Phase I Safety, Pharmacokinetic, and Pharmacodynamic …Cancer Therapy: Clinical Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of ENMD-2076, a Novel Angiogenic and Aurora

Cancer Therapy: Clinical

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study ofENMD-2076, a Novel Angiogenic and Aurora Kinase Inhibitor,in Patients with Advanced Solid Tumors

Jennifer R. Diamond1, Bruno R. Bastos2, Ryan J. Hansen3, Daniel L. Gustafson3, S. Gail Eckhardt1,Eunice L. Kwak 4, Shuchi S. Pandya5, Graham C. Fletcher6, Todd M. Pitts1, Gillian N. Kulikowski1,Mark Morrow1, Jamie Arnott6, Mark R. Bray6, Carolyn Sidor6, Wells Messersmith1, andGeoffrey I. Shapiro2

AbstractPurpose: ENMD-2076 is a unique orally bioavailable Aurora kinase and VEGFR inhibitor. The purpose

of this phase 1 study of ENMD-2076 was to determine the MTD, pharmacokinetic, and pharmacodynamic

profiles and preliminary antitumor activity.

ExperimentalDesign:Patientswith refractory advanced solidmalignancieswere treatedwithENMD-2076

orally with continuous once daily dosing. Doses from 60 to 200mg/m2were evaluated using a standard 3 (to

4)þ 3design. Pharmacokinetic parameterswere studiedondays1, 28, and30 to 35of cycle 1. ExpandedMTD

cohorts included patients with ovarian cancer, colorectal cancer, and refractory solid tumors.

Results: A total of 67 patients (46 F, 21M; ages 30–76) entered the study. Dose levels of 60, 80, 120, 200,

and 160 mg/m2 were evaluated. Two patients experienced grade 3 hypertension at 200 mg/m2, and

additional grade 3 neutropenia events limited tolerability at this dose. An intermediate dose of 160 mg/m2

was determined to be the MTD. The most common drug-related adverse events included hypertension,

nausea/vomiting, and fatigue. The pharmacokinetics of ENMD-2076 were characterized by a rapid

absorption phase (Tmax 3–7.8 hours), a t1/2 of 27.3 to 38.3 hours after a single dose, and dose proportional

exposure. Decreased plasma sVEGFR2 was observed posttreatment. Two patients with platinum refractory/

resistant ovarian cancer had RECIST partial responses.

Conclusions: ENMD-2076 was well tolerated, had a linear pharmacokinetic profile, and showed

promising antitumor activity, particularly in ovarian cancer. The recommended phase 2 dose of ENMD-

2076 is 160 mg/m2 administered orally once daily with continuous dosing. Clin Cancer Res; 17(4); 849–60.

�2010 AACR.

Introduction

The Aurora kinases are a family of serine/threoninekinases integral to mitotic cell division. Aurora A plays akey regulatory role in centrosome function during mito-

sis including formation of the bipolar mitotic spindle(1, 2). Aurora B is a chromosomal passenger protein thatplays a role in the attachment of chromosomes to themitotic spindle and cytokinesis (3, 4). The Auroras areoverexpressed in many solid tumors and have beenimplicated in tumorigenesis (5, 6). Multiple Aurorakinase inhibitors are currently in preclinical or clinicaldevelopment (7).

Angiogenic kinases include VEGF receptors (VEGFRs),platelet-derived growth factor receptors (PDGFRs), andbasic fibroblast growth factor receptors (bFGFRs). Thesereceptors transduce signals from proangiogenic factors,promoting angiogenesis (8, 9), the process by whichtumors recruit their vascular supply (10). Antiangiogenicagents can potentiate the effects of cytotoxic anticanceragents when used in combination. For example, theaddition to chemotherapy of bevacizumab, a humanizedmonoclonal antibody directed at the proangiogenic factorVEGF, results in improved rate of response, progression freesurvival, and clinically meaningful increases in overallsurvival in advanced solid tumors such as colorectal cancerand non–small-cell lung cancer (11, 12).

Authors' Affiliations: 1University of Colorado at Denver, Aurora, Colorado;2Dana-Farber Cancer Institute, Boston, MA; 3Colorado State University,Animal Cancer Center, Fort Collins, Colorado; 4Massachusetts GeneralHospital, Boston, MA; Massachusetts; 5Beth Israel Deaconess MedicalCenter, Boston, Massachusetts; 6EntreMed, Inc., Toronto, Ontario,Canada and Durham, North Carolina

Note: Supplementary data for this article are available at Clinical CancerResearch Online (http://clinicalcancerres.aacrjournals.org/).

Note: Presented in part at the 11th Annual Symposium on Anti-AngiogenicAgents, February 2009, La Jolla, CA and the American Society of ClinicalOncology (ASCO) Annual Meeting, June 2009, Orlando, Florida.

Current address for Bruno R. Bastos: Cleveland Clinic Florida, Weston,Florida.

Corresponding Author: Geoffrey I. Shapiro, Early Drug DevelopmentCenter, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA02115. Phone: 617–632-4942; Fax: 617–632-1977; E-mail:[email protected].

doi: 10.1158/1078-0432.CCR-10-2144

�2010 American Association for Cancer Research.

