Abstract:
:CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Stuurman FE,Voest EE,Awada A,Witteveen PO,Bergeland T,Hals PA,Rasch W,Schellens JH,Hendlisz Adoi
10.1007/s10637-013-9925-zsubject
Has Abstractpub_date
2013-08-01 00:00:00pages
959-66issue
4eissn
0167-6997issn
1573-0646journal_volume
31pub_type
杂志文章,多中心研究,随机对照试验abstract::Angiogenesis is recognized as an important biological process that allows growth of a tumor beyond an initial small size. PTK787/ZK222584, a potent orally active angiogenesis inhibitor capable of inhibiting all known isoforms of Vascular Endothelial Growth Factor (VEGF) receptor, belongs to the class of aminophthalazi...
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 杂志文章,随机对照试验
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pub_type: 杂志文章,多中心研究
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
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journal_title:Investigational new drugs
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pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1006104217137
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
pub_type: 杂志文章,评审
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
pub_type: 杂志文章
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journal_title:Investigational new drugs
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journal_title:Investigational new drugs
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更新日期:2018-10-01 00:00:00