Clinical trial NCT01300572
Conditions: Chronic Myelomonocytic Leukemia Previously Treated Myelodysplastic Syndrome Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Refractory Anemia With Excess Blasts Secondary Acute Myeloid Leukemia
Sponsor: Fred Hutchinson Cancer Center
Start date: 2012-01-01; Completion date: 2019-11-22
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I trial studies the side effects and maximum tolerated dose of yttrium Y 90 anti-cluster of differentiation 45 (CD45) monoclonal antibody BC8 (90Y-BC8) followed by donor stem cell transplant in treating patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) that is likely to come back or spread. Giving chemotherapy drugs, such as fludarabine phosphate (FLU), and total-body irradiation (TBI) before a donor peripheral blood stem cell (PBSC) or bone marrow transplant helps stop the growth of cancer or abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. Radiolabeled monoclonal antibodies, such as 90Y-BC8, can find cancer cells and carry cancer-killing substances to them without harming normal cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving FLU, 90Y-BC8, and TBI before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of radiation delivered via 90Y-DOTA-BC8 (90Y-BC8) when combined with FLU and 2 Gy TBI as a preparative regimen for patients aged \>= 18 with advanced AML, ALL, and high-risk MDS.

SECONDARY OBJECTIVES:

I. To determine disease response and duration of remission.

II. To determine the rates of engraftment and donor chimerism resulting from this combined preparative regimen, and to correlate level of donor chimerism with estimated radiation doses delivered to hematopoietic tissues via antibody.

OUTLINE:

PREPARATIVE REGIMEN: Patients receive 90Y-BC8 via central line on approximately day -12 and FLU intravenously (IV) over 30 minutes on days -4 to -2.

TRANSPLANTATION: Patients undergo TBI followed by allogeneic PBSC or bone marrow transplant on day 0.

GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive mycophenolate mofetil orally (PO) or IV every 12 hours on days 0-27 (for patients with related donors) or every 8 hours on days 0-40 with taper to day 96 (for patients with unrelated donors). Patients also receive cyclosporine PO or IV every 12 hours on days -3 to 56 (for patients with related donors) or 100 (for patients with unrelated donors) with taper to day 180.

After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24 months, and then annually thereafter.

Arms: arm 1: PREPARATIVE REGIMEN: Patients receive 90Y-BC8 via central line on approximately day -12, fludarabine phosphate IV over 30 minutes on days -4 to -2, and 2 Gy TBI on day 0.

TRANSPLANTATION: Patients undergo allogeneic PBSC or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients receive mycophenolate mofetil PO or IV every 12 hours on days 0-27 (for patients with related donors) or every 8 hours on days 0-40 with taper to day 96 (for patients with unrelated donors). Patients also receive cyclosporine PO or IV every 12 hours on days -3 to 56 (for patients with related donors) or 100 (for patients with unrelated donors) with taper to day 180.
Interventions: intervention 1: Allogeneic Bone Marrow Transplantation intervention 2: Allogeneic Hematopoietic Stem Cell Transplantation intervention 3: Cyclosporine intervention 4: Fludarabine Phosphate intervention 5: Indium In 111 Anti-CD45 Monoclonal Antibody BC8 intervention 6: Laboratory Biomarker Analysis intervention 7: Mycophenolate Mofetil intervention 8: Peripheral Blood Stem Cell Transplantation intervention 9: Pharmacological Study intervention 10: Total-Body Irradiation intervention 11: Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8
Intervention descriptions: intervention 1: Undergo allogeneic bone marrow transplant intervention 2: Undergo allogeneic PBSC or bone marrow transplant intervention 3: Given PO or IV intervention 4: Given IV intervention 5: Given IV (dosimetric dose) intervention 6: Correlative studies intervention 7: Given PO or IV intervention 8: Undergo allogeneic PBSC transplant intervention 9: Correlative studies intervention 10: Undergo TBI intervention 11: Given via central line (therapeutic dose)

Protocol documents:
Prot_SAP_000.pdf: 
 
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SignaturePage:
InvestigatorStatement:
IhavecarefullyreadProtocol2468entitled“AStudyEvaluatingEscalatingDosesof90YͲDOTAͲBC8(antiͲ
CD45)AntibodyfollowedbyAllogeneicStemCellTransplantationforHighͲRiskAcuteMyeloidLeukemia
(AML)AcuteLymphoblasticLeukemia(ALL),orMyelodysplasticSyndrome(MDS)”(“Protocol”)version
date11/06/2015.
IagreetocarryoutmyresponsibilitiesinaccordancewiththeProtocol,applicablelawsandregulations
(including21CFRPart312),GoodClinicalPractice:ConsolidatedGuidance(ICHͲE6),andapplicable
policiesofFredHutch.
PrincipalInvestigator:
Name(typedorprinted):_BrendaSandmaier,MD_____________________________________________
InstitutionandAddress:_FredHutchinsonCancerResearchCenter_______________________________



_1100FairviewAvenueN,M/SD1Ͳ100_______________________________



_Seattle,WA98109Ͳ1024___________________________________________
PhoneNumber:
_206Ͳ667Ͳ4961____________________________________________________
Signature:_______________________________________________Date:_______________________
 
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TABLEOFCONTENTS

1.0
INTRODUCTION................................................................................................................5
2.0
BACKGROUND..................................................................................................................5
3.0
STUDYOBJECTIVES...........................................................................................................9
3.1
PrimaryObjective.............................................................................................................9
3.2
SecondaryObjectives.......................................................................................................9
4.0
STUDYDESIGN..................................................................................................................9
4.1
DescriptionofStudy.........................................................................................................9
4.2
Endpoints..........................................................................................................................9
4.2.1 PrimaryEndpoint.........................................................................................................9
4.2.2 SecondaryEndpoints...................................................................................................9
4.3
StoppingRules..................................................................................................................9
5.0
SUBJECTSELECTION.......................................................................................................10
5.2 Exclusions.......................................................................................................................11
6.0
DONORSELECTION.........................................................................................................12
7.0
INFORMEDCONSENTOFSUBJECTANDDONOR...........................................................12
8.0
SUBJECTREGISTRATION.................................................................................................12
9.0
PLANOFTREATMENT.....................................................................................................13
10.0
NONͲINVESTIGATIONALDRUGS,IRRADIATION,STEMCELLORBONEMARROW
ADMINISTRATION......................................................................................................................20
11.0
ENGRAFTMENTANDGRAFTREJECTION........................................................................24
12.0
EVALUATIONS.................................................................................................................25
13.0
DEFINITIONS...................................................................................................................28
14.0
TOXICITIESANDCOMPLICATIONS..................................................................................29
15.0
ADVERSEEVENTREPORTING.........................................................................................33
16.0
DOSEESCALATION..........................................................................................................36
17.0
STATISTICALCONSIDERATIONS......................................................................................39
Numberofpatients...................................................................................................................40
18.0
TARGETED/PLANNEDENROLLMENT..............................................................................41
19.0
TERMINATIONOFSTUDY...............................................................................................41
20.0
DATAANDSAFETYMONITORINGPLAN.........................................................................41
21.0
DATAMANAGEMENT/CONFIDENTIALITY......................................................................42
 
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22.0
REFERENCES...................................................................................................................42
APPENDIXA:
BEARMANCRITERIAFORREGIMENͲRELATEDTOXICITY.................................50
APPENDIXB:
ACUTEGVHDASSESSMENT.............................................................................53
APPENDIXC:
CHRONICGVHDGRADING*.............................................................................55
APPENDIXD:
METHODSUSEDTOCALCULATERADIATIONABSORBEDDOSESTOPTS........57
APPENDIXE................................................................................................................................61
 
