Table Of ContentSHORT COMMUNICATION
British Journal of Cancer (2013) 108, 762–765 | doi: 10.1038/bjc.2012.604
Keywords: bortezomib; sunitinib; Phase 1; Bayesian; EWOC
A phase 1 Bayesian dose selection study of
bortezomib and sunitinib in patients with
refractory solid tumor malignancies
R D Harvey*,1,2, T K Owonikoko1,2, C M Lewis2, A Akintayo2, Z Chen3, M Tighiouart4, S S Ramalingam1,2,
M P Fanucchi5, P Nadella6, A Rogatko4, D M Shin1,2, B El-Rayes1,2, F R Khuri1,2 and J S Kauh1,2
1Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA; 2Winship Cancer
InstituteofEmoryUniversity,Atlanta,GA,USA;3DepartmentofBiostatisticsandBioinformatics,RollinsSchoolofPublicHealth,
EmoryUniversity,Atlanta,GA,USA;4SamuelOschinComprehensiveCancerInstitute,Cedars-SinaiMedicalCenter,LosAngeles,
CA, USA; 5Fred B Cohen Comprehensive Cancer and Blood Disorders Center, Newark, NJ, USA and 6Northeast Georgia
DiagnosticClinic, Gainesville,GA, USA
Background: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to
determine themaximum tolerateddose (MTD),dose-limiting toxicities (DLT), andrecommendeddoses ofthe combination.
Methods:Patientswithadvancedsolidorganmalignancieswereenrolledandreceivedbortezomibweeklywithsunitinibdailyfor
4weeks,every6weeks.Initialdosesweresunitinib25mgandbortezomib1mgm(cid:2)2.Cohortsizeanddoselevelestimationwas
performedutilisingtheEscalationwithOverdoseControl(EWOC)adaptivemethod.Sevendoselevelswereevaluated;initially,
sunitinib was increased to a goal dose of 50mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment
occurredafter each cycle usingRECIST criteria.
Results: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia
(6%) at sunitinib 50mg and bortezomib 1.3mgm(cid:2)2 were seen. Subsequent experience showed tolerability and activity for
sunitinib37.5mgandbortezomib1.9mgm(cid:2)2.Commongrade3/4toxicitieswereneutropenia,thrombocytopenia,hypertension,
and diarrhoea. The recommended doses for further study are bortezomib 1.9mgm(cid:2)2 and sunitinib 37.5mg. Four partial
responses wereseen.Stable disease46 monthswas noted inan additional six patients.
Conclusion: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2
study of thiscombination inthyroidcancer patients isplanned.
The development of receptor- and protein complex-targeted Alternative approaches inhibiting multiple interacting and inter-
anticancer agents has improved disease outcomes with favourable dependentpathways,verticallyandhorizontally,withtwoormore
tolerability profiles. While monotherapy with these drugs has had molecularlytargetedtherapiesholdsgreaterpotentialforimproved
success in cancers with historically poor outcomes (e.g., gastro- outcomes.
intestinal stromal tumours and renal cell carcinoma), single agent Sunitinib is an oral, small-molecule inhibitor of multiple
responses in other solid tumour malignancies have been limited receptors (platelet-derived growth factor, vascular endothelial
(Barrios et al, 2010; Gallagher et al, 2010). Combinations with growth factor, and others). In addition to known activity in RCC
conventional DNA-damaging agents have also generally failed to and GIST, sunitinib is efficacious in refractory differentiated and
show improvement over cytotoxics alone (Socinski et al, 2010). medullarythyroidcancers.Bortezomibisafirst-in-classreversible
*Correspondence:DrRDHarvey;E-mail:[email protected]
Received23August2012;revised3December2012;accepted10December2012;publishedonline15January2013
&2013CancerResearchUK.Allrightsreserved0007–0920/13
762 www.bjcancer.com|DOI:10.1038/bjc.2012.604
BRITISH JOURNALOF CANCER
inhibitorofthe26Sproteasome,whichleadstoapoptosisthrough Adverse events were characterised using the NCI CTCAE
multiple mechanisms. It is approved by the US Food and Drug version 4.0, and patients were evaluated weekly. Dose limiting
Administration(FDA)forthetreatmentofmultiplemyelomaand toxicity (DLT) was defined as grade 4 neutropenia, anaemia, or
relapsed mantle cell lymphoma. To date, single agent response thrombocytopenia; grade 4 fatigue, or a two-point decline in
ratesinheavilypretreatedpatientswithsolidtumourmalignancies ECOG performance status unrelated to underlying malignancy;
havebeenlow;however,combinationstrategieswithconventional grade 3 or 4 gastrointestinal toxicity despite the use of maximal
chemotherapy and molecularly targeted agents have activity and medical intervention; or any other clinically significant toxicity of
are tolerable (Fanucchi et al, 2006; Dees et al, 2008; Dudek et al, grade X3 attributed to one or both agents during the first cycle.