ClinicalCancer

Research

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Published OnlineFirst December 3, 2010; DOI: 10.1158/1078-0432.CCR-10-2144

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ENMD-2076 was identified during the course of afocused synthetic medicinal chemistry effort directedtoward discovery of novel inhibitors of Aurora kinases.However, in vitro assays defined the compound as aninhibitor of both Aurora and angiogenic kinases, targetsof which include Aurora A (50% inhibitory concentrationon recombinant kinase [IC50] 14 nM), Aurora B (IC50 350nM), VEGFR2 (IC50 58 nM), FMS-like tyrosine kinase-3(Flt-3; IC50 2 nM), stem cell factor receptor (c-Kit; IC50 120nM), and FGFR1, 2 and 3 (IC50s 93, 71 and 500 nM,respectively; ref. 13). These complementary antimitotic andantiangiogenic properties have translated to wide-rangingin vitro and in vivo antitumor activity against human cancercell lines and xenografts, includingmodels of breast cancer,colorectal cancer and hematologic malignancies (13–15).In vitro, antiproliferative effects are associated with G2/Mcell cycle arrest and induction of apoptosis, most suggestiveof an Aurora A phenotype (13, 16). At cellular concentra-tions below 500 nM in HCT116 colorectal cancer cells,these effects are accompanied by reductions in the auto-phosphorylation of Aurora A at Thr-288, consistent withselective Aurora A inhibition. At micromolar concentra-tions, in both HCT116 and multiple myeloma cells,reduced phosphorylation of Aurora A as well as histoneH3 at Ser-10 are observed, the latter indicating concomitantinhibition of Aurora B (13, 15).

Dose-dependent inhibition of tumor growth has beenobserved in H929 human plasmacytoma xenografts, withreduced expression of phospho-histoneH3, Ki-67, CD34 inmicrovasculature and phospho-FGFR3, along withincreased caspase-3 staining in tumors from mice treatedwith ENMD-2076 compared with vehicle (15). In the HT29colorectal cancer xenograftmodel, exposure to 5 daily doses

of ENMD-2076 reduced thenumber ofmitotic cells stainingpositively for phosphorylated Aurora A (13). In longer-termexperiments, ENMD-2076 induced initial tumor growthinhibition followed by regression that was accompaniedby a decrease in 18FDG uptake assessed by positron emis-sion tomography (PET) scanning, and associated with amarked reduction in proliferation, assessed by Ki-67. Treat-ment also caused reduced tumor vascular permeability andperfusion, measured by dynamic contrast-enhanced mag-netic resonance imaging (14). Similarly, regressions in theMDA-MB-231 breast cancer xenograft model were asso-ciated with substantial reductions in tumor vascularization,assessed by CD31 staining (13).

In 28-day continuous oral dosing toxicology studies inrats and dogs, dose proportional increases inCmax and AUCwere seen. Gastrointestinal toxicities were observed inboth species. In rats, liver function test abnormalities,bone marrow suppression, and adrenal cortical changesoccurred. Also observed were dental discoloration andbreakage, as well as abnormalities of the femoral growthplate attributable to disruption of the vascular invasion thatoccurs at the cartilage/bone interface during the process ofendochondral ossification; the latter is a possible signaturetoxicity of pharmacologically induced inhibition of angio-genesis (17). Many of these changes were reversible after a28-day recovery period. Additionally, no cardiovascular orrespiratory system safety signals emerged in telemeterizeddogs. Taken together, preclinical toxicology, pharmacol-ogy, and antitumor efficacy supported clinical assessmentof ENMD-2076 in a first-in-human trial.

The principal objective of this study was to determine themaximum tolerated dose (MTD) of ENMD-2076 adminis-tered orally with continuous daily dosing in patients withadvanced solid tumors. Secondary objectives includedassessment of the toxicity profile, pharmacokinetics, phar-macodynamic effects on plasma soluble VEGFR2, andpreliminary antitumor activity.

Patients and Methods

Eligibility criteriaEligible patients had advanced ormetastatic solid tumors

refractory to or without standard therapy options, evalu-able or measurable disease by Response Evaluation Criteriain Solid Tumors (RECIST; ref. 18) and Eastern CooperativeOncology Group (ECOG) performance status of 0 to 1.Patients also had to be age 18 years or older with adequatehematopoietic, hepatic, and kidney function. Exclusioncriteria included: women who were pregnant or nursing;treatment with radiotherapy or chemotherapy within2 weeks; major surgery within 3 weeks; known centralnervous system metastasis requiring anticonvulsants orsteroids; history of deep venous thrombosis or pulmonaryembolism not receiving therapeutic anticoagulation; his-tory of nephrotic syndrome or 2þ proteinuria; uncon-trolled severe cardiac disease; any medical condition thatwould impair administration of an oral medication; oruncontrolled serious medical or psychiatric illness.

Translational Relevance

ENMD-2076 was developed to test the hypothesisthat antimitotic and broad antiangiogenic activity couldbe combined in a single agent via inhibition of multipletargets including Aurora kinases, as well as vascularendothelial growth factor receptor 2 and fibroblastgrowth factor receptors 1 and 2. This first-in-human,phase I trial established that the dose of 160 mg/m2

administered orally daily continuously was tolerable.ENMD-2076 demonstrated both biologic and antitu-mor activity in several cancer types, including thoseresistant to prior antiangiogenic therapies. Consistentwith inhibition of the target kinases, the primary dose-limiting toxicity was hypertension, usually manageablewith single-agent antihypertensive therapy; non–dose-limiting neutropenia was also observed. Clinical effi-cacy was provocative in advanced platinum-resistantand platinum-refractory ovarian cancer, with bothradiographic and CA125 responses, justifying furtherexploration in this disease. The results also supportcontinued development of agents that affect dual inhi-bition of tumor proliferation and angiogenesis.

Diamond et al.

Clin Cancer Res; 17(4) February 15, 2011 Clinical Cancer Research850




The protocol was approved by the institutional reviewboards of participating institutions, and written informedconsent was obtained for all patients prior to performingstudy-related procedures in accordance with federal andinstitutional guidelines.