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1.0
INTRODUCTION
Allogeneichematopoieticcelltransplantation(HCT)isawidelyusedformoftherapyforpatientswith
hematological malignancies.  In 2007, between 15,000 and 20,000 patients were treated with this
procedureworldwideaccordingtoestimatesfromtheInternationalBoneMarrowTransplantRegistry
(IBMTR).AlthoughHCToftenoffersthebest,andsometimestheonlychanceforcure,theprocedure
too often fails to eradicate these patients’ malignancies or is associated with fatal toxicities.  It is
thereforeimportanttoimprovediseasecontrolfordiseasessuchasadvancedacutemyeloidleukemia
(AML), acute lymphoblastic leukemia (ALL), and highͲrisk myelodysplastic syndrome (MDS) patients
withoutsubstantiallyincreasingthetoxicityoftheconditioningregimenforpatientsundergoingHCT.
One recent advance, radioimmunotherapy (RIT), offers the potential to substantially improve HCT
preparativeregimens.Withtheuseofradiolabeledmonoclonalantibodies(Ab)itispossibletodeliver
high doses of radiation relatively specifically to bone marrow (BM), spleen and other sites of
hematologicalmalignancieswhilesparingotherorgans.3Ͳ34Ourgrouphasmadeconsiderableprogress
using iodineͲ131 (131I) radiolabeled Ab to achieve the goal of developing preparative regimens with
greaterantiͲtumoreffectsandoveralllesstoxicity.Wehaveused 131IͲlabeledantiͲCD45Ab(BC8)to
deliveratleast2Ͳ3ͲfoldmoreradiationtoBM,spleenandsitesofleukemiathantoanycriticalnormal
organ.
Onesignificantbarriertoexpandingtheseresultstootherclinicalandresearchcentersisthatmany
NuclearMedicinedepartmentshavedifficultyhandlinglargequantitiesof 131I.Thisislargelybecause
the highͲabundance (100%), mediumͲenergy gamma component of 131I and 8Ͳday physical halfͲlife
requirepatientstobetreatedinradiationisolation,andposesaradiationexposureriskforstaffand
family.Toaddressthischallenge,weproposereplacing131Iwithanalternativeradionuclidetomakeour
approachmorefeasibleforPhaseIIstudiesatadditionalcenters.YttriumͲ90(90Y)hasbeenselectedas
thetherapeuticradioisotopeforthecurrentclinicaltrialbecause,inpart,itisapureßͲemitterthatis
commerciallyavailableinhighspecificactivityandpurity.Moreover,thebetaparticlesfrom90Yhavea
highͲenergy(Emax=2.28MeV)withagreatertissueͲpenetratingrange(upto11mm)thatisthoughtto
bemostfavorablefordepositionofradiationinlargetumormasses.35
Inthisstudywehopetoestablishthesafety,feasibilityandoptimizeddoseof90YͲlabeledantiͲCD45Ab
(90YͲDOTAͲBC8)inpatientsundergoingRITtreatmentinconjunctionwithastandardreducedͲintensity
transplantregimenbeforeHCTforrefractoryorrelapsedAMLorhighͲriskMDS.Thisclinicalresearch
protocol and the described study will be conducted in compliance with the IRB approved protocol,
associatedfederalregulationsandallapplicableIRBrequirements.
2.0
BACKGROUND
Allogeneic HCT is a widely used tool for the treatment of patients with hematological malignancies,
however,relativelyhighͲratesofrelapsehavebeenobservedinpatientswithadvancedleukemiaand
highͲrisk MDS.  Efforts to decrease postͲHCT relapse rates have focused largely on intensification of
cytoreductivetherapy,eitherbyincreasingthetotalbodyirradiation(TBI)doseoraddingadditionalor
alternative chemotherapy.  Controlled randomized studies have shown that relapse rates can be
 
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reducedbyincreasingtheTBIdose.36Ͳ37However,inthesestudiesthenonͲrelapsemortality(NRM)was
increasedwiththehigherTBIdose,leadingtonoimprovementinoverallsurvival(OS).
2.1
TargetedhematopoieticirradiationdeliveredbyradiolabeledAb
Although studies have demonstrated benefit for improved tumor control with escalated doses of
therapy, the toxicities that occurred as a result of efforts to increase the dose of therapy can be
attributed to the nonͲspecific targeting of the therapeutic agents.36Ͳ37  In contrast, the use of AbͲ
targeted approaches to deliver radiation specifically to sites of disease while sparing normal organs
offers hope for improved tumor control with minimally increased rates of toxicity.  Hematologic
malignancies in particular provide an optimal setting in which to investigate RIT, given their relative
radiosensitivityandthecomparativeeasewithwhichcirculatingAbcangainaccesstocellsintheBM,
lymphnodes,andspleen.38Ͳ39
TheefficacyofRITdependsonmanyvariables,includingpropertiesofthetargetedantigen(cellsurface
density,accessibility,shedding,heterogeneityofexpression),thetumor(size,permeability,vascularity,
andbloodflow),andtheAb(bindingsitespecificity,immunoreactivity,invivostability,avidityandrate
ofendocytosis).AlthoughleukemiacellsexpressavarietyoflineageͲspecificantigensthatmightbe
targeted, CD33, CD45, and CD66 have emerged as the most successful antigens for RIT of
leukemia.1,27,30,34,40Ͳ48InitialRITstudiesbyourgroupforthetreatmentofAMLemployedanantiͲCD33
Ab conjugated to 131I.42  While initial localization of 131IͲantiͲCD33 Ab to the BM was convincingly
documented,theretentionof 131IinthistissuewasshortbecauseofinternalizationoftheAbͲantigen
complexandrapiddegradationoftheAbfollowedbyexcretionofsmall 131Imoietiesfromthetumor
cells,contributingtoasuboptimaltherapeuticresult.11,42OtherinvestigatorshavepursuedRITforAML
bytargetingCD66whichispresentonmaturinghematopoieticcells,butnotonleukemicblasts.CD66
targetinghasbeenusedtodeliverhomogenousradiationtonormalcellsthroughoutmarrow,relyingon
bystanderirradiationofleukemicblaststoimprovetheoutcomeofconditioningpriortoHCT.43,49
InvestigatorshavefocusedontheCD45antigenasanattractivealternativetargetforRITofleukemia
andMDS.CD45isatyrosinephosphataseexpressedasisoformsvaryinginsizefrom180to220kD.
This antigen is expressed on more than 70% of nucleated cells in normal BM, with an average copy
numberofapproximately200,000moleculespercell.11TheabundantexpressionofCD45onvirtuallyall
leukocytes,includingmyeloidandlymphoidprecursorsinBMandmaturelymphocytesinlymphnodes
aswellasmorethan90%ofAMLandALLsamples,providesahighnumberofAbbindingsitesinthese
tissuesforpatientsinremissionorrelapse.50Ͳ54AvailabledatasuggestthatCD45isnotshedintothe
bloodstreamandisnotrapidlyinternalized.11,52Thoughsomehaveexpressedconcernsabouttargeting
an antigen expressed as broadly as CD45, important advantages also must be recognized.  LineageͲ
specific radiolabeled Abs such as those targeting CD45 may be superior to leukemiaͲspecific
radiolabeled Abs for patients in remission or relapsed patients with subclinical involvement of
extramedullary tissues, since in these settings isolated malignant cells are surrounded by normal
hematopoieticcells.BecausetheradiationfromaradionuclideattachedtoanAbboundtothesurface
ofacellcanbeemittedinanydirectionwithinageographicareadefinedbythepathlengthofthe
radionuclide, the isolated malignant cell may receive a significantly greater absorbed dose if the
surroundingnormalcellsaretargetedaswell.
 
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2.2
ClinicalstudiesofRITwith131IͲantiͲCD45Ab(BC8)
WehaveconductedaseriesofPhaseIandIIclinicaltrialsemploying131IͲBC8inconjunctionwithhighͲ
dosechemotherapyandHCTforAML,ALL,andMDS.Resultsofthesetrialswillbesummarizedbriefly.
Ourinitialstudyof 131IͲBC8AbinhighͲriskpatients
withadvancedAML,MDS,orALLwasperformedto
determine the biodistribution of the targeted
radiotherapy, as well as estimate the MTD of
radiation delivered by 131IͲBC8 Ab when combined
with 120 mg/kg CY and 12 Gy TBI.30,34  When
combined with CY and TBI, the estimated MTD of
radiation delivered by 131IͲBC8 Ab to the liver, the
normal organ receiving the highest dose was 10.5
Gy.  Based on the average estimates of radiation
absorbed doses, treatment at the MTD was
projected to deliver supplemental radiation doses
of 24 Gy to BM and 50 Gy to spleen.  Based on
these promising results, the same regimen was
giveninaPhaseIIstudyto18patientsfollowedby
CY/TBIandallogeneicHCTfrommatchedrelated(n=9)orunrelated(n=9)donors.Sevenof18treated
patients(39%)arealiveanddiseaseͲfreeafterperiodsupto5.5years.Only1of9patientsreceivinga
BMdosegreaterthan7cGy/mCirelapsed,incontrastto6of9whorelapsedafterreceivingdosesless
than7cGy/mCitoBM(Fig.1).2,55
Sincesignificantsupplementaldosesofhematopoieticradiationweretoleratedwhencombinedwith
the conventional transplant preparative regimen,
wealsoperformedaseparatePhaseIIstudyof131IͲ
BC8Abcombinedwithstandardbusulfan(BU)and
CYasapreparativeregimenforpatientswithAML
infirstremission.1FortyͲsixpatientsweretreated
with102Ͳ298mCi131Idelivering5.3Ͳ19(mean11.3)
GytoBM,17Ͳ72(mean29.7)Gytospleen,and3.5Ͳ
5.25Gytotheliver.Theestimated3ͲyeardiseaseͲ
free survival (DFS) and NRM rates were 61% and
21%, respectively (Fig. 2). These results were
comparedtothosefrom509similarpatientsinthe
IBMTR transplanted using BU/CY alone.  After
adjusting for differences in age and cytogenetics,
thehazardofmortalityamong131IͲBC8treatedpatientswas0.65timesthatofRegistrypatients(95%CI
0.39Ͳ1.08;p=.09).Theencouragingresultsachievedwith131IͲBC8AbandBU/CYinyoungerpatientsled
ustoaskhowthisapproachmightbeappliedtoolderAMLpatients,sincetheoutcomeforAMLpatients
over55ispoorusingstandardchemotherapy,witha5Ͳyearsurvivalrateof<10%.56Ͳ58

