brivanib alaninate for cancer

1. Introduction

2. Brivanib

3. Conclusion

4. Expert opinion

Drug Evaluation

Brivanib alaninate for cancerIvan Diaz-Padilla & Lillian L Siu†

Princess Margaret Hospital, Toronto, Ontario, Canada

Introduction: Angiogenesis inhibition represents a rational therapeutic strat-

egy in the management of solid tumors. Brivanib is a dual tyrosine kinase

inhibitor with selectivity against VEFGR-2 and FGFR.

Areas covered: This review provides an updated summary of preclinical and

clinical experience with brivanib in cancer. Data presented in abstract form

from international conferences or journal articles found with a PubMed

search of published literature up to December 2010 are described in

this review.

Expert opinion: Brivanib appears tolerable and exhibits favorable pharmaco-

kinetic and pharmacodynamic profiles with evidence of target inhibition in

surrogate tissues. Clinical and pharmacodynamic data support an oral once

daily administration at 800 mg. Brivanib shows promising activity as single

agent in hepatocellular carcinoma and in combination with cetuximab in

colorectal cancer. Further evaluations with cytotoxic chemotherapy and in

other solid tumors are currently ongoing.

Keywords: angiogenesis, brivanib, colorectal cancer,

dynamic contrast-enhanced magnetic resonance (DCE-MRI), hepatocellular carcinoma

Expert Opin. Investig. Drugs (2011) 20(4):577-586

1. Introduction

Brivanib alaninate (BMS-582664), the L-alanine ester prodrug of brivanib(BMS-540215), an orally available small molecule inhibitor of both vascular endo-thelial growth factor receptor (VEGFR) and fibroblast growth factor receptor(FGFR), is currently under development for the treatment of cancer, both as a singleagent as well as in combination with other cancer treatment modalities (Box 1).

VEGF and its corresponding tyrosine kinase receptors play a critical role in phys-iological and pathological angiogenesis, a process of forming new capillaries fromexisting blood vessels. Angiogenesis is essential for solid tumor growth and meta-stasis [1]. Tumor-induced angiogenesis is mediated by vascular endothelial growthfactor (VEGF) and several other cytokines, such as platelet-derived growth factor(PDGF) and fibroblast growth factor (FGF), which are secreted by tumor cells. Inthe absence of angiogenesis, tumors are considered to be in a dormant state and aregenerally devoid of actively developing blood vessels. This highly complex process isknown to be regulated by positive and negative factors that both influence and areinfluenced by the tumor host microenvironment. However, when an imbalance ofthese factors occurs such that the expression of proangiogenic factors are favoredover antiangiogenic factors, the dormant tumor can undergo the so-called ‘angiogenicswitch’ resulting in rapid tumor growth and increased potential for metastasis [2].Binding of VEGF to its cognate receptor VEGFR-2, stimulates one of the mostimportant angiogenic signaling pathways, thus the blockade of this interaction is arational anticancer approach. Several compounds with an antiangiogenic mechanismof action are currently under active clinical evaluation (Table 1), and a few of them tar-get VEGFR-2 specifically [3]. A Phase I trial of ramucirumab, a fully humanizedIgG1 antibody directed against a specific epitope of the external domain of VEGFR-2,has recently been published. In this study, the indirect observation of sustained highlevels of serum unbound VEGF-A following drug administration suggests that

10.1517/13543784.2011.565329 © 2011 Informa UK, Ltd. ISSN 1354-3784 577All rights reserved: reproduction in whole or in part not permitted

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VEGFR-2 is effectively inhibited. Also, based on dynamic-con-trast enhanced MRI (DCE-MRI) findings, tumor perfusionand vascularity were decreased in a majority of patients. Hyper-tension, vascular thrombosis events and proteinuria were themost common side effects reported, in concordance with thesafety profile observed with other therapies directed againstthe VEGF/VEGFR axis [4,5].Several adverse effects have been associated with anti-

