1. Introduction

2. Development and synthesis

3. Mechanisms of increased

clinical activity of

elacytarabine

4. Pharmacokinetics

5. Efficacy

6. Safety

7. Conclusion

8. Expert opinion

Drug Evaluation

Elacytarabine -- lipid vectortechnology overcoming drugresistance in acute myeloidleukemiaAine Carol Burke† & Frank James Giles†Adelaide and Meath Hospital, Incorporating the National Children’s Hospital, Tallaght, Dublin,

Ireland

Introduction: Ara-C (cytarabine arabinoside) is a deoxycytidine analog that

has an established role in the treatment of hematologic malignancies, espe-

cially acute myeloid leukemia. Resistance to ara-C occurs and impacts nega-

tively on survival. To combat this, an elaidic acid ester of ara-C, called

elacytarabine, has been developed. This novel agent is highly efficacious in

cells with demonstrable resistance to the parent agent, including in solid

tumor xenografts.

Areas covered: The mechanisms that account for the increased clinical activity

of elacytarabine are discussed, including its ability to bypass the specialized

transmembrane nucleoside transport system on which ara-C depends, its pro-

longed retention within the cell and its alternative effect on the cell cycle. The

development and synthesis and pharmacokinetics are outlined, with emphasis

on lipid vector technology. Ten clinical trials involving elacytarabine, either as

monotherapy or part of a combination regimen, have been carried out in

both solid tumor and hematologic malignancies. The efficacy and side effect

profile results are summarized.

Expert opinion: Clinical trials in patients with hematological malignancies are

reporting very encouraging efficacy results with an acceptable side effect pro-

file. Elacytarabine has the potential to play an important role in the treatment

of multiple malignancies in the future and results from an ongoing Phase III

clinical trial are eagerly awaited.

Keywords: acute myeloid leukemia, ara-C, CP-4055, cytarabine, drug development,

elacytarabine

Expert Opin. Investig. Drugs (2011) 20(12):1707-1715

1. Introduction

Cytarabine arabinoside (1-b-D-arabinofuranosylcytosine, ara-C) is an arabinose-containing analog of the pyrimidine nucleoside, deoxycitidine. By competing withthis natural nucleoside for inclusion into deoxyribonucleic acid (DNA) during syn-thesis and repair, ara-C blocks subsequent DNA polymerase activity and the cellenters apoptosis. It is used as an antimetabolite to treat hematologic malignancies,mainly acute myeloid leukemia (AML). Although the advent of cytarabine-based therapies for this disease vastly improved response rates, survival rates stillremain poor [1]. Though the reason for this is multi-factorial, it is heavily influencedby variable factors at cell level involved in ara-C metabolism that confer innate resis-tance to the activity of the drug. Studies show that the pharmacokinetics of ara-C inplasma cannot predict for the metabolism of its active metabolite within leukemiccells [2].

10.1517/13543784.2011.625009 © 2011 Informa UK, Ltd. ISSN 1354-3784 1707All rights reserved: reproduction in whole or in part not permitted

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Similar to its native counterpart, ara-C is hydrophilic andutilizes the same specialized cellular machinery, called thehENT-1 system (human equilibrative nucleoside trans-porter-1), to enter cells. Within the cell, it undergoes severalphosphorylation steps. Ara-C monophosphate (ara-CMP) isformed by the action of the enzyme dCK (deoxycitidinekinase). This is the rate-limiting step and can be reversed bya high-Km cytoplasmic 5¢-nucleotidase called cN-II. Two fur-ther phosphorylation steps occur under influence of theenzymes deoxycytidylate kinase and nucleoside diphosphatekinase, both pyrimidine kinases, to form ara-C diphosphate(ara-CDP) and ara-C triphosphate (ara-CTP, cytarabine ara-binoside triphosphate), respectively. Ara-CTP is the majoractive intracellular metabolite and can be inactivated bydeamination by deoxycytidine deaminase (dCDA) to an inac-tive metabolite called ara-U (1-b-D-arabinofuranosyluracil).The remaining ara-CTP inhibits cell proliferation by incorpo-ration into DNA with chain termination, and potent com-petitive inhibition of DNA polymerase a (DNA POL)(Figure 1) [3,4].Intracellular concentrations of ara-CTP correlate with clin-