FIGURE 1: Probability of relapse for advanced AML
patientswhoreceived131IͲBC8AbcombinedwithCY/TBI.
Thicksolidline=dosetoBM>7cGy/mCi;thickdashed
line=dosetoBM<7cGy/mCi.2
DosetoBM>7cGy/mCi
DosetoBM<7cGy/mCi
FIGURE 2: Probability estimates of DFS, NRM, and
relapse among all patients who received 131IͲBC8 Ab,
followedbyBU/CY.1
 
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OverthepastdecadethereducedͲintensityHCTapproachhasalsobeenappliedtopatientswithAML,
ALLandMDSinordertogainthebenefitofagraftͲvsͲmalignancyeffectwithoutthetoxicitiesassociated
withastandardHCTregimen.59Ͳ72AlthoughthesestudiesmostlyhavebeenlimitedtolowͲriskremission
patients,relativelyhighrelapseratesremainatherapeuticdilemmainhighͲriskpatients,suggestingthat
agraftͲvsͲleukemia(GvL)effectalonemaybeinadequateforadvancedpatientswithAML.73Ͳ76Given
theminimaltoxicityofthisreducedͲintensityapproach,wehypothesizedthattheantiͲleukemiceffect
may be improved by the addition of
targeted
hematopoietic
irradiation
deliveredby131IͲBC8AbtothelowͲintensity
conditioning
regimen,
without
undue
toxicity.TothisendweperformedadoseͲ
escalation
study
adding
targeted
radiotherapy to our FLU/TBI reducedͲ
intensity approach in 58 highͲrisk patients
overtheageof50withadvancedAMLand
highͲriskMDS.Inthisstudyweestimated
theMTDofradiationdeliveredvia 131IͲBC8
Abtobe24Gytoliverwhencombinedwith
the reducedͲintensity regimen for older
patients.Whilethisstudywasnotdesigned
to examine potential efficacy, we were
encouragedbytheobservationthatthe3Ͳ
year diseaseͲfree survival was 38% for
patientswithactiveleukemia,aratebetterthanseeninthehistoricalexperience(Fig.3).77
2.3
RationalefortheuseofYttriumͲ90labeledantiͲCD45antibody
Wehaveused131Iastheradiolabelinourpriorclinicalstudiesbecauseitwasreadilyavailable,thereis
extensiveexperiencewithitsmedicaluse,thetechnologyfordirectlyradiolabelingAbswithiodineis
well established, and its gammaͲray component allows direct determination of labeled Ab
biodistributioninthepatientafteratracerinfusion.However,thehighͲabundancegammaradiation
componentof131Irequiresthatpatientsbetreatedinradiationisolation,andposesapotentialradiation
exposureriskforstaffandfamily.Thispresentsamajorlimitationtotheexportabilityofthismodality.
Tocontemplatesupplanting131IͲantiͲCD45AbwithanalternativeradionuclideforRITofAML,ALL,and
MDSrequirescarefulconsideration.YttriumͲ90hasbeenselectedasthetherapeuticradioisotopefor
thisproposedclinicaltrialbecause,inpart,itisapureßͲemitterthatiscommerciallyavailableinhigh
specificactivityandpurity.Moreover,thebetaparticlesfrom90YhaveahighͲenergywithgreatertissue
penetrating range that is thought to be most favorable for deposition of radiation in large tumor
masses.35Thesefavorablecharacteristicsmustbebalancedbythedesirabilityoflimitinglocalizationof
the radiation effect to antigen positive cells, and avoidance of unduly irradiating the BM stroma or
normalbystandercells.Weinvestigatedwhether 90Y,whichdoesnotemitanyphotonradiationand
doesnotrequirelongerͲtermradiationisolationofthepatient,mightresultinimprovedtherapeutic
ratiosbecauseofitshigherenergybetaparticles(Emax=2.28MeV)andshorterdecayhalfͲlife(2.7
FIGURE3:EstimatesoftheprobabilityofOS,DFS,TRM,andrelapse
amongpatientstreatedattheMTDof24Gyofradiationdeliveredto
theliverbythe131IͲBC8Ab,followedbyTBI/FLU.
 
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days)comparedto131I.ThesenonͲhumanprimatestudiessuggestedthattheuseof90Yasaradiolabel
forantiͲCD45Abresultsinanapproximatelysimilarratioofradiationdeliveredtotargetascomparedto
nonͲtargettissuesasseenwith131I.78However,theabilitytotreatpatientswith90Ywithoutrequiring
radiation isolation, and the potential for improved homogeneity of radiation delivery within tissues
givenitslongerbetaͲparticlepathͲlength,mayprovidetherapeuticadvantages.
Thecompletedosimetryof90YͲDOTAͲBC8Abinhumansisunknown,acceptablebiodistributionsofBC8
Ablabeledwitharadiometalhaveyettobedemonstrated,andthetoxicityprofileof 90YͲDOTAͲBC8
needstobedefined.Moreover,wemustestablishthatBC8Ablabeledwith 90Yhasthepotentialto
adequatelydecreaserelapsedespitetheabsenceofgammaemissionsfromthisradionuclide.Asafirst
stepwewillthereforeinvestigatetheuseof90Yasthetherapeuticradionuclideinthisstudy
3.0
STUDYOBJECTIVES
3.1
PrimaryObjective
ToestimatetheMTDofradiationdeliveredvia90YͲDOTAͲBC8whencombinedwithFLUand2GyTBIasa
preparativeregimenforpatientsagedш18withadvancedAML,ALL,andhighͲriskMDS.
3.2
SecondaryObjectives
1. Todeterminediseaseresponseanddurationofremission.
2. To determine the rates of engraftment and donor chimerism resulting from this combined
preparative regimen, and to correlate level of donor chimerism with estimated radiation doses
deliveredtohematopoietictissuesviaantibody.
4.0
STUDYDESIGN
4.1
DescriptionofStudy
Thisisanopenlabelstudyconductedunderaninvestigationalnewdrugapplication(IND)submittedto
theU.S.FoodandDrugAdministration(FDA).ThestudyisasingleͲarmtreatmentprotocoldesignedto
meettheprimaryobjectivedescribedabove.
4.2
Endpoints
4.2.1  PrimaryEndpoint
The primary safety endpoint will be the proportion of patients who develop grades III/IV Bearman
relatedtoxicitywithinthefirst100daysfollowingHCT.
4.2.2  SecondaryEndpoints
1. Ratesofengraftment,chimerism,nonͲrelapsemortality(NRM)andacuteGvHD.
2. Achievementanddurationofremission.
3. OverallanddiseaseͲfreesurvivalthroughday100.
4. Estimationofabsorbedradiationdosestonormalorgans,marrowandtumor.
4.3
StoppingRules
Dose escalation/deͲescalation will be implemented in this study to achieve the primary objective of
estimating the MTD of 90YͲDOTAͲBC8 associated with a Grade III/IV (Bearman) RRT rate of 25%.  As
 
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describedfurtherunderStatisticalConsiderations(section17.0),additionalstoppingrulesareinplace
relatedtograftrejectionandrateofgradeIIIͲIVacutegraftversushostdisease(GvHD).
Ifsufficientevidenceexistssuggestingthatthetruerateofgraftrejectionexceeds20%,theprotocolwill
be suspended and reviewed by the investigators and other experts/committees as appropriate to
determine whether the trial should be terminated, continued without change, or continued with
revisions.  Operationally, suspension would be triggered by graft rejection at any of the following
observedproportions:3/5,4/10,5/15,6/20,8/25,or9/30.Wehavenotseengraftrejectioninanyof
ourpriorstudiesofradiolabeledBC8Ab.
Theprotocolwillalsobesuspendedifsufficientevidenceexiststosuggestthatthetruerateofgrades
IIIͲIV acute GvHD at day +100 is excessive (graded according to the established criteria described in
Appendix B).  Operationally, suspension would be triggered by any of the following observed
proportionsofGvHD:4/5,6/10,8/15,10/20,12/25,or14/30.
ProportionsofgraftrejectionandgradesIIIͲIVacuteGvHDwillbeevaluatedafterevery5thenrolled
patient becomes evaluable.  Each suspension rule will be evaluated among all patients enrolled,
regardlessofthedoseof90YͲDOTAͲBC8administered.
5.0
SUBJECTSELECTION
5.1
Inclusions
1.
PatientsmusthaveadvancedAML,ALLorhighͲriskMDSmeetingoneofthefollowingdescriptions:
x
AML or ALL beyond first remission (i.e., having relapsed at least one time after achieving
remissioninresponsetoatreatmentregimen);
x
AMLorALLrepresentingprimaryrefractorydisease(i.e.,havingfailedtoachieveremissionat
anytimefollowingoneormorepriortreatmentregimens);
x
AMLevolvedfrommyelodysplasticormyeloproliferativesyndromes;or
x
MDS expressed as refractory anemia with excess blasts (RAEB) or chronic myelomonocytic
leukemia(CMML)byFABcriteria.
2.
PatientsnotinremissionmusthaveCD45Ͳexpressingleukemicblasts.Patientsinremissiondonot
requirephenotypingandmayhaveleukemiapreviouslydocumentedtobeCD45negative(because
inremissionpatients,virtuallyallantibodybindingistononͲmalignantcellswhichmakeup>95%of
nucleatedcellsinthemarrow).
3.
Patientsmustbeш18yearsofage.
4.
Patientsshouldhaveacirculatingblastcountoflessthan10,000/mm3(controlwithhydroxyureaor
similaragentisallowed).
5.
Patients must have an estimated creatinine clearance greater than 50/ml per minute by the
followingformula(serumcreatininevaluemustbewithin28dayspriortoregistration):
CrCl=(140Ͳage)(WtinKg)x0.85(female)OR1.0(male)
72xserumCr
 
