Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model.


:LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.


Invest New Drugs


Burkholder TP,Clayton JR,Rempala ME,Henry JR,Knobeloch JM,Mendel D,McLean JA,Hao Y,Barda DA,Considine EL,Uhlik MT,Chen Y,Ma L,Bloem LJ,Akunda JK,McCann DJ,Sanchez-Felix M,Clawson DK,Lahn MM,Starling JJ




Has Abstract


2012-06-01 00:00:00












  • Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors.

    abstract:BACKGROUND:To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology. METHODS:Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily....

    journal_title:Investigational new drugs

    pub_type: 杂志文章,多中心研究,随机对照试验


    authors: Galsky MD,Von Hoff DD,Neubauer M,Anderson T,Fleming M,Nagarwala Y,Mahoney JM,Midwinter D,Vocila L,Zaks TZ

    更新日期:2012-04-01 00:00:00

  • Phase I trial of neoadjuvant chemoradiotherapy (CRT) with capecitabine and weekly irinotecan followed by laparoscopic total mesorectal excision (LTME) in rectal cancer patients.

    abstract:BACKGROUND:To analyze the feasibility of capecitabine with weekly irinotecan and concurrent radiotherapy followed by laparoscopic-total mesorectal excision (LTME) in rectal cancer patients. METHODS:Eligible criteria included adenocarcinoma of the rectum staged by endoscopic ultrasonography (u), spiral abdominal and pe...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Ugidos L,Delgado S,Conill C,Ginés A,Gallego R,Ayuso JR,Miquel R,Tosca M,de Lacy A,Castells A,Maurel J

    更新日期:2009-06-01 00:00:00

  • A randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of BTH1677 (1,3-1,6 beta glucan; Imprime PGG) in combination with cetuximab and chemotherapy in patients with advanced non-small cell lung cancer.

    abstract::Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,多中心研究,随机对照试验


    authors: Thomas M,Sadjadian P,Kollmeier J,Lowe J,Mattson P,Trout JR,Gargano M,Patchen ML,Walsh R,Beliveau M,Marier JF,Bose N,Gorden K,Schneller F 3rd

    更新日期:2017-06-01 00:00:00

  • Schedule-dependent inhibition of T-cell lymphoma cells by cotreatment with the mTOR inhibitor everolimus and anticancer drugs.

    abstract:OBJECTIVE:Everolimus (RAD001) is a novel mammalian target of rapamycin (mTOR) inhibitor, and anti-proliferative activity in various malignancies has been reported. This study evaluated the anti-tumor effects and schedule-dependent synergism of everolimus in combination with other chemotherapeutic agents in T-cell lymph...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Huang JJ,Li ZM,Huang Y,Huang Y,Tian Y,He XX,Xiao J,Lin TY

    更新日期:2012-02-01 00:00:00

  • Acute left ventricular dysfunction induced by a panHER and VEGFR tyrosine kinase inhibitor in a phase I trial.

    abstract::Tyrosine kinase inhibitors (TKI) or monoclonal antibodies targeting EGFR, HER2 or VEGFR receptors have demonstrated substantial clinical benefit in patients with advanced breast cancer, colon cancer, head and neck cancer, non-small cell lung cancer, and renal cell carcinoma. Nevertheless, these drugs have some target ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Bahleda R,Massard C,Soria JC,Izzedine H,Cohen A,Ederhy S

    更新日期:2010-06-01 00:00:00

  • A phase II study of Irofulven (MGI 114) in patients with stage IV melanoma.

    abstract::Sixteen patients with stage IV melanoma, who were heavily pretreated, received 11 mg/m2/day of intravenous Irofulven for five consecutive days every 28 days. There were no objective tumor responses, although one patient exhibited stable disease after 4 cycles. The most common toxicities were grade 1/2 nausea, vomiting...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章


    authors: Pierson AS,Gibbs P,Richards J,Russ P,Eckhardt SG,Gonzalez R

    更新日期:2002-08-01 00:00:00

  • Enhancement of the action of the antivascular drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA; ASA404) by non-steroidal anti-inflammatory drugs.

    abstract:AIM:5,6-Dimethylxanthenone-4-acetic acid (DMXAA) (ASA404), a low molecular weight antivascular drug currently in clinical trial, acts both directly on the tumour vascular endothelium and indirectly through the induction of inflammatory cytokines and other vasoactive molecules from macrophages and other host cells. We w...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Wang LC,Ching LM,Paxton JW,Kestell P,Sutherland R,Zhuang L,Baguley BC

