with cavitation.
CONCLUSION:
AZD2171 can be combined with standard doses of carboplatin/paclitaxel with encouraging antitumor activity. Toxicity is increased, but predictable and manageable.

老马 · 发表于 2013-9-18 14:42:57

Eur J Cancer. 2010 Mar;46(5):901-11. doi: 10.1016/j.ejca.2009.12.023. Epub 2010 Jan 12.
Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours.
van Cruijsen H, Voest EE, Punt CJ, Hoekman K, Witteveen PO, Meijerink MR, Puchalski TA, Robertson J, Saunders O, Jürgensmeier JM, van Herpen CM, Giaccone G.
Source
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.

Abstract
AIM:
Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours.
PATIENTS AND METHODS:
Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics.
RESULTS:
Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment.
CONCLUSIONS:
Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration.
Copyright 2009 Elsevier Ltd. All rights reserved.

老马 · 发表于 2013-9-18 14:53:42

本帖最后由老马于 2013-9-18 15:30 编辑

A Study to Determine the Pharmacokinetics of Cediranib in Chinese Patients With Advanced Solid Malignancies

西地尼布中国1期临床.pdf (580.75 KB, 下载次数: 75)
Summary of safety results
The safety data presented in this section represents the primary analysis with a data cut off on
the 4th May 2010 for all 20 patients in the study. In total, all patients in the study received at
least one dose of cediranib.
All 20 patients included in this study experienced one or more AEs. A total of 18 (90.0%)
patients experienced an adverse event that was considered by the investigator to be related to
treatment.
The most frequently reported adverse events were diarrhea (11 [55.0%]), hypertension (10
[50.0%]) and proteinuria (4 [20.0%]).There appeared some evidence of a dose relationship for
hypertension.
The most commonly reported drug-related adverse events were hypertension (10 [50.0%]),
diarrhoea (10[50.0%]) and proteinuria (4[20.0%]). There appeared some evidence of a dose
relationship for hypertension.
There were no drug-related CTC Grade 3 or 4 AEs at cediranib 20 mg arm. Four drug-related
CTC Grade 3 or 4 AEs at cediranib doses of 30 mg arm were hypertension (2 [10.0%]),
oedema peripheral (1 [5.0%]), pleural effusion (1[5.0%]). All the events were of CTC grade 3.
Two patients were reported to have died as a result of an adverse event. The AEs associated
with the deaths were coma (E0001997, cediranib 30mg), pulmonary embolism (E0002999,
cediranib 30mg). None of these deaths was considered by the investigator to be caused by
cediranib.
Three patients (15.0%) had 5 SAEs other than deaths during the study. Ascites, oedema
peripheral, hypoalbuminaemia and pleural effusion accounted for 2, 1, 1 and 1 of the events
respectively.
One patient (E0001990) experienced a total of 2 SAEs other than death that were considered
by the investigator to be related to study treatment. The 2 SAEs were hypoalbuminemia and
pleural effusion.
A total of 3 (15.0%) patients discontinued due to 4 AEs in the study, which were
hypoalbuminemia, coma, pulmonary embolism and ascites, all in cediranib 30mg arm. Only
hypoalbuminemia was considered drug-rlated.
With the exception of BP, there were no clinically relevant trends in vital signs, laboratory
parameters,physical finding, or ECG observations

老马 · 发表于 2013-9-18 16:00:59

本帖最后由老马于 2013-9-18 16:07 编辑

Cediranib for Metastatic Alveolar Soft Part Sarcoma（转移性腺泡状软组织肉瘤）
http://jco.ascopubs.org/content/31/18/2296.abstract
Abstract

Purpose Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs).

Patients and Methods We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging.

Results Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis.

Conclusion In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.

cediranib (AZD2171) in alveolar soft part sarcoma.pdf (131.95 KB, 下载次数: 28)
一位28岁的脑转和肺转的ASPS病人，转移灶有效。

老马 · 发表于 2013-9-18 16:13:35

A Phase 1 Trial and Pharmacokinetic Study of Cediranib, an Orally Bioavailable Pan–Vascular Endothelial Growth Factor Receptor Inhibitor, in Children and Adolescents With Refractory Solid Tumors
http://jco.ascopubs.org/content/28/35/5174.long

Pharmacokinetic Study of Cediranib.pdf (798.74 KB, 下载次数: 30)