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6.
Patients must have normal hepatic function (bilirubin, AST and ALT < 2 times the upper limit of
normal).
7.
ECOG<2orKarnofskyш70.
8.
Patientsmusthaveanexpectedsurvivalof>60daysandmustbefreeofactiveinfection.
9.
PatientsmusthaveanHLAͲmatchedrelateddonororanHLAͲmatchedunrelateddonorwhomeets
standardSeattleCancerCareAlliance(SCCA)and/orNationalMarrowDonorProgram(NMDP)or
otherdonorcentercriteriaforPBSCorbonemarrowdonation,asfollows:
x
Relateddonor:relatedtothepatientandgenotypicallyorphenotypicallyidenticalforHLAͲA,B,
C,DRB1andDQB1.PhenotypicidentitymustbeconfirmedbyhighͲresolutiontyping.
x
Unrelateddonor:
x
MatchedforHLAͲA,B,C,DRB1andDQB1byhighresolutiontyping;OR
x
Mismatched for asingleallelewithoutantigenmismatchingatHLAͲA,B,orCasdefinedby
highresolutiontypingbutotherwisematchedforHLAͲA,B,C,DRB1andDQB1byhigh
resolutiontyping.
x
Donorsareexcludedwhenpreexistingimmunoreactivityisidentifiedthatwouldjeopardize
donorhematopoieticcellengraftment.Thisdeterminationisbasedonthestandardpractice
oftheindividualinstitution.Therecommendedprocedureforpatientswith10of10HLA
allelelevel(phenotypic)matchistoobtainpanelreactiveantibody(PRA)screenstoclassI
andclassIIantigensforallpatientsbeforeHCT.IfthePRAshows>10%activity,thenflow
cytometricorBandTcellcytotoxiccrossmatchesshouldbeobtained.Thedonorshouldbe
excludedifanyofthecytotoxiccrossmatchassaysarepositive.Forthosepatientswithan
HLAClassIallelemismatch,flowcytometricorBandTcellcytotoxiccrossmatchesshould
beobtainedregardlessofthePRAresults.ApositiveantiͲdonorcytotoxiccrossmatchisan
absolutedonorexclusion.
x
Patientanddonorpairshomozygousatamismatchedalleleinthegraftrejectionvectorare
consideredatwoͲallelemismatch,i.e.,thepatientisA*0101andthedonorisA*0102,and
thistypeofmismatchisnotallowed.
5.2
Exclusions
1.
CirculatinghumanantiͲmouseantibody(HAMA).
2.
Priorradiationtomaximallytoleratedlevelstoanycriticalnormalorgan,or>20Gypriorradiation
tolargeareasofthebonemarrow(e.g.,externalradiationtherapytowholepelvis).
3.
Patientsmaynothavesymptomaticcoronaryarterydiseaseandmaynotbeoncardiacmedications
forantiͲarrhythmicorinotropiceffects.
4.
Patientswiththefollowingorgandysfunction:
a.
Leftventricularejectionfraction<35%
b.
CorrectedDLCO<35%orreceivingsupplementalcontinuousoxygen
 
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c.
Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal
hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable
hepatic synthetic dysfunction as evidenced by prolongation of the prothrombin time, ascites
relatedtoportalhypertension,bacterialorfungalliverabscess,biliaryobstruction,chronicviral
hepatitis,orsymptomaticbiliarydisease.
5.
PatientswhoareknowntobeseropositiveforHIV.
6.
Perceivedinabilitytotoleratediagnosticortherapeuticprocedures.
7.
ActiveCNSleukemiaattimeoftreatment.
8.
Womenofchildbearingpotentialwhoarepregnant(EͲHCG+)orbreastfeeding
9.
Fertilemenandwomenunwillingtousecontraceptivesduringandfor12monthspostͲtransplant.
10. Inabilitytounderstandorgiveaninformedconsent.
6.0
DONORSELECTION
DonorsmustmeetHLAmatchingcriteriaasoutlinedinsection5.1.9aswellasstandardSCCAand/or
NMDPorotherdonorcentercriteriaforPBSCorbonemarrowdonation.
For the very few occasions where we identify a donor HPCͲA from a nonͲNMDP source, we have
proceduresinplacethroughourunrelateddonorofficetocollecttheinformationnecessarytocomply
withdonortesting,screening,anddeclarationofdonoreligibilityaccordingto21CFR1271.Werequire
thatthedonortestingbeperformedbyaU.S.CLIAapprovedlaboratory.Intheveryrarecasewherethe
donortestingisnotabletobeperformedinaCLIAapprovedlaboratory,orthereisconfirmatorytesting
thatneedstobeperformed,orforanydonoridentifiedfromEuropeandatriskforCJD,wenotethison
the donor screening form and require that the unrelated donor Medical Director or the attending
physicianapprovestheuseofthedonorHPCͲAproductunderUrgentMedicalNeed.
7.0
INFORMEDCONSENTOFSUBJECTANDDONOR
SubjectswillbereferredtoUniversityofWashington/SeattleCancerCareAllianceforconsiderationof
HCTandwillbecompletelyevaluated.Theprotocolshouldbediscussedthoroughlywithsubjectand
family,andallknownrisksshouldbedescribed.Theprocedureandalternativeformsoftherapyshould
bepresentedasobjectivelyaspossibleandtherisksandhazardsoftheprocedureexplained.Consent
willbeobtainedusingformsapprovedbytheInstitutionalReviewBoardoftheFredHutchinsonCancer
ResearchCenter.Asummaryoftheconferenceshouldbedictatedforthemedicalrecorddetailingwhat
wascovered.
DonorswillbeconsentedaccordingtoclinicalconsentingpracticesatSCCA(relateddonors)orNMDPor
atotherdonorcenters(unrelateddonors).
8.0
SUBJECTREGISTRATION
Patientswillbeassignedandregisteredutilizingtheinstitution’sstandardprocedures.
 
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9.0
PLANOFTREATMENT
9.1
GeneralTreatmentPlan
ThistrialwillassessthesafetyandfeasibilityofthisregimenandestimatetheMTDoftheradiation
absorbeddosefrom 90YͲDOTAͲBC8thatcanbedeliveredinconjunctionwithFLU,TBI,andallogeneic
stem cell or bone marrow rescue.  After informed consent, eligibility confirmation and registration,
patients will receive an infusion of 0.5 mg/kg of ideal body weight of DOTAͲBC8 trace labeled with
~5Ͳ10mCi of 111In to evaluate biodistribution and calculate the radiation absorbed doses to major
organsandthewholebody.Thesubsequenttherapyinfusionof90YͲDOTAͲBC8willdeliveranamountof
90Ycalculatednottoexceedthetargetdosetothecriticalnormalorganreceivingthehighestradiation
dose.  The therapy dose will be administered on approximately day Ͳ12 of the preparative regimen,
which will typically be approximately 1 to 2 weeks after the biodistribution dose.  Biodistribution
(dosimetric)infusionsof111InͲDOTAͲBC8willtypicallynotrequireinpatientadmission.Patientsmaybe
admittedovernighttotheUniversityofWashingtonMedicalCenter(UWMC)ortotheUWMCClinical
Research Center (CRC) for therapeutic doses of 90YͲDOTAͲBC8 as needed depending on individual
circumstances. Serum and urine samples will be collected from the first several patients enrolled to
determinepharmacokineticsofradiolabeledDOTAͲBC8.
FLU30mg/m2willbegivenondaysͲ4,Ͳ3,andͲ2priortotransplant.Patientsthenwillreceive2GyTBI
followedbyinfusionofunmanipulatedPBSCorbonemarrowonday0.ForGvHDprophylaxis,MMFwill
bedeliveredat15mg/kgevery12hoursstartingonday0andcontinuingtoday+27(forpatientswith
relateddonors),orevery8hoursstartingonday0andcontinuinguntilday+40andthentaperedand
stoppedonday+96(forpatientswithunrelateddonors).CSPwillbedeliveredat3.75mg/kgp.o.every
12hoursbeginningondayͲ3andcontinuingtoday+56,thentaperedtoday+180(forpatientswith
relateddonors),orcontinuingtoday+100andthentaperedtoday+180(forpatientswithunrelated
donors).
Table1showsthegeneraltreatmentschemaforpatientsonthisstudy,whichcombines90YͲDOTAͲBC8
radioimmunotherapywithanestablishednonͲablativeregimenofFLUand2GyTBIpriortoPBSCor
bonemarrowinfusion.Tables2and3showspecifictreatmentschema,includingimmunosuppressive
regimens,forpatientswithmatchedrelatedandunrelateddonors.
TABLE1:Generaltreatmentschema.ThedayoftreatmentislistedonlytogivealoosetimeͲframe.An
individualstudycalendariscreatedforeachpatient,withmodificationspermittedinconsiderationof
clinical and logistical needs.  It is anticipated that stem cells or bone marrow will be infused
approximately12daysafterdeliveryof90YͲDOTAͲBC8.
Day
Event
Ͳ21
111InͲDOTAͲBC8(~5Ͳ10mCi)traceͲlabeledinfusion
Gammacameraimaging
Ͳ20
BMbiopsy,gammacameraimaging
Ͳ19thruͲ16
Gammacameraimaging
Ͳ12
90YͲDOTAͲBC8therapeuticinfusion
Ͳ4,Ͳ3,Ͳ2
FLU30mg/m2/d
0
2GyTBI+PBSCorBoneMarrowinfusion
 