2009). TreatmentcycleswereinitiatediftheANCwasX1000permm3,
Basedoncomplementaryantiangiogenicactivity(Williamsetal, theplateletcountX100000permm3.Patientsexperiencinggrade
2003; Ebos et al, 2007) and an expected synergy between the two 4haematologictoxicityhadbothtreatmentsheldforupto2weeks,
compounds (Wright 2010), we conducted a phase 1 evaluation of until recovery of ANC X1000per mm3 and platelet count
sunitinibandbortezomibinpatientswithrefractorysolidtumours X100000 per mm3. For grade 3 haematologic toxicities prior to
(NCT00720148).Theprimaryobjectivewastoestablishthesafety beginningatreatmentcycle,treatmentwasheldupto2weeksuntil
anddeterminethemaximumtolerateddoses(MTD)ofbortezomib resolution to pgrade 2. For uncontrolled hypertension due to
andsunitinibincombination.Secondaryobjectivesweretodefine sunitinib, maximum doses of up to three antihypertensive agents
toxicities and obtain preliminary information on the anticancer were used prior to dose reduction or discontinuation. Bortezomib
activity of the regimen. was dose-reduced by one level for neuropathy. Patients were
deemed evaluable for DLT if they completed X75% of the first
cycle.
Tumourassessmentsweredoneatbaselineandtheendofeach
METHODS
cycle, and responses were classified using RECIST criteria. The
initialdoselevelwassunitinib25mgandbortezomib1.0mgm(cid:2)2.
Patients with confirmed solid organ malignancies refractory to Dose escalation was conducted in two stages; initially bortezomib
standard therapy, or for whom no standard therapy existed, and wasfixedwhereassunitinibwasescalatedtoitsMTD.Specifically,
measurable disease by RECIST criteria (version 1.0) were eligible. each patient received 1.0mgm(cid:2)2 bortezomib and the level of
Other eligibility criteria included age X18 years; Eastern sunitinibdeterminedbyEWOCsothat,onthebasisofallavailable
Cooperative Group (ECOG) performance status p2; adequate data, the probability that it exceeded the MTD was equal to a
bone marrow reserve, renal and hepatic function. Patients were prespecified value a. In the first stage, we started at a¼0.2 and
excluded if they had prior radiation to 430% of bone marrow increased a in increments of 0.05 until a¼0.4, this value being a
volume; ejection fraction of p45%; uncontrolled cardiovascular compromise between the therapeutic aspect of the agent and side
disease; peripheral neuropathy of Xgrade 2 by NCI Common effects.Sixteenpatientswereenrolledinthefirststageofthetrial.
Toxicity Criteria for Adverse Events (CTCAE), version 4; and/or In the second stage, sunitinib was fixed at the newly established
recent (within 30 days) history of venous thromboembolism. The MTD and bortezomib escalated from 1.0mgm(cid:2)2. During this
studywasapproved bytheEmoryUniversity Institutional Review stage,theparameterawasincreased,aftereachsuccessivepatient,
Board and was conducted in accordance with the guidelines from inincrementsof0.05fromaninitialvalueof0.4toaterminalvalue
the Helsinki declaration of 1975. All participants gave written, of 0.5. At the end of the second stage of the trial, an MTD was
informed consent. estimated using data from the second stage as the median of the
All patients received sunitinib (Sutent; Pfizer Labs; New York, posterior distribution of the MTD of bortezomib given that
NY,USA)andbortezomib(Velcade;MillenniumPharmaceuticals, sunitinib was ¼37.5mg.