ical outcome [5] and reduced levels are clearly associated withara-C resistance [6]. These levels are affected by reduced activ-ity of hENT-1 [7] and the phosphorylating enzymes (dCK,deoxycytidylate kinase and nucleoside diphosphate kinase)and increased activity of the deactivating enzymes, cN-II [8]

and dCDA [9]. The ratio of the kinase and deaminaseenzymes may be an important determinant of inter-patientvariation in ara-C metabolism, as they have been shown tovary considerably among patients with AML [10]. The prog-nostic value of expression of hENT-1, dCK, dCDA and5¢-nucleotidase (5¢-NT) at diagnosis was examined, andmultivariate analysis showed 5-NT expression and hENT-1

deficiency to be the significant factors in disease-free survivaland early death [11].

2. Development and synthesis

Altering the original pharmacologic agents, cytarabine andgemcitabine, to make them lipophilic has been under investi-gation since the 1980s. In in vivo antitumor activity assays,liposome preparations of ara-C were 2 -- 8 times more supe-rior than free ara-C at 2 -- 4 times lower doses, but the novelpreparation was up to 10 times more toxic [12].

Alternative strategies were pursued and in the late 1990s atechnique to generate lipophilic nucleoside analog derivativeswas developed. This was achieved by attaching fatty acidchains with varying C-atom chain lengths and numbers ofdouble bonds to the 5¢-position of the sugar moiety of theara-C molecule [13]. Eleven novel agents were used to treatcell lines that had induced resistance to either ara-C or gemci-tabine. A clear structure--activity relationship was observed,and unsaturated compounds with shorter acyl chain lengthshad lowest IC50 (concentration of drug causing inhibition of50% of the cells being treated) values [14,15].

Lipid vector technology (LVT) has been patented and usedto synthesize over 300 new chemical entities (NCEs) [16]. Ofthe ara-C derivatives tested, CP-4055 (elacytarabine) was cho-sen to proceed. This is a 5¢-elaidic acid ester (D18:1D9, trans,unsaturated fatty acid) of ara-C (Box 1). Elacytarabine is pre-pared by esterification of ara-C hydrochloride with elaidoylchloride in dimethylacetamide [17].

Elacytarabine received ‘Orphan Drug’ status in 2007 fromthe European Commission and in 2008 by the US Food &Drug Administration (FDA), and in December 2010, theFDA also granted it ‘Fast Track’ designation.

Box 1. Drug summary.

Drug name ElacytarabinePhase Phase IIIIndication Relapsed/refractory acute myeloid leukemiaPharmacology description A 5¢-elaidic acid ester (D18:1D9, trans, unsaturated fatty acid) of ara-CRoute of administration IntravenousChemical structure

N

N

NH2

HO

OHO

OO

O

CP-4055Pivotal trial(s) See Table 1

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and

Citeline (http://informa.citeline.com).

Elacytarabine

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3. Mechanisms of increased clinical activity ofelacytarabine

3.1 Non-reliance on transmembrane transporterThe hENT-1 transporter accounts for 80 -- 90% of totaltransmembrane transport of the pyrimidine nucleosides [18].In vitro, hENT-1-deficient cells or cells with loss of functionpoint mutations within the hENT-1 gene are highly resistantto ara-C [19-21]. The number of nucleoside transport sites onblast cells closely correlates to the accumulation of intracellu-lar ara-CTP [22]. Seventeen percent of patients with AML donot express hENT-1 at diagnosis and these patients are three

times more likely to relapse (95% confidence interval (CI)1.4 -- 6.5) and 1.8 times more at risk for an early death [11].Between 35 and 45% of elacytarabine in plasma undergoesextracellular hydrolytic cleavage of the elaidic acid moiety.This results in as much as 65% of the available drug notrequiring the hENT-1 system to enter the cell [23]. Inhibitionof nucleoside transporters in vitro partially reversed the activ-ity of ara-C, reducing cell proliferation up to 75-fold in threecell lines, compared with no effect on that of elacytara-bine [23,24]. Lymphoma cell lines with either proficient orineffective nucleoside transporters were treated withara-C and elacytarabine. While the cells deficient in the