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
TABLE2:SpecifictreatmentschemaforpatientswithHLAͲmatchedrelateddonors.Treatmentschema
forPBSCtransplantstoestablishmixedchimerisminpatientswithHLAͲidenticalrelateddonors.
Day
Ͳ21
Ͳ20
Ͳ12
Ͳ4
Ͳ3
Ͳ2
0b
+27
+28
+56
+84
+180
111InͲDOTAͲBC8a
෽











BoneMarrowBiopsy/Blood
Sample

෽










90YͲDOTAͲBC8


෽









Fludarabine30mg/m2/d



භ
෽
භ






TBI200cGy






භ





PBSCorBoneMarrow
Transplant






භ





CSP




Start




Taper

Stop
MMF






Startc
Stop




ChimerismEvaluationsd








භ
භe
භ

BoneMarrowAspirate(and
biopsyifneeded)f








භ

භ


aFollowedbygammacameraimagingimmediatelypostinfusion,andatleasttwoorthreetimestotal
ondaysͲ20throughͲ16.
bDay0shouldbescheduledaccordingtostandardpractice
cFirstdoseshouldbegiven4Ͳ6hoursafterstemcellorbonemarrowinfusion
dChimerismevaluationsfrombloodatd28,56e,and84
eOnlyif<50%ond28
fSamplesforpathology,andcytogeneticanalysis(ifpreviousabnormality).
 
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TABLE 3: Specific treatment schema for patients with HLAͲmatched unrelated donors: Treatment
schema for PBSC or bone marrow transplants to establish mixed chimerism in patients with HLAͲ
phenotypicallymatchedunrelateddonors.
Day
Ͳ21
Ͳ20
Ͳ12
Ͳ4
Ͳ3
Ͳ2
0b
+28
+40
+56
+84
+96
+100
+180
111InͲDOTAͲBC8a
෽





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BoneMarrowBiopsy/Blood
Sample
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෽
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90YͲDOTAͲBC8
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෽
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Fludarabine30mg/m2/d
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෽
෽
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TBI200cGy
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෽
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PBSCorBoneMarrow
Transplant
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භ
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CSP
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Start
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Taper
Stop
MMF
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Startc
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Taper
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Stop
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ChimerismEvaluationsd
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භe
භ
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BoneMarrowAspirate(and
biopsyifneeded)f
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aFollowedbygammacameraimagingimmediatelypostinfusion,andatleasttwoorthreetimestotal
ondaysͲ20throughͲ16.
bDay0shouldbescheduledaccordingtostandardpractice
cFirstdoseshouldbegiven4Ͳ6hoursafterstemcellorbonemarrowinfusion
dChimerismevaluationsfrombloodatd28,56e,and84
eOnlyif<50%ond28
fSamplesforpathology,andcytogeneticanalysis(ifpreviousabnormality).
9.2 InvestigationalDrugProduct
The investigational product for this study is DOTAͲBC8 radiolabeled with either 111In (biodistribution
dose)or90Y(therapydose).DOTAͲBC8isradiolabeledintheradiochemicalfacilitiesoftheDivisionof
NuclearMedicineattheUniversityofWashington.Followingthelabelingproceduretheradiolabeled
DOTAͲBC8issterilizedbyfiltrationandtestedforendotoxincontent.
9.3 DetailedInvestigationalTreatmentPlan:BiodistributionStudies
9.3.1
111InͲDOTAͲBC8Administration
In order to determine the mCi 90YͲDOTAͲBC8 required to deliver the desired dose of radiation, each
patientwillundergobiodistributionstudiespriortoreceivingatherapydose.Inthebiodistributionstep,
patients will receive a traceͲlabeled infusion of 111InͲDOTAͲBC8.  Gamma camera images and a bone
marrowbiopsywillbeobtainedoverthenextseveraldays.Onetotwoweeksafterthebiodistribution
infusions,patientswillreceiveatherapyinfusionof90YͲDOTAͲBC8.
9.3.1.1 111InͲDOTAͲBC8doseandinfusionrate
 
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111InͲDOTAͲBC8willbeadministeredatatotaldoseof0.5mg/kgidealbodyweightforpatientsator
aboveidealbodyweight,oractualbodyweightforpatientsbelowidealbodyweight.Themixtureof
111InͲDOTAͲBC8willbedilutedtoapproximately25mlandinfusedat7.5mg/hour.
9.3.1.2 Bloodsamplecollection
Bloodsamples(CMPandCBD)willbeobtainedpreͲinfusion,attheendofinfusionandonthefirstday
followinginfusionforCBD,BUN,creatinine,AST,ALT,andbilirubin.
9.3.1.3 Vitalsigns
Vitalsignswillbeobtainedpriortoinfusionof111InͲDOTAͲBC8andmonitoredevery30minutes(+/Ͳ5
minutes)forthefirst2hoursandthenhourly(+/Ͳ15minutes)untiltheinfusioniscompleteormore
oftenifclinicallyindicated.
9.3.1.4 Premedication
111InDOTAͲBC8willbeadministeredthroughacentralvenouscatheter.Premedicationswillinclude:
x
acetaminophen650mgPO
x
diphenhydramine25Ͳ50mgIV;maybegivenindivideddosesifdesired(e.g.,35mgfollowedin
onehourby15mg)
x
ondansetron8mgIV
x
ondansetron8mgIVtoberepeatedevery8hours(+/Ͳ15minutes)untilcompletionofinfusion.
x
hydrocortisone100mgIV
x
hydrocortisone100mgIVtoberepeatedevery2hours(+/Ͳ15minutes)untilcompletionof
infusion
x
granisetron1mgPOorIV;ifpatientdoesnottolerateondansetronOR
x
prochlorperazine10mgPOorIV;ifpatientdoesnottolerateondansetron
x
D5½NStostartpriortotheantibodyinfusionandcontinueuntilcompletionofinfusion
IfgradeII(NCICTCAEv.4)allergicͲtypetoxicityisencountered(seesection14.1.1),theinfusionshould
bepaused,thepatienttreatedasindicatedbelow,andtheinfusionnotrestarteduntilsymptomshave
subsided.IfGradeIIIallergictoxicityisencounteredanddoesnotresolveusingmeasuresdescribed
below,theinfusionmustbeterminatedandnotͲrestarted,andthepatientwillbeoffprotocol.Ifother
GradeIIorIIItoxicitiesareencountered(seesection14.1.1),theinfusionmaybeslowedorpaused.If
toxicitypersistsorprogresses,theinfusionwillbeterminated.IfgradeIVtoxicityoccurs,thepatientwill
beoffstudy.
Potentialacutesideeffectsandtheirplannedmanagementareasfollows:
x
fever:acetaminophen650mg(or15mg/kg)POevery4hoursPRN
x
rigors:meperidine25Ͳ50mgIV(or0.5–1mg/kg)every2Ͳ4hoursPRN
x
pruritis:diphenhydramine25Ͳ50mgPOorIVevery2Ͳ4hoursPRN
x
lowbloodpressure:upto500mlnormalsalinebolusgivenIVover30min.
mayrepeatx1PRN.
x
nausea:diphenhydramine25Ͳ50mgPOorIVevery2Ͳ4hoursPRN;prochlorperazine10mgPO
orIVevery6hoursPRN;granisetron1mgPOorIVevery12hoursPRN
x
anxiety:lorazepam0.5Ͳ2mg(0.05mg/kg)IVevery4hoursPRN
 