VEGF/VEGFR agents including hypertension, proteinuriaand thromboembolic events. One potential mechanismexplaining an anti-VEGF induced hypertension can be relatedto the inhibition of nitric oxide (NO) by the endothelium.Systemic hypertension is believed to occur because inhibitionof VEGF in arterial endothelial cells decreases the release ofNO, which normally acts on arterial smooth muscle cells tocause vasodilation [6]. Proteinuria is also a class effect ofVEGF antagonists, but its causative mechanism is not as wellunderstood as that of hypertension. Both changes in the renallevels of VEGF and downregulation of certain tight junctionproteins within the kidney seem to play a role in the pathogen-esis of proteinuria induced by angiogenesis inhibitors [7]. Theprothrombotic effect of anti-VEGF agents may partly derivefrom a platelet-dependent mechanism. In fact, VEGF signal-ing seems essential for the production of the platelet inhibitorsprostaglandin I-2 and NO. Reduced levels of prostaglandinI-2 and NO may lead to increased platelet activation andincreased incidence of thromboembolic events.Recent studies have suggested that a tumor can escape initial

VEGF inhibition by altering the regulation of other growth fac-tors that may be important for angiogenesis and tumor cell pro-liferation [8]. Therefore, to obtain the greatest effects on cellgrowth reduction it may be beneficial to target more thanone pathway. In this sense, FGF has been shown to be notonly a key central regulator of many physiological processesin the adult organism, but also implicated in tumoral angiogen-esis [9]. There are four highly conserved transmembranetyrosine kinase receptors (FGFR-1, FGFR-2, FGFR-3 and

FGFR-4). Functional outcome of FGFR activation largelydepends on the cellular context. Also, there are differences insignaling between the FGFRs [10]. Deregulated FGF-dependentpathways have been observed in several tumor types. Extracellu-lar FGFR-3-activating somatic mutations have been encoun-tered in approximately 50% of bladder cancers [11,12].Mutations in FGFR-2 have been identified in 12% of endome-trial carcinomas. FGFR-2-mutant endometrial cancer cell linesare highly sensitive to FGFR tyrosine kinase inhibitors, whichmay reflect the oncogenic addiction to the mutant-activatedFGFR [13]. With regard to FGFR-1, the amplification ofthe chromosomal region 8p11--12 (the genomic location ofFGFR-1), is one of the most common focal amplifications inbreast cancer, and occurs predominantly in estrogen receptor(ER)-positive cancers [14]. Most of these genomic aberrationslead to the constitutive receptor activation and ligand-independent signaling. Interestingly, there is crosstalk betweenFGFR and VEGFR in angiogenesis, with some data indicatingpotential mechanisms of resistance to VEGFR inhibitors actu-ally mediated by the FGFR axis [15]. Dual inhibition of bothVEGFR and FGFR pathways therefore appears to be anattractive therapeutic approach to be further investigated.

2. Brivanib

2.1 Chemical name, structure and propertiesBrivanib (BMS-540215) is a chemically synthesized, orally avail-able, (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-6-yloxy) propan-2-ol, with highpotency against VEGFR-2. The low aqueous solubility of thiscompound leads to a rapid plasma hydrolyzation, resulting inlower than expected systemic exposure following oral administra-tion. In an attempt to improve the pharmacologic and pharma-cokinetic (PK) properties of the parent compound [16], aprodrug formulation process was pursued. Several aminoacid ester prodrugs were evaluated, and brivanib alaninate(BMS-582664) was selected for further clinical evaluation, based

Box 1. Drug summary.

Drug name Brivanib alaninatePhase II and IIIIndication None approved yetMechanism of action Dual VEGFR and FGFR tyrosine inhibitorRoute of administration OralChemical structure

N

F

O

N

N

N

OO

O

N

Pivotal trial(s) Phase III trial ongoing with cetuximab in K-RAS wild-type CRC;Phase III trials ongoing in HCC; Phase II trials in multiple tumor types

Brivanib alaninate

578 Expert Opin. Investig. Drugs (2011) 20(4)

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on its high aqueous solubility and favorable CYP inhibitionprofile, thus minimizing drug--drug interactions [17].