HO

O

OHHO

N

N

NH2

O

HO

O

OHHO

N

N

O

O

ara-C

ara-U

HO

O

O

N

N

NH2

OO

OH

Deaminases(e.g., deoxycytidine deaminase)

in blood, liver,tissue or intracellular

Esterases in blood,tissue or intracellular

CP-4055

HO

O

OHPTO

N

N

NH2

O

ara-CTP

HO

O

OHPO

N

N

NH2

O

ara-CMP

Figure 1. Metabolic pathway for elacytarabine and ara-C.

Burke & Giles

Expert Opin. Investig. Drugs (2011) 20(12) 1709

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transporter were 56,700 times more resistant to ara-C activ-ity, they were only 75-fold less sensitive to the action of ela-cytarabine, compared with the cell lines with the proficienttransport system [25]. Notably, FLT3-ITD (internal tandemduplication of FLT3) induces ara-C resistance in myeloidleukemia cells through the repression of hENT-1 expressionvia hypoxia-inducible factor-1-alpha (HIF-1-a) induc-tion [26]. In bypassing this rate-limiting step of ara-C metab-olism, this novel agent has the potential to deliver higherintracellular ara-CTP levels. A commercial test to detectlow or absent hENT-1 levels by flow cytometry of bonemarrow blast cells is in development. This will enableselection of patients who will most likely benefit fromelacytarabine [27].

3.2 Increased intracellular retentionCompared with ara-C, eladic esters with chain lengths ofbetween 18 and 20C-atoms showed better activity after shorterexposure times suggesting prolonged retention within thecell [14]. This was confirmed by Bergman et al., using IC50

ratios at 4 versus 72 h [15,28]. When hENT-1-expressingCEM cells (a human T-lymphocyte cell line) were pre-treated with an hENT-1 inhibitor (nitrobenzylthioinosine),the IC50 values increased 720-fold for the ara-C-treated cellsand only 5.5-fold for elacytarabine-treated cells (567 vs0.75 µM) [25]. DNA inhibition was complete at 2 -- 4 h inara-C-exposed cells, but continued for a more prolongedperiod in elacytarabine-exposed cells [15]. In another study,ara-CTP levels peaked at the end of the incubationperiod with ara-C and fell to 40% at 2 h after removalof the drug. However, when incubated with elacytarabine,ara-CTP levels continued to rise for 120 min after removalof the drug-containing medium and reached higher totalconcentrations [23].Intracellularly, elacytarabine is mainly found in the cyto-

solic and membrane portions. It is highly protein bound,which may account for prolonged retention of the drug afterremoval from the treating medium [23]. Hydrolysis by intra-cellular and extracellular esterase enzymes forms ara-C,which then proceeds as previously described to exert its cyto-toxicity. Prior to this step, elacytarabine is not a substrate fordCDA [28]. Seventy-seven percent of intracellular ara-C israpidly deaminated to its main inactive metabolite, ara-U,by this enzyme, accounting for its short half-life [29].Therefore, the resistance of elacytarabine to dCDA activityis a possible mechanism for its prolonged intracellularretention [15].

3.3 Alternative effects on cell cycleSimilar to ara-C, elacytarabine induces cell cycle arrest inS phase [25,30]. Recent work shows it also induces accumula-tion in G2/M phase, which is at variance with the expectedactivity of the parent drug [31] and previous data [30]. Itdoes so at concentrations greater than the IC50, leading toincreased cell kill.