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x
cough, chest or throat tightness, wheezing: diphenhydramine and hydrocortisone may be
repeated;albuterolnebulizer2.5–5mguptoevery1Ͳ2hoursPRN
x
anaphylaxis:cessationof111InͲDOTAͲBC8infusionandtreatperinstitutionstandards
9.3.2
QuantitativeImaging
Due to patient variability, the most objective way to achieve consistent target doses of radiation
exposureinhumantrialsofradioimmunotherapyisbyfirstperforminggammacameraimagingusing
traceinfusionsofradionuclidetoassesspharmacokineticsandbiodistribution.26YttriumͲ90(90Y),apure
betaemittingradiometal,willbeusedasthetherapeuticradionuclideinthisstudy.90Ycannotbeused
forimagingduetothelackofdiscretegammaemissionsinthequantitativeimagingwindow.Therefore,
111In(~5Ͳ10mCi),whichisagammaemitter,willbeusedforimagingpurposes.
ThebiodistributionoftraceͲlabeled111InͲDOTAͲBC8willbedeterminedinamannersimilartothatused
inourprior 131I–BC8studies.Beforereceivingtheimagingtestdoseof 111InͲDOTAͲBC8,patientswill
havethevolumesofnormalorgans(lungs,kidneys,liver,spleen)measuredbyCTscans.Patientswill
haveatleastthreetofoursetsofgammacameraimagesperformed,beginningonthedayofinfusion:
onesetimmediatelypost111InͲDOTAͲBC8infusion,followedbyanadditionaltwotothreeimagingtime
pointsoverthecourseof5days.Eachimagingsessionwillconsistofstaticanteriorandposteriorimages
of the chest, to include the thyroid and upper humeri, static anterior and posterior images of the
abdomen,staticanteriorandposteriorimagesofthepelvis,includingtheupperfemurs,andanterior
andposteriorimagesofthewholebody.Duringeachimagingsessionaknownsourceof111Inwillbe
imagedinafixedgeometry,inbothstaticandwholebodyscanningmodes,toaccountforradioactive
decayandtodeterminegammacamerasensitivity.
DataobtainedfromgammacamerascansfollowingthetraceͲlabeledinfusionsof111InͲDOTAͲBC8willbe
usedtodeterminethe111Inbiodistributionandtocalculatetheamount(mCi)of90Ynecessarytodeliver
the prescribed target amount of therapeutic 90YͲDOTAͲBC8.  Images will be inspected for general
biodistribution of activity in the body, especially liver, kidney, bone marrow and spleen.  Radiation
absorbeddoses(cGypermCi90Yadministered)willbecalculatedforalltissuesandorgans(withspecial
attentiontobonemarrow,liver,lung,andkidney)accordingtomethodsrecommendedbytheMedical
Internal Radiation Dose (MIRD) Committee of The Society of Nuclear Medicine using OLINDAͲEXM
software as described in Appendix D.  These calculations will be based on the organ activities
determinedbyquantitativeserialgammaͲcameraimagingusingthebiodistributiondataobtainedwith
tracer 111InͲDOTAͲBC8 for all major source organs showing activity above background. Results in
absorbeddoseperunitadministeredactivityof 90Ywillbereportedforall25targetorganslistedin
OLINDAandforthewholebody.
9.3.3
Marrowbiopsies
Aunilateralbonemarrowbiopsy(noaspirate)willbeperformedintheSCCAProcedureSuiteontheday
after 111InͲDOTAͲBC8 infusion.  If that sample is judged to be inadequate, a second sample may be
obtainedwithin48hoursoftheinfusion.ThebiopsysectionwillbecollectedusingNOFIXATIVEagents.
A research technician from the Press Laboratory will prepare the research portion and send the
remainingportiontoSCCAPathologyformorphology.
 
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Smallsectionsfromthebiopsywillbeweighedandcountedusingagammacounterfor111Incontent,
with comparison to a quantitative standard of the infusion mix, allowing calculation of %injected
dose/grammarrowoflabeled111InͲDOTAͲBC8.
9.3.4
RequirementsforTherapy
9.3.4.1 HAMAtest
BloodsamplesforHAMAtestingwillbeobtainedthedaypriortotheplannedtherapeutic90YͲDOTAͲBC8
infusionandmustbenegativeinorderforthepatienttoproceedonstudy.
9.3.4.2 HepaticorRenalToxicity
Bloodsamplesdescribedundersection9.3.1.2abovewillbereviewedforevidenceofhepaticorrenal
toxicity.Ifapatientexperiencesgrade3toxicity,determinationofwhetherthepatientmayproceedto
thetherapydosewillbemadebythePrincipalInvestigator(PI)(ordesignee)inconsultationwiththe
attendingphysician.Anypatientwhoexperiencesgrade4hepaticorrenaltoxicitywillbewithdrawn
fromthestudy.
9.3.4.3 Favorablebiodistribution
Favorablebiodistribution(i.e.,radiationdosetomarrowgreaterthandosetoliver)isnotrequiredfor
thepatienttoreceiveatherapydoseof 90YͲDOTAͲBC8.Inpreviouspatientsreceivingbiodistribution
dosesonourotherstudies,theestimateddosestomarrowandspleenweregreaterthandosestolung,
kidneyandtotalbodyeveninthosefewpatientswhosemarrowdosewasslightlylowerthanliverdose.
Therefore,forthisgroupofpatientswhomightnottolerateaconventionalpreparativeregimen,wewill
proceedwithatherapyinfusionof90YͲDOTAͲBC8regardlessoftheratioofradiationdosedeliveredto
marrowcomparedtoliver.
9.4
DetailedInvestigationalTreatmentPlan:90YͲDOTAͲBC8Therapy
9.4.1
Selectionof90YͲDOTAͲBC8dosefortherapy
Thetotalamountof90YadministeredwillbeindividualizedbasedonthebiodistributionofthetraceͲ111In
labeled dose in each patient.  The amount of 90Y will be calculated to deliver the predetermined
radiationdose(dependinguponstatusofescalationschedule;seesection16.1)tothenormalcritical
organ(almostalwaysliver)predictedtoreceivethedoseͲlimitingradiationdose.Foreachpatient,the
activity (mCi) of 90Y needed will be confirmed by the PI (or designee) and Nuclear Medicine subͲ
investigator.Insomepatientswithahighbonemarrowtoliverradiationdoseratio,theremaybethe
possibility of adversely affecting engraftment by damage to the bone marrow supportive stroma
resultingfromdeliveringtoomuchradiationtothemarrow.Thesepatientsmayhavethe 90Yactivity
limited to that which would deliver the currently stipulated maximum dose to marrow (see section
16.2).
Table 4 shows the dose levels that will be used to estimate the MTD of 90YͲDOTAͲBC8 that can be
deliveredincombinationwithFLUplus2GyTBI/CSP/MMFandallogeneicHCT.
 
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TABLE4:90YͲDOTAͲBC8Doselevels
Doselevel
90YͲDOTAͲBC8
Estimatedradiationdosetonormalorgan
receivinghighestdose(Gy)
1
6
2
8
3
10
4
12
5
14
6
16
7
18
8
20
9
22
10
24
11
26
12
28
13
30
14
32
9.4.2
Timingof90YͲDOTAͲBC8TherapeuticDose
The90YͲDOTAͲBC8therapeuticdosewillgenerallybeinfusedapproximately1to2weeksafterthe111InͲ
DOTAͲBC8 biodistribution dose, but can be delayed further if necessary because of clinical
circumstances(aslongasthepatienthasnotdevelopedHAMA).Atleast6daysistypicallyrequiredto
allowcalculationofradiationabsorbeddoseandorderingofthetherapeuticdoseofisotope.Thedayof
administrationofthetherapydosewillgenerallybeday–12.
9.4.3
90YͲDOTAͲBC8administration
90YͲlabeled DOTAͲBC8 for therapy will be administered to each patient using an antibody dose and
infusionprocedures(includingpreͲinfusionandPRNmedications)identicaltothoseusedfordosimetry
studiesinthepatient(seesection9.3.1)exceptthatthehydrationinfusion,givenat200cc/hr,should
startpriortothe90YͲlabeledDOTAͲBC8infusionandcontinuefor2hoursaftertheradiolabeledantibody
infusioniscomplete.Patientsmayreceivethetherapyinfusionasanoutpatientormaybeadmittedto
thehospitalovernight,dependingonindividualcircumstances.90YͲDOTAͲBC8willbeadministeredata
totaldoseof0.5mg/kgidealbodyweightforpatientsatoraboveidealbodyweight,oractualbody
weightforpatientsbelowidealbodyweight.Themixtureof90YDOTAͲBC8willbedilutedtoatleast25
mlandinfusedat7.5mg/hour.Vitalsignswillbeobtainedpriortoinfusionandmonitoredevery30
minutes (+/Ͳ 5 minutes) for the first 2 hours and then hourly (+/Ͳ 15 minutes) until the infusion is
completeormoreoftenifclinicallyindicated.Allappropriateshieldingandradiationsafetyprecautions
willbefollowedduringtheadministration.
If necessary, the patient, when able, will be instructed in drawing his or her blood samples from a
central venous catheter and in taking his or her own vital signs using an automated blood pressure
machine. Everypatient willbeinstructedin thesafehandling ofradioactivebodyfluids.Allblood,
 