Inc.;Cambridge,MA,USA)orallydailyandintravenouslyweekly,
respectively,for4weeks,followedbya2-weekrest.Thestudywas
conducted in two phases. Initially, the dose of bortezomib was
fixedat1mgm(cid:2)2andsunitinibescalatedfrom25to37.5to50mg RESULTS
(Table 1). Once maximum tolerated dose (MTD) was determined
for the first phase, the bortezomib dose was escalated with fixed Thirty-sevenpatientsconsented,ofwhom31receivedatleastone
sunitinib. Dose selection was carried out utilising the flexible dose of the study drug and 30 were evaluable for the primary
Bayesian method of Escalation with Overdose Control (EWOC) endpoint. Demographic data are presented in Table 2. The seven
(Tighiouart and Rogatko 2010), a fully adaptive, real time dose- inevaluable patients had rapidly progressive disease and did not
finding method that uses individual patient experiences to select completecycle1.Becauseenrolmentoccurredrealtimeaspatients
subsequent doses, allowing for more rapid dose escalation while were referred, the majority of experience was with the sunitinib
minimising the number of patients who are underdosed. 50mgdoselevelandbortezomib1or1.3mgm(cid:2)2.Cycle1adverse
eventdataissummarisedinTable3.DLTswereseenatdoselevel
four(sunitinib50mgandbortezomib1.3mgm(cid:2)2)andweregrade
Table1.Cohortenrolment 4thrombocytopenia(16%)andneutropenia(4%).Followingcycle
1, the most common treatment-emergent adverse events were
Dose Sunitinib Bortezomib Patientsconsented/ thrombocytopenia,diarrhoea,mucositis,andfatigue.Twopatients
Level (mg) (mgm(cid:2)2) evaluable developedvaricellazosterinfectionsatdoselevelthree,prompting
theinstitutionofacyclovirprophylaxisinsubsequentsubjects.One
1 25 1 4/2
patient atdoselevelthree whodeveloped grade3hypertension in
2 37.5 1 5/2
cycle1(subsequentlycontrolledonlisinopril),wentontodevelop
3 50 1 13/12 grade 2 proteinuria (3239mg over 24h), which spontaneously
4 50 1.3 8/7 resolved.
Themediannumberofcyclesdeliveredwas3(range1–12),for
5 37.5 1.3 3/3
a median time on study of 18 weeks (range 6–72). Four patients
6 37.5 1.6 1/1
achieved partial response by RECIST criteria, two at dose level
7 37.5 1.9 3/3 three (medullary thyroid cancer and squamous cell cancer of the
www.bjcancer.com|DOI:10.1038/bjc.2012.604 763
BRITISHJOURNAL OF CANCER
Table2.PatientCharacteristics Table3.Cycle1AdverseEventSummary(n¼31)
Number 31 Grade3 Grade4
Totaln(%)
Sex(male) 21 n(%) n(%)
Age(years) Haematologic
Median 63.5 Leukocytopenia 20(54%) 4(11%) 4(11%)
Range 35–80 Neutropenia 2(6%) 0 2(6%)
Anaemia 15(40%) 2(6%) 1(3%)
Race Thrombocytopenia 21(58%) 6(17%) 5(14%)
AfricanAmerican 8 Non-haematologic
Caucasian 23
Hypoalbuminemia 20(54%) 0 0
ECOGPerformanceStatus Elevatedalkaline 17(46%) 9(24%) 0
phosphatase
0 22
ElevatedALT 13(35%) 0 0
1 9
Anorexia 20(54%) 1(3%) 0
Cancertypes ElevatedAST 19(51%) 0 0
Hyperbilirubinemia 9(24%) 1(3%) 0
Thyroid 7 Hypocalcemia 25(68%) 0 0
Papillary 3 Constipation 12(32%) 0 0
Hurthlecell 2 Diarrhoea 15(40%) 1(3%) 0
Medullary 2 Dysgeusia 7(19%) 0 0
Pancreas 5 Dyspnoea 10(27%) 0 0
Neuroendocrine 1 Oedema 6(17%) 0 0
Colon 4 Fatigue 16(43%) 0 0
Headandneck 4 Hypertension 8(22%) 1(3%) 0
Non-smallcelllung 3 Mucositis 6(17%) 0 0
Melanoma 3 Nausea 10(27%) 1(3%) 0
Breast 2 Peripheralneuropathy 10(28%) 0 0
Adenocarcinomaofunknownprimary 1 Pain 30(81%) 2(6%) 0
Rectal 1 Hypokalemia 9(24%) 0 1(3%)
Sarcoma 1 Hyponatremia 20(56%) 0 0
Vomiting 7(19%) 1(3%) 0
Numberofpriortreatmentregimens
Median 2
Range 0–5 (Yeramian et al, 2012). These preclinical data, along with
favourable toxicity profiles, support the combination evaluated.
