The purpose of this study was to determine the maximum tolerated dose and the recommended dose of BN80927 in patients with advanced malignant solid tumors.

开始日期2004-11-01

申办/合作机构

Ipsen SA

100 项与依洛替康相关的临床结果

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100 项与依洛替康相关的转化医学

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100 项与依洛替康相关的专利（医药）

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项与依洛替康相关的文献（医药）

2012-08-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Population pharmacokinetic/pharmacodynamic modeling of drug-induced adverse effects of a novel homocamptothecin analog, elomotecan (BN80927), in a Phase I dose finding study in patients with advanced solid tumors

4区 · 医学

Article

作者: Concepción Peraire ; Rosendo Obach ; Frédérique Cvitkovic ; Patrick Delavault ; Iñaki F. Trocóniz ; Paola Principe ; Elena Soto ; Thierry Lesimple ; Ana Perez-Mayoral ; Josep-María Cendrós ; Joan Pruñonosa

PURPOSETo characterize the pharmacokinetic profile of elomotecan, a novel homocamptothecin analog, evaluate the dose-limiting toxicities, and establish the relationship between exposure and toxicity in the first Phase I study in patients with advanced malignant solid tumors. Preliminary antitumor efficacy results are also provided.DESIGNElomotecan was administered as a 30-min intravenous infusion at doses ranging from 1.5 to 75 mg once every 3 weeks to 56 patients with advanced solid tumors. Plasma concentration data and adverse effects were modeled using the population approach.RESULTSElomotecan showed linear pharmacokinetics, and clearance was decreased with age. The model predicts a 47 and 61 % reduction in CL for patients aged 60 and 80 years, respectively, when compared with younger patients (30 years). Neutropenia represented the dose-limiting toxicity. The maximum tolerated dose and the recommended dose (RD) were 75 and 60 mg, respectively. Elomotecan elicited a 20, 5, 2, and 2 % severe (grade 4) neutropenia, asthenia, nausea, and vomiting at the RD, respectively. Of the subjects in the RD cohort, 41.7 % had a stable disease mean duration of 123.6 ± 43.4 days.CONCLUSIONSThe pharmacokinetic parameters and the toxicity pattern of elomotecan suggest that this novel homocamptothecin analog should be further explored in the clinical setting using a dose of 60 mg administered as a 30-min intravenous infusion, once every 3 weeks.

2004-07-15·Cancer Research1区 · 医学

BN80927

1区 · 医学

Article

作者: Coulomb, Helène ; Prévost, Grégoire ; Huchet, Marion ; Lavergne, Olivier ; Camara, José ; Bigg, Dennis C. H. ; Demarquay, Danièle ; Kasprzyk, Philip G. ; Lesueur-Ginot, Laurence

AbstractBN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered β-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition. Moreover, a Topo I-altered cell line (KBSTP2), resistant to SN38, remains sensitive to BN80927, suggesting that a part of the antiproliferative effects of BN80927 are mediated by a Topo I-independent pathway. This hypothesis is also supported by in vitro data showing an antiproliferative activity of BN80927 on a model of resistance related to the noncycling state of cells (G0-G1 synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC50 values consistently lower than those of SN38 in tumor cell lines as well as in their related drug-resistant lines. BN80927 shows high efficiency in vivo in tumor xenograft studies using human androgen-independent prostate tumors PC3 and DU145. Altogether, these data strongly support the clinical development of BN80927.

2003-01-01·Current Topics in Medicinal Chemistry4区 · 医学

Dual Topoisomerase I / II Inhibitors in Cancer Therapy

4区 · 医学

Review

作者: Denny, William A. ; Baguley, Bruce C.

While the majority of topoisomerase (topo) inhibitors show selectivity against either topo I or topo II, a small class of compounds can act against both enzymes. These can be divided into three classes. The first and largest class comprise drugs that bind to DNA by intercalation and include the clinically-evaluated acridine DACA, the benzopyridoindole intoplicine, the indenoquinolinone TAS-103, the benzophenazine XR11576, and the pyrazoloacridine NSC 366140. The second category comprises hybrid molecules, prepared by physically linking separate inhibitors of topo I and topo II, or by linking pure topo inhibitors to other DNA-interactive carriers. While several derivatives (e.g., camptothecin-epipodophyllotoxin and ellipticine-distamycin hybrids) have been prepared, there have been no detailed studies. The third category are less well defined as a structural class, but apparently recognize structural motifs that are present in both topo I and II enzymes. These include a series of benzoisoquinolinium quaternary salts such as NK 109, and more interestingly modified versions of classical topo I or topo II inhibitors; e.g., the modified camptothecin BN 80927 and the modified epipodophyllotoxin tafluposide (F-11782). There is as yet no detailed understanding of the factors that result in selective or dual inhibition, but structure-activity studies in several classes show that structural changes can influence topo I/II selectivity. DNA intercalation mode also appears to play a part. The basis for the high antitumor activity of some topo inhibitors is not yet understood but may depend on the complex pattern of activities that include both inhibition and poisoning of the two enzymes.

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床1期	法国	Ipsen SA	2004-11-01
肿瘤	临床1期	-	F. Hoffmann-La Roche Ltd.	-

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ASCO2010	临床1期	晚期恶性实体瘤	56	BN80927	(鏇蓋糧餘襯獵壓選壓構) = 選膚製顧壓選壓廠齋衊積鏇鬱鹹鹹簾鏇糧製壓 (淵蓋觸觸夢範選獵遞齋 ) 更多	-	2010-05-20