2.2 Preclinical data

2.2.1 In vitroBrivanib shows potent and selective inhibition of VEGFR andFGFR tyrosine kinases. Brivanib is an ATP-competitive inhibi-tor of humanVEGFR-2, with an IC50 of 23 nmol/l. In addition,it inhibits VEGFR-1 (IC50 = 350 nmol/l) and VEGFR-3(IC50 = 10 nmol/l). Brivanib also showed good selectivity forFGFR-1 (IC50 = 150 nmol/l), FGFR-2 (IC50 = 125 nmol/l),and FGFR-3 (IC50 = 68 nmol/l), whereas the IC50 values forother kinases (e.g., PDGFRb, EGFR, PKCa, JAK3) are over2500 nM (Figure 1). Furthermore, brivanib has been shown toselectively inhibit the proliferation of endothelial cells stimulatedby VEGF and FGF (but not with EGF) in vitrowith IC50 valuesof 40 and 276 nmol/l, respectively [18]. However, when testedagainst a panel of human tumor cell lines, brivanib showed lowerantiproliferative potency (IC50 > 2 µM), supporting the conceptthat the efficacy of the compound is driven by its antiangiogenicproperties [18]. Brivanib also inhibits FGF2-induced tumor cellproliferation in vitro, blocking FGFR-1 phosphorylation. Inter-estingly, both FGF2 and FGFR-1 RNA expression correlatedpositively with cell sensitivity to the drug, which could serve asa potential predictive marker to brivanib efficacy [19].

2.2.2 In vivoPreclinical efficacy data for brivanib have been intensivelyevaluated in xenografts. It has shown significant dose-dependent tumor growth inhibition in breast (H3396), colon(HCT/VM46) and lung (L2987) human tumor models [20].The dual inhibition of VEGFR and FGFR activity has alsobeen reported in bevacizumab-resistant colon cancer models,suggesting that enhanced tumor growth inhibition can beachieved by interfering with the synergistic angiogenic effectsof both VEGF and FGF on tumor vasculature [21]. Hepatocel-lular carcinoma (HCC) mouse models have been used to eval-uate the in vivo efficacy of brivanib, as higher levels of basicFGF (bFGF) seem to predict early postoperative recurrence

in this disease [22]. As in other solid tumor models, maximaltumor inhibition has been observed at doses in the range of100 mg/kg. No overt toxicity, mainly defined by body weightloss in animals, was observed [23].

2.3 Safety and tolerabilityThe CA182-002 study is a Phase I multiple ascending dosestudy that has evaluated brivanib alaninate in subjects withadvanced or metastatic solid tumors. In the dose-escalationpart of study (n = 18), subjects were treated with five dosecohorts of brivanib alaninate (180, 320, 600, 800 and1000 mg/day). Dose limiting toxicities (DLT) were observedat 1000 mg, and mainly consisted of grade 3 adverse events(AEs) including fatigue, altered mental status, and dehydra-tion. All of them started approximately a week after thedrug was initiated. Accordingly, the recommended Phase IIdose (RPTD) was established at 800 mg daily. Most otherAEs were mild, with the most common being: fatigue(59%), nausea (57%), diarrhea (48%), vomiting (44%),reversible elevation of transaminases (40%), hypertension(34%), and headache (28%). The most frequently reportedgrade 3/4 toxicities were fatigue and reversible elevation oftransaminases. Other common reported laboratory abnormal-ities were hyponatremia (32%) and increased hemoglobin(22%). Elevation in thyroid stimulating hormone has alsobeen observed in some patients treated with brivanib, butthe exact incidence of symptomatic hypothyroidism is uncer-tain. There was no clear dose--response relationship for anyAE [24].

In the CA182-003 dose escalation Phase I study thecombination of escalating doses of brivanib alaninate (startingday 1) with fixed dose of cetuximab (400 mg/m2 day 8,250 mg/m2 weekly thereafter) was evaluated in patients withadvanced gastrointestinal cancers, with an expansion cohortfor colorectal cancer (CRC). The toxicity profile of the com-bination across brivanib alaninate dose escalation cohorts(320, 600 and 800 mg) was consistent with the previouslyreported single-agent Phase I trial CA182-002. At thebrivanib alaninate 800 mg RPTD cohort, the most frequent

Table 1. Selected antiangiogenic drugs in current clinical development.

Drug Class of compound Target Phase of development

Bevacizumab mAb VEGF-A ApprovedRamucirumab mAb VEGFR-2 I/IIAflibercept Peptide-fusion Ab VEGF ligand IIIAMG 386 Peptide-fusion Ab Ang1, Ang2 I/IISunitinib TKI VEGFR-1, KIT, PDGFRb ApprovedSorafenib TKI VEGFR-1,-2,-3, PDGFRb, RAF1, B-RAF ApprovedPazopanib TKI VEGFR-1,-2,-3, PDGFRa, PDGFRb, KIT ApprovedAxitinib TKI VEGFR-1,-2,-3, PDGFRb, KIT IIICediranib TKI VEGFR-1,-2,-3, KIT II/IIIVandetanib TKI VEGFR-1, EGFR1, RET III

Ang: Angiopoietin; PDGFR: Platelet--derived growth factor receptor; TKI: Tyrosine-kinase inhibitor.