4. Pharmacokinetics

Elacytarabine is 5¢-O-(trans-9¢¢-octadecenoyl)-1-b-D-arabino-furanosyl cytosine formulated as a colloidal suspension forintravenous infusion. Accumulated pharmacokinetic datafrom two clinical trials using 30 and 120 min infusions havebeen reported [32-36]. Plasma concentrations measured asAUC (area under the plasma concentration versus time curve)and Cmax (maximum concentration) rose linearly withincreasing doses. The ara-U/ara-C AUC ratio is three timeshigher for the novel agent compared with standard treatment,which confirmed intracellular retention of the novel drug [34].Elimination was biphasic for doses over 30 mg/m2 perinfusion and the drug was undetectable at 24 h. Inter-patient variation was low for most parameters excepthalf-lives, where there was over 80% variability [36].

5. Efficacy

5.1 Preclinical studiesAvailable preclinical in vitro data on elacytarabine are lim-ited [14]. The efficacy of elacytarabine was demonstratedin vivo using two hematologic, and seven solid tumor, xeno-graft models. Following toxicity and dose-finding studies, theanimals were treated with equitoxic dose elacytarabine andara-C (at respective maximum tolerated dose (MTD)), equi-molar dose ara-C and saline [24]. In a murine leukemic modeland a Raji lymphoma model, there were long-term survivalrates of 60 -- 80% when treated with elacytarabine and nosurvivors in the control and ara-C-treated groups. The solidtumor panel included three malignant melanomas, onebreast carcinoma, one non-small cell lung adenocarcinoma(NSCLC) and two osteogenic sarcomas. In the breast carci-noma and sarcoma models, both ara-C and elacytarabinewere inactive, except for minimal effect against the former.Partial or complete tumor regression was seen in the lungcarcinoma and the three malignant melanomas after treat-ment with elacytarabine. In one melanoma model, ara-Cand elacytarabine were equally active, but in the other twoand in the NSCLC model, elacytarabine was significantlysuperior [24].

5.2 Clinical trialsClinical trials have been carried out using elacytarabine bothas monotherapy and in combination regimens in both solidand hematological malignancies (Table 1).

5.2.1 Solid tumorsThere have been two Phase I trials carried out insolid malignancies.

In one study, 34 heavily pre-treated patients received atotal of 85 cycles of treatment. Two dosing intervals andinfusion durations were tested. A late neutropenic nadir(18 -- 26 days) was noted and administering the agent dailyfor 5 days, every 4 weeks, was decided as optimal. Infusion

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duration (30 min vs 2 h) did not affect the safety profile. TheMTD was 200 mg/m2/day in the three-weekly schedule and240 mg/m2/day in the four-weekly schedule. One patientwith malignant melanoma responded with time to progression(TTP) of 22 months. Stable disease was seen in 12 patients,lasting between 11 and 33 weeks and was reported across alltumor types (NSCLC, ovarian cancer and malignantmelanoma) [32,33,37].

The other trial studied the drug in 74 patients, using fourdifferent dosing schedules, across 11 dose levels. It was admin-istered as a 2-h infusion on either days 1 and 8 every 3 weeks,days 1 and 15 every 4 weeks, days 1, 8 and 15 every 4 weeks ordays 1 and 2 every 4 weeks, and the dosing levels werebetween 100 and 1650 mg/m2/day. Thirteen patients had sta-ble disease for > 3 months (range 3.3 -- 11.7 months), mostnotable in heavily pre-treated NSCLC and colorectal cancerpatients. No MDT was established [34,38].

There are four Phase II trials in solid tumors, all with aninfusion schedule over 5 consecutive days. Nineteen patientswith metastatic malignant melanoma treated with the elacy-tarabine/sorafenib combination have been reported. A totalof 45 cycles of therapy were administered (range 1 -- 6 perpatient). Six patients were withdrawn due to safety concerns(skin rash/hypersensitivity, diarrhea, elevated bilirubin,pleural effusion, thrombosis). Most common moderate tosevere side effects were myelosuppression and pyrexia. Nopartial or complete response was achieved, however, fivepatients achieved stable disease for > 8 weeks. Best responsenoted was a 25% reduction in tumor size [35,39].

