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).

Start Date01 May 2012

Sponsor / Collaborator

Eisai, Inc.

NCT01127178 / TerminatedPhase 1

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.

Start Date29 Mar 2010

Sponsor / Collaborator

Eisai, Inc.

100 Clinical Results associated with E-7016

100 Translational Medicine associated with E-7016

100 Patents (Medical) associated with E-7016

Literatures (Medical) associated with E-7016

01 Jan 2011·Drug Metabolism and DispositionQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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.

15 Jan 2009·Clinical Cancer ResearchQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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 Deals associated with E-7016

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Malignant melanoma stage IV	Phase 2	US	Eisai, Inc.	01 May 2012
Unresectable Melanoma	Phase 2	US	Eisai, Inc.	01 May 2012
Glioma	Phase 2	US	Eisai Co., Ltd.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01127178 (CTgov)	Phase 1	Advanced Malignant Solid Neoplasm	12	Temozolomide+E7016 (Dose Escalation Part, All Participants: E7016 + Temozolomide)	zszyfpivev(hgvdkiuikr) = aewengnmbr wavskjpruy (hhtvhkhjmg, hdnduizjop - owsodreuij)	-	10 Oct 2024
				Temozolomide+E7016 (Dose Escalation Part: E7016 4 mg/kg/Day + Temozolomide 150 mg/m^2)	lnnakznzdn(jqqbyqxmcg) = qgmvhusxyh tvwturzlcw (zustetgcmr, smkxhywqhq - ptlnjhdqds) View more

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