Diaz-Padilla & Siu

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grade 3/4 toxicities were fatigue (22%) and increased alanineaminotransferase (ALT) (11%). Overall, this study showedthat there is no significant overlapping toxicities for this regi-men.Notably, one episode of pulmonary embolism wasreported in the 320 mg cohort [25]. Further evaluation of bri-vanib alaninate in combination with folinic acid, fluorouraciland oxaliplatin (FOLFOX) or folinic acid, fluorouraciland irinotecan (FOLFIRI) chemotherapy (CA182-007) wasstopped early due a higher than expected incidence (47%)of arterial and venous thrombotic adverse events (TREs),even at doses of brivanib alaninate as low as 60 -- 180 mg.The frequencies of TREs were 43% in the FOLFIRI arm(all venous); and 50% in the FOLFOX arm (arterial andvenous) [26]. TREs do not appear to be dose-related, sinceevents occurred subsequent to treatment with brivanib alani-nate at doses ranging from 60 -- 180 mg with FOLFIRI andat doses of 400 -- 600 mg with FOLFOX. In general, identi-fication of TREs did not follow a pattern of onset as theywere reported 14 to 114 days after treatment was initiated,and in two instances occurred after treatment with brivanibalaninate was discontinued. The incidence of TREs reportedin other brivanib alaninate studies (both monotherapy andin combination with cetuximab) ranged from 0 to 8%.A potential increased risk for TREs when antiangiogenicdrugs are combined with chemotherapy cannot then be dis-carded. Further evaluation of brivanib alaninate in combina-tion with different chemotherapeutic drugs is currentlyongoing (clinicaltrials.gov identifier: NCT00798252 [27]). In

this trial patients considered as having an increased risk forvenous or arterial thrombosis at baseline are excluded.

2.4 PharmacodynamicsAs the primary putative mechanism of action of brivanib is viaits antiangiogenic actions, detailed characterization of its effectson tumor vasculature in preclinical models would help confirmif target inhibition is actually achieved. DCE-MRI is becomingan accepted noninvasive technique to assess changes in tumorvasculature, and is currently also being used in early clinicalstudies of several antiangiogenic drugs [28,29]. Preclinically,Malone and colleagues performed DCE-MRI evaluations in aL2987 human lung carcinoma xenograft model, where briva-nib alaninate administered orally on a once-daily schedulehad previously demonstrated dose-dependent tumor growthinhibition. After delivery of a once-daily efficacious dose, forthree consecutive days, a significant reduction in contrastuptake in tumors was observed when comparing baseline priorto dosing to different time-points after dosing. Conversely, arecovery of tumor microcirculation was also observed whenthe drug was stopped, suggesting that continuous daily dosingmight be necessary [30].

The identification of potential biomarkers of antitumoractivity in the clinical setting would also facilitate the clinicaldevelopment of brivanib alaninate. In this sense, microarraystechnologies have been used to characterize the mRNAexpression patterns in different tumor types. Certain geneexpression profiles have raised the possibility of predicting

HN

F

(S)

(R)

O

NN

NOO

O

NH2

IC50 (nM)

350

23

10

150

125

68

VEFGR-1

VEGFR-2

VEGFR-3

FGFR-1

FGFR-2

FGFR-3

Target enzyme/receptor

Figure 1. Chemical structure of brivanib and in vitro activity.