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urine,andtissuesamplescontainingradioisotopeswillbeclearlyidentifiedassuch.Samplescontaining
highlevelsofactivity(>50μCi)willbetransportedinshieldedcontainers.Allsampleswillbeprocessed
bypersonneltrainedintheuseofradioisotopes.
9.5
TimingofPBSCorBoneMarrowInfusion
For patients with estimated marrow biologic halfͲtimes of less than 96 hours as estimated by the
biodistributiondose,donorPBSCorbonemarrowwillnormallybeinfusedapproximately12daysafter
the therapy dose of 90YͲDOTAͲBC8.  In the unlikely event that a patient has an estimated marrow
biologichalfͲtimelongerthan96hours,PBSCorbonemarrowinfusionwillbedelayedaccordinglyand
theactualnumberofdayspriortoPBSCorbonemarrowinfusionthatthetherapydoseofantibodyis
administeredwillbeadjusted.TreatmentsandscheduleassociatedwithPBSCorbonemarrowinfusion
arefurtherdescribedbelow.
10.0 NONͲINVESTIGATIONALDRUGS,IRRADIATION,STEMCELLORBONE
MARROWADMINISTRATION
10.1
Fludarabine
Fludarabinewillbeadministeredatadoseof30mg/m2/dayondays–4,Ͳ3,andͲ2.Fludarabinewill
typicallybegivenintheSCCAoutpatientdepartment.
10.2
TotalBodyIrradiation(TBI)
TBIwillbeadministeredatadoseof2GyperstandardpracticeonDay0,followedbyPBSCinfusion.TBI
willnormallybeadministeredbetween11:00a.m.and2:00p.m.toavoidproximitytoadministrationof
CSP/MMF.
10.3
CollectionandInfusionofDonorPBSC
10.3.1 GͲCSFAdministrationtoRelatedDonorsandPBSCCollection
Related donors will undergo GͲCSF administration and PBSC collection as per SCCA standard clinical
practice.Theproceduresdescribedheremayvaryinaccordancewithallowablevariancesinclinical
activities or as required by modifications to the SCCA Standard Practice Manual.  Related donors
typicallywillreceiveGͲCSF16μg/kg/dayfor5consecutivedaysfromday–4today0.GͲCSFwillbe
administeredbyasubcutaneousdailyinjectionbeginning4dayspriortoday0.ThescheduleofGͲCSF
administrationandPBSCcollectionscanonlybeascertainedonceday0isidentified.Thesedoseswillbe
administered daily in the SCCA Outpatient Department.  The treatment regimen schedule and the
schedule ofGͲCSF administration and PBSC collections must be confirmed with the personnel in the
apheresisroom.PBSCwillbecollectedintheafternoonofday–1,storedintherefrigeratorat4°C
overnight,andinfusedonday0.Ifthecollectiononday–1containslessthan5.0×106CD34+cellsper
kgrecipientweight,asecondcollectionwillbeperformedthefollowingmorningandtransfusedonday
0.DonorswillpreferablyundergoveinͲtoͲveincollections.IfPBSCcannotbecollectedbyaveintovein
technique,apercutaneousMahurkarcatheterwillbeinserted.Generalprocedureswillincludetheuse
of a standard apheresis machine (COBE Spectra, Lakewood Colo.), and processing up to 16 liters of
wholebloodduringthecollection.
 
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10.3.2 GͲCSFAdministrationtoUnrelatedDonorsandPBSCCollection
Timing of PBSC collection for unrelated donors is prearranged through the donor center where the
donor was procured and the schedule of GͲCSF administration and stem cell collections can only be
ascertainedonceday0isidentified.PBSCwillbecollectedaccordingtothedonorcenterstandardsand
thephysicianresponsibleforPBSCcollectionwillobtaininformedconsentfromthedonor.Thetarget
celldoseis5.0x106CD34+cells/kgofpatientweightforunrelateddonorstemͲcellcollection.Ifthis
collection goal is not met, the patient may be infused with all available cells as appropriate in
accordancewithstandardpractice.Ifthecelldoseisbelow2.5x106CD34+cells/kg,infusionwillbeat
thediscretionoftheattendingphysician.
10.4
PBSCANDBoneMarrowInfusion
AllpatientswillreceiveunmodifiedHSCT(PBSCorbonemarrow)infusiononday0ofthetreatment
regimen.Day0shouldbeonaTuesdaytoThursdaywhenpossible.
10.5
ImmunosuppressionDosingSchedules
Day–3: BeginCSPat3.75mg/kgPOQ12hours(or1.5mg/kgIVQ12hoursiforalpreparationisnot
tolerated).Forpatientswithrelateddonor,continuetoday+56andthentapertoday+180.
Forpatientswithunrelateddonor,continuetoday+100andthentapertoday+180.
Day0:
BeginMMFat15mg/kgPO(orsamedoseIViforalpreparationisnottolerated).Forpatients
withrelateddonor,continueMMFQ12hourstoday+27.Forpatientswithunrelateddonor,
continueMMFQ8hoursuntilday+40andthentapertoday+96.
CSPdoseswillbegivenQ12hours,andMMFdoseswillbegivenQ12hours(patientwithrelateddonor)
or Q8 hours (patients with unrelated donor).  Since significant nausea may accompany this
immunosuppression, particularly in the days after TBI, regularly scheduled antiͲemetic therapy is
recommended for all patients for at least one week after transplant. Adjustments may be made to
immunosuppressiondrugs,dosing,&scheduleduetoclinicalreasons.SeerecommendationsforCSP&
MMFbelow.
10.6
Cyclosporine(CSP)
10.6.1 Dosing
Forpatientswithmatchedrelateddonors,CSPisgivenat3.75mg/kgPOQ12hoursfromday–3today
+56, and then is tapered to day +180 unless GVHD develops.  For patients with matched unrelated
donors,CSPisgivenfromday–3today+100,andthenistaperedtoday+180.Ifthereisnauseaand
vomitingatanytimeduringCSPtreatment,thedrugshouldbegivenIVat1.5mg/kgQ12hours.BothIV
andoraldosesofCSParecalculatedusingtheadjustedweight.
10.6.2 Monitoring
Bloodpressure,renalfunction(creatinine,BUN),electrolytesandmagnesiumwillbefollowedatleast
onceperweek,ormoreoftenifclinicallyindicated,whilereceivingCSP.
 
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10.6.3 DoseAdjustments
CSPwholeblood“trough”levels(i.e.,justpriortothenextdose)willbeevaluatedonday0andadjusted
ifnecessarytomaintainbloodlevelsthattarget240Ͳ320ng/ml.Dosereductionsshouldonlybemadeif
CSPtoxicityispresentoratexcessivelevelsintheabsenceoftoxicityatthediscretionoftheAttending
Physician.FurtherCSPdeterminationsshouldbeperformedtwiceweeklyuntilCSPisstoppedunless
excessivehighlevelsaredetectedortoxicityissuspected,inwhichcasemorefrequentmonitoringwill
be performed as clinically indicated. In this group of patients, close monitoring of renal function is
essential.Dosereductionsforhighlevelswithouttoxicityshouldbeconservative(e.g.,25%),toavoid
inadequateimmunosuppression,particularlyinthefirstmonthpostͲtransplant.
10.6.4 DrugInteractions
Drugs that may affect CSP levels include: dilantin, phenobarbital (may lower CSP levels), steroids,
fluconazole, voriconazole, posaconazole, ketoconazole, cimetidine (may increase CSP levels).  A
completeandcurrentlistofdrugsthatmayaffectCSPlevelsmaybefoundintheBMTStandardPractice
Manual.
10.7
MycophenolateMofetil(MMF)
10.7.1 Dosing
Forpatientswithmatchedrelateddonors,oraladministrationofMMFwillbeat15mg/kgQ12hours
(30mg/kg/day)fromtheeveningofday0(firstdosetooccur4Ͳ6hoursafterPBSCorbonemarrow
infusion)untilday+27postͲtransplant,atwhichpointitwillbestoppedwithouttapering.Forpatients
with matched unrelated donors, oral administration of MMF will be at 15 mg/kg Q8 hours (45
mg/kg/day),startingonday0andadministeredthroughday+40,atwhichpointitwillbetaperedtoday
+96.  Doses will be rounded to the nearest 250 mg.  If the patient cannot tolerate oral MMF, the
medicationcanbeadministeredintravenouslyatthesamedose.BothIVandoraldosesarecalculated
usingtheadjustedweight.
10.7.2 DoseAdjustments
TheprincipaladversereactionsassociatedwiththeadministrationofMMFincludediarrhea,leukopenia,
sepsis,andvomiting.Ifintheclinicaljudgmentoftheattendingphysiciantheobservedtoxicityisrelated
toMMFadministration,adoseadjustmentmaybemade.Basedonpreviousorgantransplantstudies,
doseadjustmentsarelikelytooccurbecauseofhematopoieticorgastrointestinaladverseeffects(see
section14.0“Toxicitiesandcomplications”).BasedonpreviousexperienceinpatientsafterHCT,dose
adjustmentsarelikelytooccurbecauseofhematopoieticadverseeffects,inparticularneutropenia.A
thoroughevaluationofneutropeniashouldoccursuchasperipheralbloodchimerismstudies,marrow
aspiration,andreviewofmarrowsuppressivemedications(e.g.bactrim).Ifallotherpotentialcausesof
marrow toxicity are ruled out, dose adjustments will only be made for severe neutropenia (ANC
<100/mm3 for > 5 days) that persists after day 21 postͲtransplant. Dose reductions should be
conservative(20%).Afterday21,theuseofGͲCSFwillbepermittedforneutropenia.Forseveretoxicity
relatedtoMMF(gradeIVneutropenia>5daysrefractorytoGͲCSF),MMFmaybetemporarilystopped.
TheMMFshouldberestartedat20%reduceddosewhentheunderlyingtoxicitysubsides.Intheevent
 