Drug administration and dose-escalation proceduresENMD-2076 was supplied by EntreMed, Inc. and total

daily dose was calculated based on body surface area.ENMD-2076 was supplied as capsules of various strengthsand was orally administered to fasting patients on a oncedaily continuous dosing schedule. An exception to this wasa 7-day observation period at the completion of cycle 1,prior to the initiation of cycle 2. ENMD-2076 was admi-nistered in the fasting state since a human food effect studyhas not been performed. The starting dose was 60 mg/m2,calculated as one-tenth the dose that was lethal in 10% ofrats (LD10), the most sensitive species. This dose is also 3.3-fold below the no observed adverse effect level (NOAEL) indogs.For the dose-escalation portion of the study, patients

were enrolled sequentially into escalating dosing cohortsusing a standard 3(to 4) þ3 design. Initially, 5 dose levelswere predetermined, but subsequently modified based ontoxicity. Intrapatient dose escalation was not permitted.Dose-limiting toxicity (DLT) was defined as any grade � 3nonhematologic toxicity despite maximum supportive care(e.g., for nausea, diarrhea, or electrolyte abnormalities) orgrade � 4 hematologic toxicity occurring during the firstcycle at least possibly related or of unknown relationship toENMD-2076. If a single patient in any cohort of 3 to 4patients developed DLT, the cohort was expanded to 6patients. If 2 or more patients in any expanded cohortdeveloped DLT, dose escalation was stopped and thecohort immediately below was further evaluated byexpanding to include 6 patients. The MTD was definedas the highest dose level at which no more than 1 patientexperienced DLT in a cohort of 6 patients. In the 200 mg/m2 cohort, 2 patients were treated with 350 mg/m2 for2 days before being de-escalated to 200 mg/m2 due todelayed toxicity occurring in the prior dosing cohort.Toxicology and clinical data from these patients wereanalyzed with the 200 mg/m2 cohort, while day 1 PKparameters were analyzed individually. Additional patientswere enrolled at the MTD in 3 expansion arms includingovarian cancer (n ¼ 12), colorectal cancer (n ¼ 10), andother refractory solid tumors (n ¼ 15) to further evaluatetolerability and preliminary antitumor activity.

Clinical evaluation and safety assessmentPrior to study entry, patients underwent clinical history

and physical examination, performance status assessment,vital signs, complete blood count (CBC), chemistries, coa-gulation parameters, urinalysis, serum pregnancy test,tumor markers, EKG, and baseline tumor measurements.While on study, patients underwent weekly evaluationincluding brief history and physical examination, vitalsigns, CBC and chemistries. Urinalysis was repeated each

cycle and EKG repeated every other cycle. To addresspreclinical adrenal cortical pathology, cortisol levels wereobtained on day 1 of each cycle, with a plan for an ACTHstimulation test if levels were below 80 nM/L. Based onknown effects of other VEGFR inhibitors, TSH wasobtained at baseline, at the conclusion of cycle 2, andsubsequently if clinically indicated. Adverse events wereclassified/graded weekly according to the Common Termi-nology Criteria of Adverse Events, version 3.0. Responsewas assessed every 2 cycles and evaluated by modifiedRECIST (18).

Pharmacokinetic sampling and assayIn the dose escalation portion, blood samples were

collected in sodium heparin tubes immediately prior tothe first dose on cycle 1, day 1 and then at 0.5, 1, 2, 4, 6, 8,10 to 12, and 24 hours following dosing. Samples wereobtained on cycle 1, day 28 predose and at the same timepoints as on day 1. Additional samples were obtained ondays 30, 31, and 35 (during the observation period) tobetter model terminal elimination rates. For cycle 2 andbeyond, trough samples were obtained on day 15. In theMTD expansion arms, limited sampling occurred, includ-ing prior to the first dose on cycle 1, day 1, 24 hoursfollowing dosing, day 28, and day 15 for cycles 2 andbeyond.

Plasma concentrations for ENMD-2076 and its activemetabolite, ENMD-2060, were determined using a vali-dated liquid chromatography tandem mass spectrometricmethod (LC/MS/MS) using ion transition parameters opti-mized for each analyte. A manuscript is in preparation withdetailed procedures. The lower limit of quantification forboth ENMD-2076 and ENMD-2060 was 1 ng/mL. Phar-macokinetic parameters were calculated from plasma con-centration-time data with standard noncompartmentalmethods using Excel.

Pharmacodynamic analysisBlood samples for plasma soluble VEGFR2 (sVEGFR2)

were collected immediately prior to dosing on cycle 1,day 1 and on cycle 1, day 28. During subsequent cycles, asingle blood sample was obtained immediately prior todosing on day 15. Plasma samples were diluted 1:5 andconcentrations determined by ELISA, per the man-ufacturer’s instructions (R&D Systems). ELISA plateswere read at 450 nm on a Synergy 2 plate reader (Biotek).

Skin biopsies were performed in a subset of patientsenrolled in the MTD expansion arms. Formalin-fixed,paraffin-embedded samples were analyzed by immunohis-tochemistry using an anti–phospho-histone H3 (pHH3)antibody (Cell Signaling Technology) as amarker of Aurorainhibition (19).

Statistical methodsDescriptive statistics were used for baseline character-

istics, safety assessments, pharmacokinetic variables(including Cmax, Tmax, AUC0-inf, and t1/2) and explora-tory assessments, including time to progressive disease,

Phase I Study of ENMD-2076

www.aacrjournals.org Clin Cancer Res; 17(4) February 15, 2011 851




tumor response and pHH3 immunohistochemistry inkeratinocytes. Measurements of sVEGFR2 before andduring ENMD-2076 were subjected to the unpairedStudent’s t-test. Linear regression was used to evaluatethe relationship of pharmacokinetic variables with doseand patient age, weight, estimated creatinine clearanceand albumin concentration. Correlation of percentdecrease of plasma sVEGFR2 and reduction of tumormeasurements was assessed by Pearson’s correlationcoefficient. P values < 0.05 were considered statisticallysignificant. Statistical analyses were performed usingGraphPad Prism software.

