Phase1and Pharmacokinetic Study of Lexatumumab in Patients with Advanced Cancers RuthPlummer, 1 GerhardtAttard, 2 SimonPacey, 2 LouiseLi, 1 AlbiruniRazak, 1 RebeccaPerrett, 1 MaryBarrett, 2 IanJudson, 2 StanKaye, 2 NormaLynnFox, 3 WendyHalpern, 3 AlfredCorey, 3 HilaryCalvert, 1 andJohanndeBono 2 Abstract Purpose: Toassessthesafetyandtolerability,pharmacokinetics,andearlyevidenceofantitumor activity of escalating doses of lexatumumab (HGS-ETR2), a fully human agonistic monoclonal antibody which targets and activates the tumor necrosis factor^related apoptosis-inducing ligandreceptor2(TRAIL-R2)inpatientswithadvancedsolidmalignancies. Experimental Design: Inthisphase1,openlabelstudy,patientswithadvancedsolidmalignan- ciesweretreatedwithescalatingdosesoflexatumumabadministeredi.v.over30to120minevery 21days.Acohortoffourpatients,whichcouldbeexpandedtosixpatients,wasstudiedateach doselevel.Thedose-limitingtoxicity(DLT)dosewasdefinedasthedoseatwhichtheincidence ofDLTinthefirsttwocycleswas z33%.Themaximumtolerateddosewasdefinedasthehighest dose at which <33% of subjects experienced DLT.The pharmacokinetics andimmunogenicityof lexatumumabwerealsocharacterized.Tumorspecimensfromhistoricalorcurrentbiopsies,when available,werestainedforTRAIL-R2usingimmunohistochemistrytechniques. Results: Thirty-seven patients received120 cycles of lexatumumab at doses ranging from 0.1to 20 mg/kg every 21days as of May 2006.The 20 mg/kg dose was identified as the DLTdose based on DLTs in three of seven patients treated with this dose; DLTs included asymptomatic elevations of serum amylase, transaminases, and bilirubin.The 10 mg/kg dose cohort was expanded to12 patients and the10 mg/kg dose was identified as the maximum tolerated dose. Themean(FSD)clearanceandapparentterminalhalf-lifevaluesatthe10mg/kgdoseaveraged 6.0(2.9)mL/d/kgand16.4(10.9)days,respectively.Twelvepatientshaddurablestabledisease thatlastedamedianof4.5months,includingthreepatientswithsarcomahavingprolongedstable disease(z6.7months).ImmunohistochemistryforTRAIL-R2showedspecificstainingin >10%of tumorcellsfor16ofthe20evaluablespecimenssubmitted(80%). Conclusions: Lexatumumabwassafeandwelltoleratedatdosesuptoandincluding10mg/kg every 21days. Lexatumumab was associated with sustained stable disease in several patients. Pharmacokineticswerelinearoverthedoserangestudied,andconsistentwithatwo-compartment model with first-order elimination from the central compartment. Additional evaluation of this novel apoptosis-inducing agent, particularly in combination with chemotherapy agents, is warrantedandongoing. The ability to directly induce apoptosis in cancer cells is a novel approach to cancer treatment that has only recently begun to be evaluated in clinical studies. Several targeted agents, such as bortezomib and oblimersen sodium, indirectly induce apoptosis in tumor cells by altering the production or expression of apoptotic and antiapoptotic proteins. One emerging area of research is the evaluation of agents which activate the tumor necrosis factor (TNF)–related apoptosis- inducing ligand (TRAIL) death receptors (TRAIL-R1 and TRAIL-R2), members of the TNF receptor superfamily that, when activated, directly induce programmed cell death in cancer cells. Lexatumumab (HGS-ETR2) is a fully human high-affinity agonist monoclonal antibody that specifically targets and activates TRAIL-R2 (DR5; ref. 1). Lexatumumab mediates the induction of apoptosis through the activation of the extrinsic apoptosis pathway. The binding of lexatumumab to TRAIL-R2 results in the formation of a death-inducing signaling complex with the adaptor protein FAS-associated death domain. This complex activates caspases 8 or 10, which then activate caspases 3, 6, and 7, leading to the degradation of key cellular signaling and structural components, resulting in programmed cell death (1–3). Cancer Therapy: Clinical Authors’Affiliations: 1 Northern Institute for Cancer Research, Newcastle University, Newcastle uponTyne, 2 Royal Marsden Hospital, Sutton, United Kingdom,and 3 HumanGenomeSciences,Rockville,Maryland Received4/20/07;revised6/22/07;accepted8/2/07. Grant support: HumanGenomeSciences,Inc. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.Thisarticlemustthereforebeherebymarked advertisement inaccordance with18U.S.C.Section1734solelytoindicatethisfact. Requests for reprints: Ruth Plummer, Northern Institute for Cancer Research, PaulO’GormanBuilding,FramlingtonPlace,NewcastleuponTyneNE24HH,United Kingdom.E-mail:Ruth.Plummer@newcastle.ac.uk. F 2007AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-07-0950 www.aacrjournals.org ClinCancerRes2007;13(20)October15,2007 6187 Research. on May 16, 2017. © 2007 American Association for Cancer clincancerres.aacrjournals.org Downloaded from