nasopharynx), and one each at dose levels four (Hurthle cell Theaddition of bortezomib to sunitinib was well tolerated and
thyroid)andseven(papillarythyroidcancer).Stablediseaselasting demonstrated meaningful anticancer activity in a number of solid
46monthswasnotedinanadditionalsixsubjects,specificallyin tumours. We observed intolerable haematologic toxicity with
patientswithpapillary(two)andmedullary(one)thyroidcancers, sunitinib50mgandbortezomib1.3mgm(cid:2)2,leadingtoescalation
pancreatic neuroendocrine tumour, melanoma, and pleomorphic of bortezomib at a lower dose of sunitinib to gain further insight
sarcoma. Taken together,theclinical benefit ratewas 30%. Atthe into the relative contribution of each agent to haematologic
conclusion of dose escalation and after considering the overall toxicity.TheadaptiveBayesiandesignallowedaccrualtoboththe
toxicity profile, the recommended phase 2 doses of the combina- known safest and most effective dose during the trial, as well as
tionusingEWOCweresunitinib37.5mgPOdailyandbortezomib informed decision-making for subsequent evaluation. When
1.9mgm(cid:2)2 IV weekly, each given 4 weeks of 6. compared with different up-and-down schemes, including ‘3þ3’
designs, EWOC assigns fewer patients to either subtherapeutic or
toxic dose levels, treats more patients at optimal dose levels and
estimates the MTD with smaller average bias and mean squared
DISCUSSION error (Babb et al, 1998).
Wepreferentiallyenrolledpatientswiththyroidcancers,dueto
Anticancerdrugdevelopmenthasevolvedtoincludecombinations thepreviouslyreportedactivityofsunitinib(Carretal,2010).Both
oftargetedagentswithouttraditionalcytotoxicpartners.Although the radiographic and biochemical activity noted in thyroid cancer
multitargeted receptor tyrosine kinase inhibitors such as sunitinib in our trial compares favourably to prior data with single agent
have advanced therapy in the single agent setting, the goal of sunitinib. The sunitinib dose selected here is slightly lower than
further tumour burden reduction and clinically meaningful prior experiences; however, improved long-term tolerability in
prolongation of disease control is likely going to require multiple combination withbortezomib formed the basis oftherecommen-
agentstoachieve.Thecombinationofbortezomibandsunitinibis dation. Subsequent evaluation of the combination in thyroid
arationalone,asproteasomeinhibitionimpairs cycleprogression cancer is warranted.
and proliferation, activates apoptosis, and inhibits angiogenesis
and metastasis (Boccadoro et al, 2005). Additionally, bortezomib-
induced inhibition of the NFkB pathway is augmented in the ACKNOWLEDGEMENTS
presenceofsunitinib,suggestingatleastadditiveifnotsynergistic
activity in combination (Sorolla et al, 2012). Furthermore, We thank Pfizer for their global support of the trial and
sunitinib sensitises cancer cells to bortezomib-induced apoptosis Millennium Pharmaceuticals for the provision of bortezomib.
764 www.bjcancer.com|DOI:10.1038/bjc.2012.604
BRITISH JOURNALOF CANCER
tumor-independentandcorrelatewithantitumorefficacy’.ProcNatlAcad
DISCLAIMER
SciUSA104(43):17069–17074.
FanucchiMP,FossellaFV,BeltR,NataleR,FidiasP,CarboneDP,Govindan
The authors take full responsibility for the scope, direction, and R,RaezLE,RobertF,RibeiroM,AkerleyW,KellyK,LimentaniSA,
content of the manuscript and have approved the submitted CrawfordJ,ReimersHJ,AxelrodR,KashalaO,ShengS,SchillerJH(2006)
manuscript. ‘RandomizedphaseIIstudyofbortezomibaloneandbortezomibin
combinationwithdocetaxelinpreviouslytreatedadvancednon-small-cell
lungcancer’.JClinOncol24(31):5025–5033.
