Phase 2 Study of the Poly(ADP-Ribose) Polymerase Inhibitor E7016 in Combination With Temozolomide in Subjects With Wild Type BRAF Stage IV or Unresectable Stage III Melanoma

This is a Phase 2, open-label, multicenter study to assess the PFS-6m of E7016 at the selected dose of 320-mg once daily (QD) in combination with 150-mg/m2 of Temozolomide (TMZ) in subjects with wt BRAF Stage IV or unresectable Stage III melanoma with disease progression. Eligible subjects must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST).

开始日期2012-05-01

申办/合作机构

Eisai, Inc.

NCT01127178 / Terminated临床1期

Phase 1 Study of the Poly (ADP-Ribose) Polymerase Inhibitor E7016 in Combination With Temozolomide in Subjects With Advanced Solid Tumors

The purpose of this study is to determine the maximum tolerated dose (MTD) of poly (ADP-Ribose) polymerase inhibitor E7016 when used with temozolomide (TMZ) in patients with advanced solid tumors and gliomas.

开始日期2010-03-29

申办/合作机构

Eisai, Inc.

100 项与 E-7016 相关的临床结果

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100 项与 E-7016 相关的转化医学

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100 项与 E-7016 相关的专利（医药）

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项与 E-7016 相关的文献（医药）

2011-01-01·Drug Metabolism and Disposition2区 · 医学

A Baeyer-Villiger Oxidation Specifically Catalyzed by Human Flavin-Containing Monooxygenase 5

2区 · 医学

Article

作者: Moniz, George A. ; Farah, Nadia ; Lai, W. George ; Wong, Y. Nancy

10-((4-Hydroxypiperidin-1-yl)methyl)chromeno[4,3,2-de]phthalazin-3(2H)-one (E7016), an inhibitor of poly(ADP-ribose) polymerase, is being developed for anticancer therapy. One of the major metabolites identified in preclinical animal studies was the product of an apparent oxidation and ring opening of the 4-hydroxypiperidine. In vitro, this oxidized metabolite could not be generated by incubating E7016 with animal or human liver microsomes. Further studies revealed the formation of this unique metabolite in hepatocytes. In a NAD(P)(+)-dependent manner, this metabolite was also generated by liver S9 fractions and recombinant human flavin-containing monooxygenase (FMO) 5 that was fortified with liver cytosol fractions. In animal and human liver S9, this metabolic pathway could be inhibited by 4-methylpyrazole, bis-p-nitrophenylphosphate (BNPP), or a brief heat treatment at 50°C. Based on these results, the overall metabolic pathway was believed to involve a two-step oxidation process: dehydrogenation of the secondary alcohol in liver cytosol followed by an FMO5-mediated Baeyer-Villiger oxidation in liver microsomes. The two oxidation steps were coupled via regeneration of NAD(P)(+) and NAD(P)H. To further confirm this mechanism, the proposed ketone intermediate was independently synthesized. In an NAD(P)H-dependent manner, the synthetic ketone intermediate was metabolized to the same ring-opened metabolite in animal and human liver microsomes. This metabolic reaction was also inhibited by BNPP or a brief heat treatment at 50°C. Methimazole, the substrate/inhibitor of FMO1 and FMO3, did not inhibit this reaction. The specificity of FMO5 toward catalyzing this Baeyer-Villiger oxidation was further demonstrated by incubating the synthetic ketone intermediate in recombinant enzymes.

2009-01-15·Clinical Cancer Research1区 · 医学

In vitro and In vivo Radiosensitization of Glioblastoma Cells by the Poly (ADP-Ribose) Polymerase Inhibitor E7016

1区 · 医学

Article

作者: Russo, Andrea L. ; Kwon, Hyuk-Chan ; Slusher, Barbara S. ; Chakravarti, Arnab ; Tofilon, Philip J. ; Beam, Katie ; Burgan, William E. ; Camphausen, Kevin ; Carter, Donna ; Weizheng, Xu ; Zhang, Jie

AbstractPurpose: Poly (ADP-ribose) polymerase (PARP) inhibitors are undergoing clinical evaluation for cancer therapy. Because PARP inhibition has been shown to enhance tumor cell sensitivity to radiation, we investigated the in vitro and in vivo effects of the novel PARP inhibitor E7016.Experimental Design: The effect of E7016 on the in vitro radiosensitivity of tumor cell lines was evaluated using clonogenic survival. DNA damage and repair were measured using γH2AX foci and neutral comet assay. Mitotic catastrophe was determined by immunostaining. Tumor growth delay was evaluated in mice for the effect of E7016 on in vivo (U251) tumor radiosensitivity.Results: Cell lines exposed to E7016 preirradiation yielded an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1 from 1.4 to 1.7. To assess DNA double-strand breaks repair, γH2AX measured at 24 hours postirradiation had significantly more foci per cell in the E7016/irradiation group versus irradiation alone. Neutral comet assay further suggested unrepaired double-strand breaks with significantly greater DNA damage at 6 hours postirradiation in the combination group versus irradiation alone. Mitotic catastrophe staining revealed a significantly greater number of cells staining positive at 24 hours postirradiation in the combination group. In vivo, mice treated with E7016/irradiation/temozolomide had an additional growth delay of six days compared with the combination of temozolomide and irradiation.Conclusions: These results indicate that E7016 can enhance tumor cell radiosensitivity in vitro and in vivo through the inhibition of DNA repair. Moreover, enhanced growth delay with the addition of E7016 to temozolomide and radiotherapy in a glioma mouse model suggests a potential role for this drug in the treatment of glioblastoma multiforme.

100 项与 E-7016 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
IV期恶性黑色素瘤	临床2期	美国	Eisai, Inc.	2012-05-01
不可切除的黑色素瘤	临床2期	美国	Eisai, Inc.	2012-05-01
胶质瘤	临床2期	美国	Eisai Co., Ltd.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01127178 (CTgov)	临床1期	晚期恶性实体瘤	12	Temozolomide+E7016 (Dose Escalation Part, All Participants: E7016 + Temozolomide)	願窪夢淵鑰夢廠簾壓鏇(選醖廠顧窪夢夢醖蓋醖) = 獵製構餘齋選壓顧網壓廠醖廠鹹憲積遞襯積鹹 (醖觸顧構觸餘顧鏇積醖, 窪窪壓製鑰製鏇構醖製 ~ 衊鬱膚繭糧網衊鏇範鹹)	-	2024-10-10
				Temozolomide+E7016 (Dose Escalation Part: E7016 4 mg/kg/Day + Temozolomide 150 mg/m^2)	範繭網遞憲鏇鹹網襯鏇(壓鹽積齋構齋蓋壓網鏇) = 構鹽膚製廠壓鑰鬱夢簾廠範鑰蓋鏇醖淵窪憲鬱 (襯壓製簾憲鏇網壓醖繭, 鹽顧築願網廠糧鏇糧積 ~ 艱壓獵觸製顧齋鏇憲積) 更多