    更新日期:2009-06-01 00:00:00

  • N-benzoxazol-2-yl-N'-1-(isoquinolin-3-yl-ethylidene)-hydrazine, a novel compound with antitumor activity, induces radicals and dissipation of mitochondrial membrane potential.

    abstract::The novel compound N-benzoxazol-2-yl-N'-1-(isoquinolin-3-yl-ethylidene)-hydrazine (EPH136) has been shown to exhibit antitumor activity in vitro and in vivo. A COMPARE analysis showed that the patterns of cellular effects of EPH136 are not related to any of 175 standard antitumor agents with a known mechanism of actio...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Hofmann J,Easmon J,Puerstinger G,Heinisch G,Jenny M,Shtil AA,Hermann M,Condorelli DF,Sciré S,Musumarra G

    更新日期:2009-06-01 00:00:00

  • Differences in drug approval processes of 3 regulatory agencies: a case study of gemtuzumab ozogamicin.

    abstract::Major discrepancies concerning risk-benefit assessments and regulatory actions are frequent among regulatory agencies. We explored the differences by scrutinizing a case of gemtuzumab ozogamicin (GO) in patients with acute myeloid leukaemia (AML). Assessment reports of GO were retrieved form the websites of the US Foo...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,评审


    authors: Tanimoto T,Tsubokura M,Mori J,Pietrek M,Ono S,Kami M

    更新日期:2013-04-01 00:00:00

  • Phase II trial of intravenous melphalan in advanced colorectal carcinoma.

    abstract:BACKGROUND:Relatively few studies have examined the activity of alkylating agents in the treatment of advanced colorectal adenocarcinoma. Recent reports have suggested possible therapeutic activity for high-dose intravenous melphalan administered with autologous bone marrow transplantation (BMT) support. We conducted a...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章


    authors: Moore DF Jr,Pazdur R,Abbruzzese JL

    更新日期:1994-01-01 00:00:00

  • Phase I study of 4-demethoxydaunorubicin.

    abstract::4-demethoxydaunorubicin (4-dm DNR), a new analog of daunorubicin, was tested at an every 3-week dose schedule in 63 evaluable patients with various forms of disseminated malignancy. Utilizing the intravenous (i.v.) route of administration, the maximum tolerated dose (MTD) was 15-18 mg/m2; with the oral route the MTD w...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Bonfante V,Ferrari L,Villani F,Bonadonna G

    更新日期:1983-01-01 00:00:00

  • A phase I study of vitamin E, 5-fluorouracil and leucovorin for advanced malignancies.

    abstract::Six patients with incurable malignancies were originally treated with vitamin E, 3200 IU/day for fourteen days, followed by the same dose of vitamin E daily plus LCV (20 mg/m2 i.v. bolus daily x 5) with 5FU (425 mg/m2 i.v. bolus immediately following LCV). The same schedule of LCV and 5FU was repeated 4 weeks later, t...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章


    authors: Blanke CD,Stipanov M,Morrow J,Rothenberg M,Chinery R,Shyr Y,Coffey R,Johnson DH,Leach SD,Beauchamp RD

    更新日期:2001-01-01 00:00:00

  • Topophore C: a liposomal nanoparticle formulation of topotecan for treatment of ovarian cancer.

    abstract::We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on loading method that involves formation of a complex between copper and the water soluble camptothecin. The loading methodology developed for irinotecan was evaluated to develop a LNP topotecan formulation (referred to herein a...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Patankar NA,Waterhouse D,Strutt D,Anantha M,Bally MB

    更新日期:2013-02-01 00:00:00

  • Chloroquinoxaline sulfonamide: a sulfanilamide antitumor agent entering clinical trials.

    abstract::Chloroquinoxaline sulfonamide (CQS) has been developed to the clinical trial stage based on its activity in the Human Tumor Colony Forming Assay (HTCFA). In the HTCFA, CQS demonstrated inhibition of colony formation against breast, lung, melanoma and ovarian carcinomas. The mechanism of action of CQS is unknown. It do...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,评审


    authors: Fisherman JS,Osborn BL,Chun HG,Plowman J,Smith AC,Christian MC,Zaharko DS,Shoemaker RH

    更新日期:1993-02-01 00:00:00

  • Phase II trial of edatrexate in relapsed or refractory germ cell tumors: a Southwest Oncology Group study (SWOG 9124).