REFERENCES GallagherDJ,MilowskyMI,GerstSR,IshillN,RichesJ,RegazziA,BoyleMG,
TroutA,FlahertyAM,BajorinDF(2010)‘PhaseIIstudyofsunitinib
inpatientswithmetastaticurothelialcancer’.JClinOncol28(8):
BabbJ,RogatkoA,ZacksS(1998)‘CancerphaseIclinicaltrials:efficientdose
1373–1379.
escalationwithoverdosecontrol’.StatMed17(10):1103–1120.
SocinskiMA,ScappaticciFA,SamantM,KolbMM,KozloffMF(2010)
BarriosCH,LiuMC,LeeSC,VanlemmensL,FerreroJM,TabeiT,PivotX,
‘Safetyandefficacyofcombiningsunitinibwithbevacizumabþpaclitaxel/
IwataH,AogiK,Lugo-QuintanaR,HarbeckN,BrickmanMJ,ZhangK,
carboplatininnon-smallcelllungcancer’.JThoracOncol5(3):
KernKA,MartinM(2010)‘PhaseIIIrandomizedtrialofsunitinibversus
354–360.
capecitabineinpatientswithpreviouslytreatedHER2-negativeadvanced
SorollaA,YeramianA,VallsJ,DolcetX,Bergada`L,Llombart-CussacA,
breastcancer’.BreastCancerResTreat121(1):121–131.
Mart´ıRM,Matias-GuiuX(2012)’BlockadeofNFkappaBactivityby
BoccadoroM,MorganG,CavenaghJ(2005)‘Preclinicalevaluationofthe
SunitinibincreasescelldeathinBortezomib-treatedendometrial
proteasomeinhibitorbortezomibincancertherapy’.CancerCellInt5(1):18.
carcinomacells’.MolOncol6(5):530–541.
CarrLL,MankoffDA,GoulartBH,EatonKD,CapellPT,KellEM,Bauman
TighiouartM,RogatkoA(2010)’Dosefindingwithescalationwithoverdose
JE,MartinsRG(2010)‘PhaseIIstudyofdailysunitinibinFDG-PET-
positive,iodine-refractorydifferentiatedthyroidcancerandmetastatic control(EWOC)incancerclinicaltrials’.StatSci25:217–226.
medullarycarcinomaofthethyroidwithfunctionalimagingcorrelation’. WilliamsS,PettawayC,SongR,PapandreouC,LogothetisC,McConkeyDJ
ClinCancerRes16(21):5260–5268. (2003)‘Differentialeffectsoftheproteasomeinhibitorbortezomibon
DeesEC,O’NeilBH,LindleyCM,CollichioF,CareyLA,CollinsJ,Riordan apoptosisandangiogenesisinhumanprostatetumorxenografts’.Mol
WJ,IvanovaA,EsseltineD,OrlowskiRZ(2008)‘AphaseIand CancerTher2(9):835–843.
pharmacologicstudyofthecombinationofbortezomibandpegylated WrightJJ(2010)‘Combinationtherapyofbortezomibwithnoveltargeted
liposomaldoxorubicininpatientswithrefractorysolidtumors’.Cancer agents:anemergingtreatmentstrategy’.ClinCancerRes16(16):
ChemotherPharmacol63(1):99–107. 4094–4104.
DudekAZ,Lesniewski-KmakK,ShehadehNJ,PandeyON,FranklinM, YeramianA,SorollaA,VelascoA,SantacanaM,DolcetX,VallsJ,AbalL,
KratzkeRA,GreenoEW,KumarP(2009)‘PhaseIstudyofbortezomib MorenoS,EgidoR,CasanovaJM,PuigS,VilellaR,Llombart-CussacA,
andcetuximabinpatientswithsolidtumoursexpressingepidermal Matias-GuiuX,Mart´ıRM(2012)’Inhibitionofactivatedreceptortyrosine
growthfactorreceptor’.BrJCancer100(9):1379–1384. kinasesbySunitinibinducesgrowtharrestandsensitizesmelanoma
EbosJM,LeeCR,ChristensenJG,MutsaersAJ,KerbelRS(2007)‘Multiple cellstoBortezomibbyblockingAktpathway’.IntJCancer130(4):
circulatingproangiogenicfactorsinducedbysunitinibmalateare 967–978.
www.bjcancer.com|DOI:10.1038/bjc.2012.604 765