5.2.2 Hematologic malignanciesUsing the previously acquired Phase I data in solid malignan-cies, a Phase I trial in hematologic malignancies was initiatedto establish the MTD and preferred infusion time in this

Table 1. Clinical trials of elacytarabine.

Indication Phase Clinical trials

identifier

Drug dosing schedule Status Location

Late-stage AML III NCT01147939 1000 mg/m2/day CIV on days1 -- 5 every 3 weeks

Recruiting 75 study locations inthe USA & Europe

Second-line therapy inpatients with advancedcolorectal cancer

III NCT00498407 200 mg/m2/day, days 1 -- 5 every4 weeks, 30 min infusion

Complete UK

AML as second courseremission-induction, incombination withidarubicin

II NCT01035502 1000 mg/m2/day as a CIV on days1 -- 5, every 3 weeksIdarubicin fixed dose 12 mg/m2/day,days 1 -- 3 every 3 weeks

Recruiting USA/France/Germany/Norway

Previously untreatedpatients with malignantmelanoma

II NCT00232726 200 mg/m2/day, days 1 -- 5 every4 weeks

Complete USA/Norway/Sweden

In combination withsorafenib in metastaticmelanoma

II NCT00498836 200 mg/m2/day on days 1 -- 5every 4 weeks, 30 min infusionSorafenib 400 mg/b.i.d

Complete USA/Norway/Sweden

Platinum-resistant ovariancancer

I/II NCT00831636 75, 100 or 125 mg/m2/day,days 1 -- 5 and 8(+2) -- 12(+2)every 4 weeks

Complete Belgium/Italy

Relapsed/refractory AML I/II NCT00405743 Escalating dose levels, i.v. ondays 1 -- 5 every 3 weeks

Complete USA/UK/France/ItalyGermany/Norway

Relapsed/refractory AML I NCT01258816 2000 mg/m2/day as a CIV ondays 1 -- 5 every 3 weeks

Recruiting UK

Refractory solid tumors I CP4055-101 Multi-schedule30 -- 200 mg/m2/day, 30 min i.v.,days 1 -- 5 every 3 weeks240 mg/m2/day, 30 min i.v., days1 -- 5 every 4 weeks240 mg/m2/day, 2 h i.v., days1 -- 5 every 4 weeks

Complete Four European centers

I CP4055-102 Multi-schedule100 -- 1650 mg/m2/day, 2 h i.v.days 1, 8, every 3 weeks100 -- 1650 mg/m2/day, 2 h i.v.days 1, 15, every 4 weeks

Complete

Sources: www.Clinicaltrials.org June 2011, Meeting reports.

AML: Acute myeloid leukemia; CIV: Continuous intravenous infusion; i.v.: Intravenous.

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population. Seventy-seven patients were treated on days1 -- 5 every 3 weeks with either a 2 -- 4-h infusion daily(n = 37) or a continuous 24-h infusion (CIV) (n = 40), start-ing at either 300 or 200 mg/m2/day, respectively. A total of125 cycle of therapy were administered. The MTD in botharms was 2500 mg/m2/day. Activity was seen at doses morethan or equal to 875 mg/m2/day. A complete response withincomplete platelet recovery (CRp) or better was achievedin 17% (5/29 patients) of patients with relapsed/refractoryAML treated with this dose or higher [40,41]. The recom-mended Phase II dose was 2000 mg/m2/day as a CIV fordays 1 -- 5 every 21 days.Phase I data have also been collated for elacytarabine in

combination with idarubicin in refractory/relapsed AML.The starting dose of 1150 mg/m2/day was established as theMTD, the two DLTs (dose-limiting toxicities) includedtyphilitis and hand-foot syndrome. At the recommendedPhase II dose, 1000 mg/m2/day CIV, with fixed dose idarubi-cin, 12 mg/m2/day, 25% (4/15) of evaluable patients achieveda partial complete response or better (three achieved CR andone achieved CRp) [41,42].Phase II testing, both with elacytarabine as monotherapy and