Results

Patient demographics and treatmentSixty-seven patients, 29 in the dose-escalation portion

and 38 in the MTD expansion, were enrolled fromApril 2008 to October 2009 (Table 1). A total of 257 cycleswere administered. The median number of cycles perpatient was 3 (range, 1–24). Reasons for study disconti-nuation were progressive disease in 41 patients (61%), anadverse event in 6 (9%), and other reasons in 11 (17%). Atthe time of data analysis, 9 patients (13%) continue ontreatment.

Table 1. Baseline demographics and patient characteristics

Characteristic Dose escalation (N ¼ 29) Expansion at MTD (N ¼ 38)

No. % No. %

SexMale 12 41 9 24Female 17 59 29 76

Age (years)Median 60 53Range 35–76 30–75

ECOG performance status0 10 34 11 291 19 66 27 71

Previous lines of systemic therapiesMedian 4 3Range 1–13 1–15

Previous therapyChemotherapy 25 86 35 92Radiotherapy 10 34 19 50Hormonal 2 7 7 18VEGF-targeting antibody 16 55 18 47VEGF-targeting TKI 5 17 6 16EGFR or HER2 directed antibody 10 34 9 24Vaccine 2 7 0 0Other immunotherapy 2 7 1 3Investigational Agent 11 38 12 32

Tumor typeColorectal cancer 9 10Ovarian cancer 8 12Renal cancer 3 1Pancreatic cancer 2 0Cervical cancer 1 3Breast cancer 1 2Neuroendocrine tumor 1 2Other 4* 8†

Abbreviations: ECOG, Eastern Cooperative Oncology Group; VEGF, vascular endothelial growth factor; TKI, tyrosine kinase inhibitor.*One patient each with bladder cancer, melanoma, thyroid cancer, and urachal cancer.†One patient eachwith bladder cancer, melanoma, adenoid cystic carcinoma, alveolar soft parts sarcoma, endometrial cancer, gastriccancer, hepatocellular carcinoma, and mesothelioma.

Diamond et al.





Dose escalation and determination of MTDDoses from 60 to 200 mg/m2 were evaluated. The dose-

escalation scheme, median number of cycles, frequenciesof dose delay and dose reductions, and DLTs in cycle 1 bydosing cohort are summarized in Table 2. One patientexperienced a DLT in the first cohort (60 mg/m2) withgrade 4 hypertension and grade 3 pain in the setting ofgrade 3 cholecystitis. The patient recovered and was treatedwith a dose reduction to 30 mg/m2 for 5 cycles beforecoming off study for disease progression. This cohort wasexpanded to include 7 patients and no further DLTs wereobserved. Patients were subsequently enrolled to dosingcohorts 2 (80 mg/m2) and 3 (120 mg/m2) with no DLTsobserved. Among 4 patients initially treated in the fourthdosing cohort (200 mg/m2), no dose-limiting toxicitieswere observed, prompting enrollment to the fifth dosingcohort at 350 mg/m2. However, at the time the first 2patients initiated dosing at 350 mg/m2, grade 3 neutrope-nia beyond cycle 1 was documented in 1 patient at the 200mg/m2 dose level. Study drug was held and eventuallyresumed at 120 mg/m2 once the absolute neutrophilaccount improved to grade 2. However, it was felt thatadditional patients should be evaluated at 200 mg/m2, sothat the 2 patients in the fifth dosing cohort received 350mg/m2 for only 2 days and were subsequently de-escalatedto 200 mg/m2. One additional patient was enrolled at 200mg/m2 to comprise an additional cohort of 3 patients atthis dose level. Among this latter group, 2 patients experi-enced grade 3 hypertension meeting DLT criteria. Further-more, among the entire group treated at 200 mg/m2, 3patients developed grade 3 neutropenia requiring dosedelay and reduction, although not meeting DLT criteria.Therefore, the 200 mg/m2 dose level was not consideredtolerable and an intermediate dose level of 160 mg/m2 wasevaluated. At 160 mg/m2, 1 of 8 patients experienced DLTwith grade 3 fatigue, dehydration, and hyponatremia.These events occurred in the setting of rapid disease

progression ultimately leading to death. The 160 mg/m2

dose level was chosen as the MTD, at which the expansionarms were enrolled.

SafetyThe most frequently observed drug-related adverse

events seen in all courses were hypertension, nauseaand/or vomiting, fatigue, and diarrhea (Table 3; Supple-mentary Tables S1 and S2). Nausea and/or vomiting wereobserved in 10/29 patients (38%) during dose escalationand 16/38 (42%) in the expanded 160 mg/m2 cohort.Nausea was a reason for dose reduction in only 1 patient.Grade 3 and 4 drug-related events included hypertension,fatigue, diarrhea, dyspnea, dehydration, neutropenia,hypophosphatemia, and elevated AST/ALT. Toxicityevents leading to dose reduction in 2 or more patientsincluded fatigue, hypertension, neutropenia, dyspnea,abdominal pain, and diarrhea. Fatigue was more com-monly seen at higher dosing levels including 12/38(32%) of patients in the expanded 160 mg/m2 cohort,reaching grade 3 to 4 severity in 2 of these patients andnecessitating dose reduction in 5 patients. Fatigue was notexplained by hypothyroidism, which occurred in only 2patients, both in the expanded 160 mg/m2 cohort. Ofnote, despite preclinical concerns, adrenal insufficiencywas not observed.