    abstract::Up to 30% of patients with advanced germ cell tumors will fail induction chemotherapy or will relapse. New agents with activity in this still potentially curable subgroup of patients are needed. Edatrexate (10-ethyl, 10-deaza-aminopterin) is a methotrexate analogue that has preclinical and clinical activity in breast,...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章


    authors: Meyers FJ,Lew D,Lara PN Jr,Williamson S,Marshall E,Balcerzak SP,Rivkin SE,Samlowski W,Crawford ED

    更新日期:1998-01-01 00:00:00

  • IL-4R expression in AIDS-KS cells and response to rhIL-4 and IL-4 toxin (DAB389-IL-4).

    abstract::Interleukin-4 (IL-4) is a pleiotropic cytokine affecting growth and differentiation of various cell types as well as regulating other cytokines. To study the effect of IL-4 on AIDS-related Kaposi's sarcoma (AIDS-KS) cells, we first examined the tumor cells for IL-4 receptor (IL-4R) expression. KS cells express a singl...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Cai J,Zheng T,Murphy J,Waters CA,Lin GY,Gill PS

    更新日期:1997-01-01 00:00:00

  • The new isothiocyanate 4-(methylthio)butylisothiocyanate selectively affects cell-cycle progression and apoptosis induction of human leukemia cells.

    abstract::We investigated proliferation and apoptosis induction in Jurkat T-leukemia cells by the new isothiocyanate 4-(methylthio)butylisothiocyanate (MTBITC). To help elucidate whether the effects of MTBITC are specific for cancer cells, we tested MTBITC on freshly isolated, non-transformed human peripheral T lymphocytes. The...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Fimognari C,Nüsse M,Iori R,Cantelli-Forti G,Hrelia P

    更新日期:2004-04-01 00:00:00

  • Metabolic carbonyl reduction of anthracyclines - role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents.

    abstract::Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to seconda...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,评审


    authors: Piska K,Koczurkiewicz P,Bucki A,Wójcik-Pszczoła K,Kołaczkowski M,Pękala E

    更新日期:2017-06-01 00:00:00

  • A study of a different dose-intense infusion schedule of phenylacetate in patients with recurrent primary brain tumors consortium report.

    abstract:PURPOSE:To compare two different infusion schedules of phenylacetate (PA) in patients with primary brain tumors and to assess the feasibility of the administration in a multi-institutional setting. PATIENTS AND METHODS:Adult patients with recurrent primary brain tumors were treated with PA on two different schedules. ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Chang SM,Kuhn JG,Ian Robins H,Clifford Schold S,Spence AM,Berger MS,Mehta MP,Pollack I,Gilbert M,Prados MD

    更新日期:2003-11-01 00:00:00

  • T cell cytotoxicity toward hematologic malignancy via B7-H3 targeting.

    abstract::T cells are important effectors in anti-tumor immunity, and aberrant expression of B7 family members may contribute to tumor evasion. In this study, we analyzed expression of costimulatory molecules on human hematologic tumor cells and explored whether B7-H3, a member of the B7 superfamily, is an effective target for ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Sun X,Yu Y,Ma L,Xue X,Gao Z,Ma J,Zhang M

    更新日期:2020-06-01 00:00:00

  • A retrospective pooled analysis of trabectedin safety in 1,132 patients with solid tumors treated in phase II clinical trials.

    abstract:PURPOSE:To summarize the safety experience obtained from phase II clinical trials conducted with trabectedin as single-agent therapy in patients with advanced solid tumors. METHODS:This retrospective analysis includes 1,132 patients exposed to trabectedin in 19 phase II trials carried out between February 1999 and Apr...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Le Cesne A,Yovine A,Blay JY,Delaloge S,Maki RG,Misset JL,Frontelo P,Nieto A,Jiao JJ,Demetri GD

    更新日期:2012-06-01 00:00:00

  • Alterations in human circulating and bone marrow mononuclear cell polyamine levels in hematologic malignancies as a consequence of difluoromethylornithine administration.

    abstract::The effect of administering increasing intravenous doses of difluoromethylornithine on human tumor cell polyamine levels was determined in patients with hematologic malignancies. Difluoromethylornithine from 5.5. to 64 gm/m2 per day was administered to nine patients with refractory acute leukemia or multiple myeloma. ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Maddox AM,Freireich EJ,Keating MJ,Frasier-Scott KF,Haddox MK

    更新日期:1988-06-01 00:00:00

  • Effects of 13-hydroxy SM5887 in combination with other anticancer agents on human tumor cell lines.

    abstract::A new anthracycline derivative, SM5887, in combination with commonly used anticancer agents was evaluated against T-cell leukemia MOLT-3 and human osteosarcoma MG-63 cell lines in culture. MOLT-3 and MG-63 cells were incubated with various concentrations of 13-hydroxy SM5887 (SM5887-OH, the active metabolite of SM5887...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Takagi T,Yazawa Y,Suzuki K,Yamauchi Y,Kano Y