Brivanib alaninate


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clinical outcomes, which might be integrated into thedecision-making process of selecting adjuvant therapies in cer-tain tumor types [31-33]. Using athymic mice bearingL2987 human tumor xenograft treated with brivanib alani-nate, a gene expression signature was determined. Tumorsamples were collected from these xenografts and RNA wasextracted for gene expression profiling. A defined set of genesidentified to be coexpressed with VEGFR-2 from a clinicaltumor gene expression profiling database was used as a refer-ence for further anaylsis. By merging these two approaches,genes were discovered that are co-regulated with VEGFR-2in humans and are modulated by brivanib in tumor models.The L2987 lung carcinoma model was chosen for this typeof gene expression analysis of brivanib due to its high vascular-ity. Tumors were allowed to grow to a predetermined size andanimals were treated with brivanib. Tumors were then excisedfrom animals, and half of the tumor was used for RNA isola-tion and subsequent transcriptional profiling, and the otherhalf was fixed with formalin for further immunohistochemicalanalysis. Five potential candidate genes were identified, dem-onstrating a significant differential expression between pre-and post-treatment. These markers were tyrosine kinase withimmunoglobulin-like and EGF-like domains 1 (Tie-1), colla-gen type IV, component C1q receptor1 (C1QR1), angioten-sin receptor-like 1 and VE-cadherin. Further validation ofthese differences in mRNA expression at a protein level wascarried out. Only collagen type IV and C1QR1 showed paral-lel changes in immunohistochemical staining in paired pre-and post-treatment tumor tissues. This finding may be dueto protein degradation or mRNA post-translational modifica-tions, amongst other potential reasons. In addition, collagentype IV expression in blood from treated xenografts wasmeasured by ELISA, showing a marked decrease in its levelsfollowing brivanib alaninate treatment, corroborating thechanges at the tumoral level. These preliminary results couldsupport the hypothesis that collagen type IV may be a relevantpharmacodynamic biomarker of efficacy not only for brivanibalaninate therapy, but also for other antiangiogenic agents,but validation in the clinical setting is awaited [34].

Interestingly, both DCE-MRI changes and collagentype IV blood expression levels have been further evaluatedas potential surrogate markers of efficacy in a Phase I trial ofbrivanib alaninate (CA182-002) in patients with advancedsolid tumors. Preliminary results not only have confirmedprevious data from animal models, but it has also been dem-onstrated in responding patients a positive correlationbetween a reduction in DCE-MRI parameters and a decreasein peripheral blood levels of collagen type IV (measured byELISA), when doses of brivanib alaninate were given in therange of 600 and 800 mg [24].

As mentioned, brivanib inhibits FGFR enzymes in thenanomolar range. It has also been observed in the Phase I trialCA182-002 that brivanib alaninate treatment can be associ-ated with less tumor growth in patients with FGF2-positivetumors [35]. This finding may be clinically relevant as a greater

proportion of patients whose tumors overexpressedFGF2 were able to achieve clinical benefit from therapy,with either objective response or prolonged disease stabiliza-tion, than those whose tumors lacked FGF2 expression. Theseresults should however be interpreted with caution, due to thesmall number of subjects and the retrospective nature of theanalyses [36].

2.5 Pharmacokinetics and metabolismIn vitro and in vivo studies have shown that brivanib alaninateis rapidly and efficiently converted to the parent drug brivanib;thus minimizing systemic exposure to the potential toxic effectsof the prodrug. The serum protein binding of brivanib is98.7% in humans. Preclinical studies have also suggested thatbrivanib should have adequate permeability for absorptionthrough the gastrointestinal tract [37], which was subsequentlyconfirmed in clinical studies (estimated oral bioavailability ofbrivanib 86%). Data from early Phase I studies show a linearincrease in systemic exposure to brivanib at steady state withincreasing doses of brivanib from 180 -- 1000 mg/day, withlow to moderate inter-subject variability at each dose level(coefficient of variation (CV) 15 -- 41%) [35]. The terminalhalf-life is dose-independent and ranges from 12 to 16 h formost subjects, which makes oral administration of brivanib ala-ninate compatible with once-daily dosing schedules. A Phase Istudy (CA182-022) evaluating the food effect on brivanib ala-ninate pharmacokinetics has also been carried out in advancedcancer patients. There was no clinically meaningful effect of ahigh-fat meal on exposure to brivanib alaninate, therefore itwas concluded that it can be given with or without food [38].

Brivanib alaninate mainly undergoes oxidative hepaticmetabolism, equally shared by CYP3A4 and CYP1A2; and isprimarily eliminated in feces. Renal clearance of the drug isnegligible. Interestingly, further pharmacokinetic evaluationsof concurrent administration of brivanib alaninate and ketoco-nazole (a potent CYP3A4 inhibitor) on one hand, and brivanibalaninate and midazolam (a CYP3A4 substrate) on the other,showed that Cmax and AUC were not significantly altered.Therefore, brivanib alaninate could be safely co-administeredwithout dose adjustments to CYP3A4 inhibitors and/or sub-strates. Preliminary results from an ongoing Phase I study ofbrivanib alaninate in HCC patients with various degrees ofhepatic impairment (Child-Pugh A, B or C class), confirmthe similarity of brivanib PK profiles between subjects withadvanced solid tumors who have normal hepatic function andsubjects with HCC with both mild and moderate hepaticimpairment, at a dose of 400 mg of brivanib alaninate (clinical-trials.gov identifier: NCT00437424 [39]). These results shouldextrapolate to the 800 mg dose of brivanib alaninate giventhe linearity in PK of brivanib in humans. However, the PKof brivanib alaninate in patients with severe (Child-Pugh C)hepatic impairment is still unknown as enrollment in thesegroups is still ongoing.