Hypertension was seen in 55% of total patients, occurredat all dose levels and reached grade 3/4 severity in 21%(Table 3). Inmost cases, hypertension was easily controlledwith addition of 1 antihypertensive agent (71%), mostcommonly a dihydropyridine calcium channel blockeror an angiotensin-converting enzyme inhibitor. Hyperten-sion resulted in dose delay or reduction in 16% of patients,but only resulted in study discontinuation for 1 patient.The median time to onset of hypertension following initialdosing was 14 days (range 2–60 days). A prior history ofhypertension was noted in 46%of these patients. There was

Table 2. Number of patients with dose delays, reductions and DLTs per dose level

Cohort no. ENMD-2076 doselevel (mg/m2)

No. ofpatients

No. of cycles No. of patientswith dose delays

No. patients withdose reductions

No. of patientswith DLT (cycle 1)

Median Range

1 60 7 2 1–24* 2 (29%) 1 (14%) 1†

2 80 4 4.5 3–6 3 (75%) 1 (25%) 03 120 3 2 2–3 1 (33%) 0 04 200 7 3 1–6 7 (100%) 3 (43%) 2z

5 160 8 3 1–11* 3 (38%) 1 (13%) 1Expansion 160 38 3 1–8* 24 (63%) 14 (37%) 12§

Abbreviations: DLT, dose-limiting toxicity.*Includes patients still receiving study drug.†Grade 4 hypertension and grade 3 pain in the setting of grade 3 cholecystitis in 1 patient.zTwo patients with grade 3 hypertension and 3 patients with neutropenia requiring dose delay not meeting DLT criteria, but dose levelwas not felt to be feasible.>Grade 3 dehydration, fatigue, and hyponatremia in 1 patient.§Number of patients in the expansion that met the definition of DLT.






no correlation between the development of hypertensionand clinical benefit (data not shown).

Neutropenia was first seen at 200 mg/m2 during doseescalation in 4 of 7 patients (57%); 3 of 7 (43%) had grade3 neutropenia requiring dose delay and reduction (Table 3).One episode of grade 4 neutropenia was seen in this cohortduring cycle 3, and so did not constitute a DLT. In theexpanded 160 mg/m2 cohort, 3 of 38 patients (8%) devel-oped grade 1/2 neutropenia, and 2 of 38 (5%) developedgrade 3/4 neutropenia (Supplementary Table S2). Themedian time to onset of neutropenia was 36 days (range19–181 days), and themedian time to recovery was 12 days(range 6–19 days). With dose reduction to 120 mg/m2 inpatients with grade 3 neutropenia at higher doses, furtherinstances of neutropenia requiring dose modification werenot encountered. There were no cases of neutropenic feverand no patient required growth factor support.

Oral mucosal-related complaints were common withENMD-2076 treatment. In patients treated at all dose levels,11/67 (16%) experienced glossodynia, 10/67 (15%) experi-enced mucositis, and 7/67 experienced (10%) dysgeusia.These AEs were more common at higher dosing levels, andsymptoms were often exacerbated by carbonated beveragesor spicy foods. Four patients treated in the expanded 160mg/m2 cohort experienced tooth discoloration.

Dose delays occurred in 24/38 (63%) of patients in theMTD expansion. In 4 patients, the reason for delay was an

intercurrent illness not due to ENMD-2076. The mostcommon reasons for ENMD-2076-related dose delaysincluded fatigue (n ¼ 6) and hypertension (n ¼ 5). Thefrequency of dose-reductions by dosing cohort is shown inTable 2 and individual events are listed in SupplementaryTable S3. In the MTD expansion, 14/38 (37%) requireddose reduction. The reasons for dose reduction in thisgroup included: fatigue (n ¼ 5), hypertension (n ¼ 2),diarrhea (n ¼ 2), neutropenia (n ¼ 2), dyspnea (n ¼ 2),abdominal pain (n ¼ 1), hyponatremia (n ¼ 1), poly-cythemia (n ¼ 1), and mucositis (n ¼ 1). Dose reductionwas based on multiple adverse events in 3 patients; only 1patient was dose-reduced during the first cycle.

In the MTD expansion, 12/38 (32%) patients experi-enced 16 adverse events meeting DLT criteria. The majorityof these (n¼ 7) were due to hypertension of grade 3 (n¼ 6)or grade 4 (n ¼ 1) severity. Other events included grade 3fatigue (n¼ 2), elevated AST/ALT (n¼ 2), elevated alkalinephosphatase (n ¼ 1), hypophosphatemia (n ¼ 1), hypo-natremia (n ¼ 1), congestive heart failure (n ¼ 1), anddyspnea (n ¼ 1).

Pharmacokinetic studiesPharmacokinetic parameters were determined for

ENMD-2076 and ENMD-2060, an active metabolite(Table 4), and plasma concentrations plotted by dosingcohort (Fig. 1A–C). The absorption kinetics of ENMD-2076

Table 3. Treatment-related hematologic and nonhematologic adverse events: worst grade per patient in allcycles in at least 10% of all patients and laboratory changes in at least 5% of patients

Adverse event* All patients (N ¼ 67)

Any grade Grade 3 Grade 4

No. of patients % No. of patients % No. of patients %

Patients reporting related adverse events 61 91 19 28 6 9Hypertension 37 55 12 18 2 3Nausea/vomiting 26 39 0 0 0 0Fatigue 21 31 2 3 0 0Diarrhea 17 25 2 3 0 0Anorexia 16 24 0 0 0 0Dehydration 12 18 1 1 0 0Glossodynia 11 16 0 0 0 0Constipation 10 15 0 0 0 0Mucositis 10 15 0 0 0 0Dyspnea 8 12 3 4 0 0Dysgeusia 7 10 0 0 0 0