    更新日期:1996-01-01 00:00:00

  • Phase II trial of low-dose N-(phosphonacetyl)-disodium L-aspartic acid and high-dose 24-hour infusional 5-fluorouracil in advanced gastric adenocarcinoma. A Southwest Oncology Group study.

    abstract::N-(phosphonacetyl)-disodium L-aspartic acid (PALA) demonstrates a synergistic antitumor effect when combined with 5-Fluorouracil (5-FU) in in vitro studies. In a Phase II trial, 23 eligible patients with unresectable or metastatic adenocarcinoma of the stomach were treated with weekly i.v. bolus PALA (250 mg/M2) follo...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章


    authors: Martino RL,Fleming TR,Morrell LM,Ardalan B,Richman SP,Macdonald JS

    更新日期:1996-01-01 00:00:00

  • Phase I trial of 5-fluorouracil by 24-hour infusion weekly.

    abstract::A novel schedule of 5-fluorouracil administration has been developed for biochemical modulation studies. In combination with the pyrimidine synthesis inhibitor PALA, 5-fluorouracil has been given as a 24-hour infusion, repeated weekly: a dose of 2600 mg/m2 is well tolerated. To identify a suitable dose of 5-fluorourac...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章


    authors: Haas NB,Hines JB,Hudes GR,Johnston N,Ozols RF,O'Dwyer PJ

    更新日期:1993-05-01 00:00:00

  • Sequential studies on the role of mitoxantrone in the treatment of acute leukemia.

    abstract::Mitoxantrone (Novantrone; 1, 4-dihydroxy-5, 8-bis [[2-[(2-hydroxyethyl) amino]ethyl]amino-] 9, 10 anthracenedione dihydrochloride (NSC 301739] is a synthetic anthracenedione with intercalating properties. Activity has been shown in preclinical studies in mice bearing intraperitoneal P388 and L1210 leukaemias, ADJ-Pc6 ...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章


    authors: Prentice HG,Wimperis JZ,Robbins G

    更新日期:1985-01-01 00:00:00

  • Predictors for establishing recommended phase 2 doses: analysis of 320 dose-seeking oncology phase 1 trials.

    abstract:INTRODUCTION:For decades, determination of the recommended Phase 2 dose (RP2D) was based on the toxicity (especially the maximum tolerated dose or MTD) experienced by patients enrolled in dose-escalating Phase 1 trials investigating anti-cancer agents. Recent studies suggest that this toxicity-based strategy is not sui...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Penel N,Duhamel A,Adenis A,Devos P,Isambert N,Clisant S,Bonneterre J

    更新日期:2012-04-01 00:00:00

  • Phase II study of oral S-1 with irinotecan and bevacizumab (SIRB) as first-line therapy for patients with metastatic colorectal cancer.

    abstract::Fluorouracil (5-FU) plus irinotecan combined with bevacizumab has significant activity in metastatic colorectal cancer (mCRC), but S-1 has become a substitute for continuous infusion of 5-FU and has a very low incidence of hand-foot syndrome. With the S-1 plus irinotecan regimen (SIR), the response rate was 62.5%, and...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Yamada Y,Yamaguchi T,Matsumoto H,Ichikawa Y,Goto A,Kato K,Hamaguchi T,Shimada Y

    更新日期:2012-08-01 00:00:00

  • Generation and tumor recognition properties of two human monoclonal antibodies specific to cell surface anionic phospholipids.

    abstract::Phosphatidylserine (PS) and other anionic phospholipids, which become exposed on the surface of proliferating endothelial cells, tumor cells and certain leukocytes, have been used as targets for the development of clinical-stage biopharmaceuticals. One of these products (bavituximab) is currently being investigated in...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Bujak E,Pretto F,Neri D

    更新日期:2015-08-01 00:00:00

  • The activity of flavone acetic acid (NSC 347512) on human colon cancer cells in vitro.

    abstract::Flavone acetic acid (FAA) was incubated for 1 to 48 hr with 3 established human colon cancer cell lines endowed with distinct degrees of phenotypic properties. All 3 lines responded to FAA in almost identical fashion; when incubated with the drug for only 1 hr, an initial decrease in survival was observed for concentr...

    journal_title:Investigational new drugs

    pub_type: 杂志文章


    authors: Drewinko B,Yang LY

    更新日期:1986-01-01 00:00:00