Population PK studies of brivanib alaninate have also beencarried out. Body weight effect on clearance was found to be

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statistically significant (p < 0.01), while age, gender, and racewere not found to have a significant effect on the PK of briva-nib alaninate. Although body weight correlated with brivanibalaninate clearance, there was considerable inter-subject vari-ability in clearance (50.7%), with considerable overlap acrosssubjects when body weight varied from 50 to 100 kg. There-fore, this supported the use of fixed dose brivanib alaninate inclinical trials.

2.6 Clinical efficacy2.6.1 Colorectal cancerPreclinical work showed some hints of activity in several tumortypes (e.g., colorectal, hepatocellular, breast, sarcoma, ovarianand lung) [18,19], where further clinical development of brivanibalaninate has subsequently been more focused, such as in CRC.Preliminary results of the enriched (95% CRC) Phase I studyCA182-003 (n = 62) with the combination of cetuximab andescalating doses of brivanib alaninate in patients with advancedCRC showed 17% occurrence of partial response (PR) and62% of stable disease (SD), when brivanib alaninate wasadministered at 800 mg. Those patients not previously treatedwith either anti-VEGF or anti-EGFR therapies benefitted themost from therapy [25]. Interestingly, metabolic response(MR) assessments by [18F] fluorodeoxyglucose positron emis-sion tomography (FDG PET) at days 15 and 56 post-therapy,as defined by a 25% decrease in the maximal standardizeduptake value (SUVmax), have shown a 53% MR rate at day15 and a 42% MR rate at day 56. Median progression-free survival (PFS) was in the range of 5 months for responders,whereas for non-responders PFS was only 2.7 months [40]. Thisencouraging preliminary efficacy data should be confirmedprospectively. Further subset analysis of K-RAS mutational sta-tus in fresh tumor biopsies showed that only the wild-type K-RAS patient subpopulation (n = 24) achieved clinicalbenefit from therapy (PR+SD), suggesting that futurePhase II/III evaluation of cetuximab and brivanib alaninateshould be restricted to K-RAS wild-type patients [41].Two additional chemotherapy combination studies rele-

vant to CRC are currently ongoing. The first study combinesbrivanib alaninate with irinotecan and cetuximab (clinical-trials.gov identifier: NCT00594984 [42]). Preliminary resultshave shown that the safety profile of brivanib in combinationwith cetuximab plus irinotecan seems consistent with mono-therapy toxicities. In addition, the incidence of TREs withthis combination is within the expected range for metastaticCRC patients treated with chemotherapy (3 out of 28 =10.7% of patients, all venous and asymptomatic) [43]. The sec-ond study combines brivanib with FOLFIRI is currentlyongoing (clinicaltrials.gov identifier: NCT01046864 [44]).The efficacy of brivanib alaninate in refractory CRC is cur-

rently under active evaluation through a randomized Phase IIItrial in patients with advanced K-RAS wild-type CRC com-paring cetuximab plus brivanib alaninate with cetuximabplus placebo (NCIC CTG CO.20), and accrual has beencompleted (clinicaltrials.gov identifier: NCT00640471 [45]).

2.6.2 Hepatocellular carcinomaRemarkable tumor growth inhibition was previously observedin mouse models of human HCC, which has prompted its clin-ical evaluation in this patient population. Preliminary efficacydata of a Phase II open-label study of single-agent brivanib ala-ninate (800 mg once daily) both in first- and second-line treat-ment of patients with advanced HCC (n = 96) has beenreported. For patients who had not receive prior systemic ther-apy (Cohort A, n = 55) time to progression (TTP) was2.8 months, whereas patients previously treated with one priorregimen of an angiogenesis inhibitor (Cohort B, n = 41)showed a TTP of 1.4 months [46,47]. Safety data from thesetwo studies add further to earlier experience from Phase I stud-ies, with the most frequent AEs being fatigue, gastrointestinalsymptoms, hypertension and headache.