Laboratory changes occurring in �5% of patientsNeutropenia 9 13 3 4 2 3Proteinuria 11 16 0 0 0 0Hypophosphatemia 7 10 1 1 0 0Elevated AST, ALT, or Alk Phos 7 10 1 1 2 3Anemia 4 6 0 0 0 0

Abbreviations: ALT, alanine amino-transferase; AST, aspartate amino-transferase.*Graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diamond et al.





were rapid after single and multiple doses with time tomaximum observed plasma concentration (Tmax) rangingfrom 3.0 to 7.8 hours for day 1 and 2.7 to 4.7 for day 28over all dose levels. The mean terminal phase eliminationhalf-life (t1/2) after a single dose is estimated to range from27.3 to 38.3 hours and from 44.9 to 53.1 hours aftermultiple doses. Using noncompartmental modeling, themaximum plasma concentration (Cmax) and area under theplasma concentration-time curve (AUC0-inf) were doseproportional after single and multiple doses (Fig. 1Dand E). With continuous daily dosing during cycle 1,accumulation of ENMD-2076 was observed with an aver-age factor of 3.4 (�1.1) across all doses (Cmax day 28/Cmax

day 1). However, additional accumulation was not seenbased on analysis of subsequent trough levels in a subset ofpatients who remained on study for greater than 2 cycles(Supplementary Fig. S1).The activemetabolite, ENMD-2060, reached amaximum

plasma concentration (Cmax) between 6.0 to 19.4 hours onday 1 and 2.7 to 11.4 hours on day 28. ENMD-2060 had alonger t1/2 than ENMD-2076, which ranged from 89.9 to139 hours, and by linear regression, there was a signifi-cant inverse correlation between t1/2 and dose cohort

(P ¼ 0.0171). There was no statistically significant doseproportionality in either AUC0-inf or Cmax for ENMD-2060(Fig. 1F).

Correlation of patient characteristics with ENMD-2076 and ENMD-2060 pharmacokinetic variables

Patient age, weight, estimated creatinine clearance, andalbumin concentration were independently analyzed forcorrelation to pharmacokinetic variables of ENMD-2076on days 1 and 28 and of ENMD-2060 on day 28. Patientweight correlated with ENMD-2076 AUC0-inf/fixed dose forday 1 (P¼ 0.0095), as well as Cmax/fixed dose (P¼ 0.0493)and Vd/F (P ¼ 0.0495) for day 28 (SupplementaryFig. S2A–C). Patient weight also correlated with ENMD-2060 fixed dose corrected Cmax (P ¼ 0.0093) for day 28(Supplementary Fig. S2D). No other correlations betweenpatient characteristics and pharmacokinetic parameterswere observed.

Pharmacodynamic analysis: plasma sVEGFR2The effect of ENMD-2076 on plasma sVEGFR2 was

determined after 28 days of continuous dosing. The meanplasma sVEGFR2 decreased from 8,419 pg/mL (95% CI

Table 4. Plasma pharmacokinetic parameters of ENMD-2076 (free base) and active metabolite ENMD-2060 on day 1 and day 28

Dose level(mg/m2)

No. ofpatients

Tmax

(hours)Cmax

(ng/mL)t1/2(hours)

AUC(0-inf)

(mg � h/mL)CL/F (L/h) Vd/F (L)

ENMD-2076 (free base) day 1 pharmacokinetic parameter (mean � SD)60 6 7.8 � 7.8 64 � 23 36.4 � 19.3 3.16 � 1.34 37.9 � 19.3 1707 � 52080 4 4.0 � 1.6 101 � 59 31.8 � 7.6 3.85 � 1.60 45.9 � 13.0 2029 � 458120 3 6.0 � 3.5 93 � 14 27.3 � 5.8 3.59 � 1.26 64.3 � 16.9 2436 � 242200 5 4.0 � 2.4 229 � 65 38.3 � 10.0 10.65 � 4.90 41.5 � 13.3 2283 � 874350* 2 3.0 � 1.4 300 � 18 31.1 � 14.4 12.16 � 5.10 55.2 � 12.9 2339 � 566160 8 3.5 � 1.4 157 � 52 28.6 � 8.4 5.94 � 2.41 52.9 � 18.4 2021 � 388

ENMD-2076 (free base) day 28 pharmacokinetic parameter (mean � SD)60 6 4.7 � 3.0 218 � 95 53.1 � 20.4 15.26 � 8.91 10.4 � 7.9 699 � 44980 3 3.4 � 1.2 233 � 76 51.0 � 18.7 14.66 � 3.78 10.8 � 3.3 748 � 148120 3 2.7 � 3.2 314 � 73 44.9 � 8.6 16.74 � 1.12 13.0 � 1.4 847 � 210200 4 4.5 � 2.5 557 � 191 47.6 � 12.7 34.50 � 18.31 14.0 � 4.7 907 � 242160 5 4.4 � 2.1 558 � 222 46.1 � 9.5 34.60 � 16.49 9.1 � 2.9 600 � 229

ENMD-2060 day 28 pharmacokinetic parameter (mean � SD)60 6 8.7 � 6.8 43.1 � 10.2 139 � 45 7.44 � 0.83 N/A† N/A80 3 11.4 � 10.9 29.4 � 2.9 115 � 50 4.72 � 2.04 N/A N/A120 3 2.7 � 3.2 60.9 � 21.1 93.3 � 18.3 7.13 � 0.87 N/A N/A200 4 6.0 � 3.3 60.4 � 18.1 89.9 � 17.7 7.54 � 3.02 N/A N/A160 5 4.8 � 3.3 95.0 � 34.1 92.5 � 22.6 12.55 � 3.33 N/A N/A

NOTE: PK parameters were estimated by noncompartmental modeling.Abbreviations: SD, standard deviation; Tmax, time to maximum plasma concentration; Cmax, maximum plasma concentration; t1/2,terminal phase elimination half-life: AUC0–inf, area under the curve to infinity; CL/F, systemic clearance; Vd/F, apparent volume ofdistribution; %CV, percentage coefficient of variation.*Two patients were treated at 350mg/m2 for 2 days before de-escalation to 200mg/m2 due to toxicity in previous cohort. One of thesepatients is included in the 200 mg/m2 cohort for day 28 PK parameters.†Not determined as ENMD-2060 is a metabolite of ENMD-2076.