in combination with idarubicin, was undertaken. Results todate are from the monotherapy arm and are very encou-raging [43,44]. Sixty-one patients have been treated with2000 mg/m2/day as a CIV for 5 days every 3 weeks. A CR/CRp rate of 18% was achieved (compared with historicalcontrol, p = < 0.0001) and the median overall survival (OS)was 5.3 months, compared with historical control of1.5 months [1]. The median time from start of treatment toremission was 48 days (range 28 -- 114 days) and the medianduration of remission was 95 days (range 4 -- 230 days). Amongthe CR/CRp population (n = 11), the median OS was10.9 months and 6-month survival was 63.6% (Table 2). Six-teen percent of patients (n = 10) were subsequently referredfor stem cell transplant [45]. As of January 2011, the combina-tion arm had enrolled 16 patients at 8 sites, and aims to recruitup to 50 patients at 10 sites in theUSA and Europe. The chosenindication is second course remission-induction therapy inpatients with AML. While one main objective is to deter-mine response rates to the combination of elacytarabine andidarubicin, another is to evaluate, by immunohistochemistry,

the hENT-1 status of AML cells at the time of diagnosisand/or before elacytarabine treatment [46].

A Phase III clinical program in patients with relapsed/refractory AML was announced in December 2009. EntitledCLAVELA (title of phase III study of ELAcytarabine fromCLAVis pharma), this is an open-label, randomized-controlled trial comparing elacytarabine with the investigators’choice of treatment in patients with late-stage AML. The pri-mary end point is OS [47]. A data monitoring committee(DMC) review in November 2010 advised continuing the trial.Up to 350 patients will be recruited at 75 sites in the USA, Can-ada, Australia and Europe. The key inclusion criteria requireadult patients, with confirmed AML according toWHO classi-fication (excluding acute promyelocytic leukemia), who havereceived two or three previous induction regimens or patientsage ‡ 65 years with adverse cytogenetics who have receivedone to three previous induction/re-induction regimens. Patientsmust have either:

. never attained CR or CRi (primary refractory),

. failed initial induction but attained CR or CRi aftersalvage therapy, and then relapsed after < 6 months,

. attained CR or CRi after induction therapy, and thenrelapsed after < 12 months and failed to respond tosalvage therapy or

. relapsed within < 6 months after the latest CR or CRi.

5.2.3 Combination studiesPreclinical in vitro combination studies examined antiprolifer-ative activity of elacytarabine in combination with cloretazine,idarubicin, gemcitabine, irinotecan and topotecan in a humancell lines (HL-60 and U937). There was significant synergywith gemcitabine (CI = 0.4), moderate synergy with topote-can and irinotecan (CI = 0.8) and additive interactions withidarubicin and cloretazine in HL-60 cells (combination index(CI) = 1.0). The IC50 of elacytarabine could be reduced10-fold, and that of gemcitabine 3-fold, in combinationversus each agents alone [30,48].

In solid tumors, the effect of the combinations of elacytar-abine with oxaliplatin and docetaxel, and the monoclonalantibodies, bevacizumab, cetuximab and trastuzumab wastested in vitro and in vivo. Oxaliplatin, bevacizumab and tras-tuzumab enhanced cytotoxicity of elacytarabine and warrantfurther investigation for appropriate patient groups [48,49].

6. Safety

In the first clinical trial in solid malignancies, there were nounexpected significant adverse reactions, although all patientsexperienced at least one treatment-related adverse event. Mye-losuppression accounted for 76% of all grade 3 -- 4 toxicities.This consistedmainly of neutropenia (24 events in 19 patients),which was more dependent on administration schedule ratherthan dosing level. Other reported CTC (common toxicitycriteria developed by the National Cancer Institute) grade

Table 2. Survival in Phase II trial -- elacytarabine as

second salvage therapy in relapsed/refractory AML.