There is renewed interest in tailoring the standard radiolog-ical evaluation in certain tumor types [48]. In this regard, a mod-ified response evaluation criteria in solid tumors (mRECIST)were applied to retrospectively reassess response and, subse-quently, clinical outcome (i.e., time to progression (TTP)), inthe aforementioned trial [47]. By using mRECIST versus themodified World Health Organization (mWHO) criteria therewas a clear shift towards an increased response rate both inthe treatment-naıve group (Cohort A) and in the pretreatedgroup (Cohort B). More interestingly, TTP increased from2.8 to 5.4 months in the treatment-naıve group, and from1.4 to 6.9 months in the pretreated group. Two multi-centerPhase III randomized clinical trials are currently ongoingevaluating brivanib alaninate both in the first-line treatment,versus sorafenib (BRISK-FL study), and as a second-line ther-apy, versus placebo (BRISK-PS) (clinicaltrials.gov identifier:NCT00858871 [49] and NCT00825955 [50]). There is also anactive randomized Phase III trial addressing the value of addingbrivanib alaninate as an adjuvant therapy post trans-arterialchemoembolization in HCC (clinicaltrials.gov identifier:NCT00908752 [51]).

2.6.3 Other cancersBrivanib alaninate is also being studied in a Phase I, multi-arm, dose-escalation study (CA182-030), in combinationwith different chemotherapeutic drugs: capecitabine, doxoru-bicin, ixabepilone, paclitaxel or docetaxel (clinicaltrials.govidentifier: NCT00798252 [52]). Patients with different tumortypes are eligible. This trial will also help to better quantifythe potential associated risk for TREs when brivanib alaninateand cytotoxic chemotherapy are administered simultaneously.

A randomized Phase II discontinuation trial (CA 182-026),currently underway, is evaluating an initial open-label adminis-tration of brivanib alaninate (800 mg once daily) for twelveweeks (clinicaltrials.gov identifier: NCT00633789 [53]). Thosepatients who either respond or achieve stable disease after12 weeks are further randomized (double blind) to brivanib ala-ninate or placebo. Treatment assignment may be unblinded forpatients who progress during this phase of the trial. If receivingplacebo, the subject treatment may be crossed over to brivanib

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alaninate. One fundamental principle of this study relies ondetermining if the presence of FGF-2, as measured by immu-nohistochemistry in tumor tissue, may help defining a popula-tion who is more likely to respond to brivanib alaninatetherapy. This assay is based on the degree of FGF stainingwithin the cytoplasm of tumor cells. The degree of staining isgraded on a scale from 0 (absence of staining) to grade 1(mild), grade 2 (moderate) or grade 3 (strong) staining ingreater than 10% of cells. The retrospective review of Phase Itumor specimens indicate that the cut-off of 0, versus 1,2 and 3 was the most effective to differentiate between subjectslikely to respond and those not. An attempt to confirm this cutoff point prospectively will be madein the context of this study.The primary objective of the CA182-026 study is then to com-pare PFS for brivanib alaninate versus placebo in subjects withadvanced solid tumors, with FGF-2 overexpression and whohave obtained SD after 12 weeks of treatment with brivanibalaninate. Initial tumor types for this study were advancednon-small cell lung cancer (NSCLC), transitional cell carci-noma, soft tissue sarcoma, gastric/esophageal adenocarcinomaand pancreatic cancer including ampulla of Vater tumors.

Brivanib alaninate is also being evaluated in a Phase IItrial for patients with chemo-naıve recurrent endometrialcarcinoma. First results are expected by the end of2011 (clinicaltrial.gov identifier: NCT00888173 [54]).

3. Conclusion

Targeting tumor angiogenesis is an active area of research indrug development [55]. A better understanding of the regula-tory pathways that govern the angiogenic cascade allows theidentification of new targets and, it could aid the developmentof combination regimens with improved efficacy. VEGF andits receptors are key central regulators of angiogenesis andhave thus been the targets of multiple angiogenic inhibitors.However, simultaneous targeting of more than one mediatorof angiogenesis could rationally lead to a more effective bio-logical inhibition of the pathway and, hopefully, to improvedclinical efficacy. In this sense, FGF, upon binding to itscognate receptors, has been shown to be another growth factorwith an active role in tumor angiogenesis. Aberrant FGFsignaling is frequently observed in different tumor types,which accordingly has prompted focus on the developmentof FGF inhibitors.