7,716, 9,122) at cycle 1, day 1 to 5,600 pg/mL (95% CI5,086, 6,113) at cycle 1, day 28 (P < 0.001; Fig. 2A). Adecrease in sVEGFR2 at day 28 compared to baseline wasseen in all dosing cohorts (Fig. 2B), and persisted through

multiple treatment cycles (data not shown). There was noassociation between percent decrease in sVEGFR2 andmaximum decrease in tumor measurements by modifiedRECIST by Pearson’s Correlation (r2 ¼ 0.027, P ¼ 0.28).

Figure 1. Plasma ENMD-2076 and ENMD-2060 concentrations and relationship of drug exposure to dose level. Points represent mean concentration forENMD-2076 on day 1 (A) and day 28 (B) and for ENMD-2060 on day 28 (C) at the indicated dose level. Relationship of ENMD-2076 exposure (AUC0-inf) on day 1(D) and day 28 (E) with actual dose of ENMD-2076 received, and ENMD-2060 exposure (AUC0-inf) on day 28 with actual dose of ENMD-2076 received (F).Points represent individual patients and lines represent linear regression of data. The r2s for D, E, and F are 0.627, 0.401, and 0.118, respectively.

Diamond et al.





Histone H3 phosphorylation in keratinocytesPretreatment and on-treatment (cycle 1, day 28) skin

biopsies were obtained from 9 patients treated at the MTDand analyzed by immunohistochemistry to determine ifthere was a consistent pattern of increased or decreasedHH3 phosphorylation on treatment, suggestive of Aurora Aor Aurora B inhibition, respectively (19). Consistent withresults of previous studies, the number of pHH3-positivecells detected was low, ranging from 0 to 3/section (20, 21).No clear trend emerged. Among the 9 paired biopsies, thenumber of pHH3-positive cells decreased posttreatment in3 samples, remained the same in 4 samples and increasedin 2 samples (Supplementary Table S4 and SupplementaryFig. S3).

Antitumor activityFifty-eight out of 67 patients were evaluable for tumor

response. Of these, 2 patients (3%) had partial responses(PR; 1 confirmed), 49 had stable disease (SD; 85%), and 7had progressive disease (PD; 12%) as their best response(Fig. 3). Both patients with PR have ovarian cancer. Thefirst, considered platinum-resistant, was treated in theinitial dosing cohort (60 mg/m2) and remains on studyafter 24 months. The second, considered platinum-refrac-tory, was treated at 160 mg/m2, and remains on study after6 months. Twenty patients (30%) had decreases in tumormeasurements from baseline that did not qualify as PR.Multiple patients who experienced PR or SD � 12 weekshad prior exposure to anti-VEGF therapy (SupplementaryTable S5). Patients who experienced clinical benefit forgreater than 6 months included 5 patients with ovariancancer, as well as patients with hepatocellular carcinoma,neuroendocrine carcinoma (including large cell and insu-linoma), melanoma, colorectal carcinoma, renal cell

carcinoma, triple-negative breast cancer, and alveolar softpart sarcoma. Of the 20 ovarian cancer patients enrolled atall dose levels, 18 were platinum-resistant or refractory.Twelve (60%) experienced PR or SD � 12 weeks and 9(45%) had a 50% decrease in CA125 (SupplementaryFig. S4). Of the 19 colorectal cancer patients enrolled, 5(26%) had SD � 12 weeks, including patients with Kras-mutant tumors. There was no correlation between dose-level and responses.

Discussion

ENMD-2076 is a novel multitargeted kinase inhibitorthat combines antimitotic and antiangiogenic activitythrough inhibition of both Aurora and angiogenic kinases.Pharmacokinetics of ENMD-2076 demonstrated dose-pro-portionality of both Cmax and AUC0-inf. ENMD-2076 waswell tolerated based on the toxicity profile and prolongedduration of treatment inmany patients. The most commonadverse events, including hypertension, fatigue, nausea,and diarrhea, were consistent with those reported withother antiangiogenic agents (22–29). Myelosuppressionwas seen at higher dose levels as has occurred with otherAurora kinase inhibitors (20, 21, 30, 31) as well as multi-targeted kinase inhibitors such as sunitinib and sorafenib,whose targets, like ENMD-2076, include c-Kit and Flt3(32, 33).