Median OS

(months)

6-month

survival rate (%)

All patients (n = 61) 5.3 42.6Patients in CR (n = 5) 13.3 80Patients with CR/CRp (n = 11) 10.9 63.6Patients transplanted (n = 10) 7.2 not available

AML: Acute myeloid leukemia; CR: Complete response; CRp: Partial complete

response; OS: Overall survival.

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3 or higher events included anemia (n = 3), thrombocytopenia(n = 3), fatigue (n = 3) and infection (n = 3). The DLTsincluded fatigue (grade 3) and neutropenia (grade 4).

In the hematological trials, myelosuppression was the pre-dominant adverse event. Reversible elevations of liver func-tion tests (LFTs), typhlitis and hand-foot syndrome were theDLTs. Other common adverse events included gastrointesti-nal upset and drug-related fever. The median duration to neu-trophil recovery in the peripheral blood in AML patients whoachieved remission was 28 days (range 22 -- 40 days).

7. Conclusion

The metabolism of ara-C is well described. Addition of a fattyacid chain to ara-C, to develop the novel drug, elacytarabine,is an attempt to alter its metabolism for more effective treat-ment of AML. Evidence that the novel agent enters the cell,at least in part, independent of the hENT-1 transport systemis clear. Also clear is the role hENT-1 plays in ara-C resistanceand in the relatively poor clinical outcome of patients withlow or absent expression of this receptor. Therefore, the abil-ity of elacytarabine to by-pass the transport system is one ofthe central aspects of its success. Prolonged retention of elacy-tarabine within the cell is being postulated as another impor-tant aspect of its pharmacokinetics. While evidence based ondownstream metabolites show it is retained longer thanara-C in the cell, exactly why this is so is not yet clear. Itseffect on the cell cycle continues to be investigated and thoughit is known that the cell arrests in different stages of the cellcycle, how this happens and its eventual relevance remainsthe subject of further research.

Elacytarabine showed good preclinical efficacy. A 25%response rate in Phase I trials in hematologic malignancieswas very encouraging and full Phase II data are awaited.Toxicity was predictable. Results of the ongoing Phase IIICLAVELA study are eagerly awaited.

8. Expert opinion

The development of elacytarabine is an exciting innovativeapproach to improving the efficacy of ara-C. The novelLVT employed is an important development in the arena ofdrug development. By converting known agents to lipophilicderivatives, this technology has the potential to generatemultiple generations of more potent agents.

Whether the improved delivery and longer intracellularretention times achieved by elacytarabine increases toxicityparallel to increasing efficacy is an important consideration.Elacytarabine has activity in cells known to be resistant toara-C. In bypassing the hENT-1-dependent mechanismfor cell entry elacytarabine can partly overcome ara-Cresistance in leukemic cells. It is worth noting thatseveral other resistance mechanisms develop in this diseaseto which elacytarabine is as equally susceptible to as theparent drug.

The results of clinical trials have been very positive to date.Activity was shown in Phase I trials, with a 25% of partici-pants achieving a partial response or better. Early Phase IIresults in AML produced an improvement in survival inpatients receiving second salvage treatment. It must beacknowledged that although the difference is highly statisti-cally significant, the actual numbers of patients achieving aresponse is still low, reflecting the intensely refractory natureof leukemia at this stage. Full Phase II data are awaited andthe initiation of an international Phase III study (CLAVELA)is encouraging.

Declaration of interest

AC Burke states no conflict of interest and has receivedno payment in preparation of this manuscript. FJ Gilesis an advisor and recipient of research funding fromClavis Pharma.

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B287

AffiliationAine Carol Burke†1 & Frank James Giles2

†Author for correspondence1Adelaide and Meath Hospital,

Incorporating the National Children’s Hospital,

Tallaght, Dublin 24, Ireland

E-mail: draineburke@gmail.com2National University of Ireland Galway &

Trinity College Dublin,

HRB Clinical Research Facility,

Dublin, Ireland

Burke & Giles

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