Brivanib is a dual VEGFR2 and FGFR inhibitor underactive clinical development. Due to its low aqueous solubility,a modified ester prodrug approach was undertaken to producebrivanib alaninate, in an attempt to improve the pharamacoki-netic properties of the parent compound. In vitro, brivanib hasshown selective inhibitory capacity for VEGFR and FGFR,both in the nanomolar range. Significant tumor growth inhibi-tion has been demonstrated in multiple xenograft models. Earlyclinical trials of brivanib alaninate have shown that the drug isrelatively well tolerated. The most common reported toxicitieswere fatigue, hypertension, gastrointestinal symptoms and

reversible elevation of transaminases. The recommended doseof brivanib alaninate for further testing as a single-agent wasestablished as 800 mg once daily on a continuous schedule.The systemic exposure of brivanib alaninate at steady stateincreases proportionally with the dose, up to 1000 mg/day.Although brivanib alaninate is mainly metabolized by the liver,little PK interaction has been observed with other CYP3A4substrates. Pharamacodynamic endpoints are also beingaddressed throughout the clinical development of brivanib ala-ninate, in an attempt to identify potential predictive bio-markers of efficacy that can ultimately help select whichpatient subpopulations are more likely to benefit from therapy.Biomarkers of promise include the reduction in contrast uptakeby the tumor, measured by DCE-MRI, and a decrease in theserum levels of collagen type IV, measured by ELISA, havebeen shown to correlate with responses to brivanib alaninatewhen given at efficacious doses. Based on the encouraging pre-clinical evidence of activity of brivanib observed in animalmodels, further Phase II/III clinical development is currentlyongoing mainly in HCC and CRC patients.

4. Expert opinion

Brivanib alaninate is a dual tyrosine kinase inhibitor with selec-tivity against VEGF and FGF receptors, two of the mostimportant regulators of malignant angiogenesis. Once-dailyoral administration of brivanib alaninate at efficacious doseshas consistently been shown both in preclinical and clinicalstudies to inhibit tumor microcirculation when measured byDCE-MRI and, more importantly, a clinical correlation withoutcome has also been outlined. Its toxicity profile is manage-able and most adverse events reported so far are consistentwith those observed with other antiangiogenic agents. Theidentification of potential predictive biomarkers of brivanibefficacy (e.g., collagen type IV) may help tailor treatments forpatients. Furthermore, the relevant biologic role of FGF inthe pathogenesis of certain tumor types has also driven brivanibalaninate clinical development, especially towards advancedHCC. In addition, clinical evaluation of brivanib alaninateis currently ongoing in a wide range of tumor types (e.g.,breast, sarcoma, endometrial, ovarian, NSCLC, esophagealand transitional cell cancers).

Malignant tumors are driven by many different stimuli andthe interaction of the tumor with the surrounding tissues (e.g.,endothelium, stroma) has been shown to be crucial for tumorproliferation andmetastasis. Therefore, combinational strategieswith different targeted drugs or with chemotherapymight possi-bly represent the next step in the way malignant tumors shouldbe treated more effectively. To that end, the combination of bri-vanib alaninate with cetuximab, amonoclonal antibody directedagainst EGFR, has shown promising activity and good tolerabil-ity in K-RAS wild-type CRC patients. The evaluation of othertargeted agents in conjunction with brivanib alaninate shouldalso be pursued. Despite the occurrence of TREs when brivanibalaninate was delivered in combination with certain cytotoxic

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chemotherapeutic regimens, further evaluation of this agent insuch settings through careful patient selection and monitoringremains relevant. In the competitive landscape of antiangiogenictherapies, brivanib alaninate has unique properties thatmay ren-der it a useful agent to add to the treatment armamentarium forhuman malignancies.

Declaration of interest

LL Siu has received research support from Bristol-MyersSquibb. I Diaz-Padilla is supported in part by the grant“Programa de Formacion Avanzada en Oncologia (PAO)”from the Asociacion Espanola Contra el Cancer (AECC)”.

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AffiliationIvan Diaz-Padilla MD & Lillian L Siu†

†Author for correspondence

Princess Margaret Hospital,

Toronto, Ontario, M5G2M9 Canada

E-mail: [email protected]

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brivanib alaninate for cancer

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