At theMTDof 160mg/m2, 33%of patients required dosereduction due to toxicity, similar to rates of dose modifica-tion required with other multitargeted kinase inhibitors(22, 24). For example, among 375 renal cell carcinomapatients treated at the recommended phase 2 dose ofsunitinib in the comparison with interferon-alfa, 38%and 32% experienced at least 1 treatment-related dose

Figure 2. A, Plasma sVEGFR2 was assayed at baseline (cycle 1, day 1) and at cycle 1, day 28 (*P < 0.001). B, Plasma sVEGFR2 on day 1 and day 28 aftercontinuous dosing during cycle 1 by dosing cohort (*P < 0.001 compared to day 1 in same dosing cohort, **P < 0.05 compared to day 1 in samedosing cohort). (Inset) Percent decrease in plasma sVEGFR2 on day 28 compared to day 1 after continuous dosing during cycle 1 by dosing cohort. Differencesin percent change between dosing cohorts are not statistically significant by one-way ANOVA (P ¼ 0.23).






delay or reduction, respectively. Additionally, the rates ofgrade � 3 fatigue (7%), hypertension (8%), and neutrope-nia (11%; refs. 22, 23) were comparable to the rate of suchevents among the 46 patients treated with ENMD-2076 at160 mg/m2, which were 7% (3/46), 24% (11/46), and 4%(2/46), respectively. The 160mg/m2 dose is tolerable basedon protocol definitions during the first cycle and has amanageable side effect profile thereafter, with hypertensionreadily controlled. In future phase 2 studies, it may beinformative to investigate 2 dose levels of ENMD-2076,the RP2D and a dose level below, to further characterizethe toxicityprofile andapossibledose-effectwith treatment.Considering the long half-life and late appearance of toxi-cities in some patients, intermittent schedules (e.g. 3 weekson/1 week off) could also be evaluated.

A decrease in plasma sVEGFR2 was seen with ENMD-2076 treatment at all dose levels and persisted throughmany treatment courses. This is congruent with effects seenwith other VEGFR2 inhibitors (32), and demonstrates invivo VEGFR2 inhibition at doses of ENMD-2076 belowthe MTD. In contrast, pharmacodynamics of Aurora kinaseinhibition were not established among a small set ofskin biopsies analyzed at MTD. Of note, this dose level

produced only mild neutropenia, so effects of ENMD-2076on Aurora activity may have been modest. In preclinicalmodels, ENMD-2076 induces G2/M arrest consistent withAurora A inhibition (13, 16), and increases in mitoticindex, evidenced by increased pHH3 staining, were seenin 2 samples. However, exposures achieved suggest thatcombined Aurora A/B inhibition was possible, which mayaccount for reduced pHH3 after treatment in some samples(19). Other explanations for the lack of an anticipatedincrease in pHH3 following treatment include the smallsample size, small numbers of pHH3 positive cells persample, and unknown skin penetration of free ENMD-2076. Further work to address the effects of ENMD-2076on Aurora kinase activity in tumor cells is ongoing in aphase 1 study in patients with relapsed acute myelogenousleukemia (34).

In this heavily pretreated population, including 67%having received prior antiangiogenic agents, prolongedclinical benefit was seen in patients with a variety of solidtumors, notably in ovarian cancer. Two patients withplatinum-resistant disease achieved PR (1 confirmed).Several patients remained on ENMD-2076 at least 6months, with multiple CA125 reductions observed.

Figure 3. Waterfall plot of the change in the sum of the longest diameters of target lesions observed at the time of best response. Not shown, n ¼ 9,due to unavailable tumor measurements. Dose cohorts are shown in parentheses. White bars and/or *s represent patients who remained on ENMD-2076at least 6 months.

Diamond et al.





A correlation between the development of hypertensionand clinical benefit has been reported with a number ofantiangiogenic agents, including bevacizumab, sunitinib,and axitinib (35–37). We did not observe this associationwith ENMD-2076. There was also no correlation betweenthe magnitude of decrease in plasma sVEGFR2 and clinicaloutcome. Furthermore, prior exposure to antiangiogenictherapy did not preclude clinical benefit. This may indicatea lack of cross-resistance between ENMD-2076 and otherantiangiogenic agents, or the additional impact of conco-mitant Aurora kinase and/or FGFR inhibition.In summary, daily oral ENMD-2076was well tolerated in

solid tumor patients to at least 24 months with promisingpreliminary anticancer activity. These data support futureclinical trials evaluating this agent, both alone and incombination. A single-agent phase 2 study of ENMD-2076 in ovarian cancer is underway.

Disclosure of Potential Conflicts of Interest

S. G. Eckhardt: consultant, EntreMed, Inc., and stock ownership,EntreMed, Inc.; G. C. Fletcher: employment, EntreMed, Inc.; J. Arnott:

employment, EntreMed, Inc.; M. R. Bray: employment, EntreMed, Inc.;C. Sidor: employment, EntreMed, Inc.

Acknowledgments

We thank the following physicians, nurses and clinical research coordi-nators who assisted with this trial: Anne Leyba, NP; MaryKay Schultz, NP;Stacy Grolnic, RN; Kian Behbakht, MD; Andrew Wolanski, NP; Tracy Bell,RN; Caryn Kata, RN; Illya Dixon; James Cleary, MD; Linda Pointon;Fernanda Nery; Bruce Dezube, MD; Susan Gotthardt, RN; Myles Clancy;Janine Morrissey; Marguerite Parkman, RN; Michael Birrer, MD; LarryBlaszkowsky, MD; and Jill Allen, MD.

Grant Support

Supported by EntreMed, Inc. (NCT00658671), including a SponsoredResearch Agreement with Colorado State University for performance ofpharmacokinetics.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.

Received August 9, 2010; revised November 10, 2010; acceptedNovember 15, 2010; published OnlineFirst December 3, 2010.

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2011;17:849-860. Published OnlineFirst December 3, 2010.Clin Cancer Res Jennifer R. Diamond, Bruno R. Bastos, Ryan J. Hansen, et al. Inhibitor, in Patients with Advanced Solid TumorsStudy of ENMD-2076, a Novel Angiogenic and Aurora Kinase Phase I Safety, Pharmacokinetic, and Pharmacodynamic

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