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ofgastrointestinaltoxicitythatrequiresmedicationforcontrolofpersistentvomitingordiarrheathatis
consideredtobeduetoMMF,a20%dosereductionwilloccurfirstandifthereisnoimprovement,
MMFwillbereducedafurther20%.ForsevereG.I.toxicityrelatedtoMMF(severerefractorydiarrhea,
orovertgastrointestinalbleeding),theMMFmaybetemporarilystopped.Patientsshouldbeevaluated
byaGastroenterologyconsultantanddiscussedwiththeprincipalinvestigatorbeforestoppingMMF.
DoseadjustmentswillbemadebasedonoccurrenceofMMFtoxicity.

10.8
ModificationsofImmunosuppression
10.8.1 Modificationsofimmunosuppressionfordiseaseprogressionorrelapse
Guidelines provided in this section are for patients who demonstrate either: i) progression of stable
diseasepresentatthetimeoftransplantorii)relapseoftheirunderlyingdiseasebeforediscontinuation
ofimmunosuppressionhasbeencompleted.Persistenceofstable,underlyingdiseasedoesnotinitself
mandateacceleratedtaperofimmunosuppression.
Patientswithprogressivediseasedefinedasanyevidenceofrelapsebymorphologicorflowcytometric
evaluationofabonemarrowaspiratewillundergorapidreductionofimmunosuppression,aftercareful
evaluationforGvHD,atthediscretionoftheAttendingPhysician,PrincipalInvestigator,and/orstudy
subͲinvestigator(s). In the event that patients with early disease progression or relapse do not have
GvHD,immunosuppressionshouldbediscontinued.
DLIwillnotbegivenforprogressiveorrelapseddiseaseonthisprotocol,andpatientswithrelapseor
progressionwouldbeeligibleforotherongoingDLIprotocolsortreatmentplans.
10.8.2 Modificationsofimmunosuppressionforlowdonorchimerism
ImmunosuppressionshouldbediscontinuedasperprotocolunlessthepatientdevelopsGVHDorhas
fallingdonorchimerismwithoutevidenceofpersistence,progression,orrelapseofdisease.Inthelatter
situation, MMF should be continued at full dose for a month and then tapered over a month.  CSP
should be continued until MMF is discontinued and then tapered over 3 months.  Guidelines for
managementofGvHDareprovidedundersection11.3.
10.9
PostͲTransplantGrowthFactorsandNeutropenia
ItisrecommendedthatpatientsnotreceivegrowthfactorsduringtreatmentwithMMFbeforeday21
postͲtransplantbecauseofthepossibleriskofpotentiatingMMFtoxicitybyforcingmoreprogenitor
cellsintoadividingandproliferatingstate.GͲCSFmaybeadministeredtopatientswhohavesevere
neutropenia(ANC<100/mm3for>5days)persistingafterday21orifpatientsareneutropenic(ANC
<500/mm3) with active infection.  If ANC drops to <500/mm3 then prophylactic broad spectrum
antibioticsmaybegiven.
10.10 IntrathecalTherapyandTreatmentofCNSDisease
ActiveCNSdiseaseattimeoftreatmentisanexclusioncriterionforthisprotocol;however,patients
withhistoryofCNSdiseasewillnotbeexcluded.CNSassessmentandprophylactictreatmentwillbe
managed in accordance with the SCCA Standard Practice Manual (with treatment modifications
 
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determinedbytheAttendingPhysicianifclinicallyindicated).Allpatientswillhaveadiagnosticlumbar
punctureperformedduringtheinitial preͲtransplantworkupintheoutpatientdepartment.Patients
withpast historyorsignificantriskof CNSdisease mayreceive prophylactic intrathecaltherapywith
methotrexate (dose per the Standard Practice Manual).  Patients with evidence of CNS leukemic
involvement will have instillation of methotrexate, and will also be considered by the Attending
Physician to receive up to 18 Gy (10 fractions of 1.8 Gy) cranial or cranialͲspinal irradiation as
consolidation if indicated, beginning approximately day 32 postͲtransplant or as soon as engrafted,
whichevercomeslater.
10.11 InfectionProphylaxis
Patients will receive prophylaxis for PCP, HSV and Candida as per standard practice manual.  If
amphotericin is required, patients should receive liposomal or other lipidͲbased amphotericin rather
than regular amphotericin in order to reduce risk of nephrotoxicity that may compromise the
administrationofCSP.
11.0 ENGRAFTMENTANDGRAFTREJECTION
11.1
DonorChimerism
Chimerism testing methods will be in accordance with Standard Practice Guidelines, with timing
consistentwithotherreducedͲintensitytransplantprotocols(e.g.,FHCRC1938).Chimerismevaluations
willbeperformedonperipheralbloodonapproximatelydays+28,+56(if<50%atday+28),and+84.
Mixedorfulldonorchimerismwillbeevidenceofdonorengraftment.Definitionsofmixedandfull
chimerism,aswellasincreasingandlowdonorchimerism,aredescribedinSection13.0.
Patients who obtain mixed or full donor chimerism after reducedͲintensity HCT, but subsequent
chimerismstudiescannotdetectgreaterthan5%donorTͲcells(CD3+)asaproportionofthetotalͲcell
population,willbedefinedashavingdevelopedgraftrejection.
Graftrejectioncanoccurbecauseofimmunologicrejectionofdonorcells,orbecauseofinadequate
stromalsupportofthegrowthofdonorcells.Theriskofimmunologicgraftrejectionisconsideredtobe
lowforthisprotocolbasedonpreviousFHCRCmixedchimerismexperienceinwhichpatientswhohad
previouslyreceivedintensivechemotherapyhad<10%riskofgraftrejection.Inthisprotocol,additional
immunosuppression may be provided by lymphohematopoietic irradiation from 90YͲDOTAͲBC8.
However,intheeventofmarrowstromaldamagefromexcessiveradiationexposure,patientsmight
haveinadequatehematopoiesisyetnotmeetthepreviouslydefinedcriteriaforgraftrejection.Every
effortwillbemadetodeterminegraftstatusforpatientswithslowrecoveryofneutrophils.Forpatients
whoarecriticallyillandnotexpectedtosurvivetoday+28,aneffortwillbemadetoobtainamarrow
samplepriortodeathinordertoascertaingraftstatus.Similarly,chimerismstudieswillbeperformed
priortoday+28ifnecessary.
Patientswithslowengraftmentofneutrophilsshouldbeconsideredfortreatmentwithhematopoietic
growth factor as specified in section 13.0.  Those patients with grade IV thrombocytopenia and
neutropeniaafterday+21thatlasts>2weeksandisrefractorytogrowthfactorsupport,intheabsence
ofcontributingcausesuchasmedication(e.g.,MMF),sepsis,orCMVinfection,willbeconsideredto
haveneverengrafted.
 
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11.2
EvaluationofChimerism
Atdays+28,+56(ifneeded),and+84,patientswillbeevaluatedforlymphoidormyeloidchimerismin
theperipheralblood.Patientswhohavemixedorfulldonorchimerismatday+56orlater,andwho
haveevidenceofpersistent,progressiveorrelapsedAMLwillbeconsideredonaseparateprotocolfor
DLI,withthegoalofmaximizingthepotentialGvLeffect.Patientswhohavestablemixedorfulldonor
chimerism on day +56, whose disease is stable or responding, and who remain on full dose
immunosuppression will continue to be observed, and will not be considered for DLI at that time.
PatientswithevidenceofGradeIIorgreaterGvHDalsowillnotbeconsideredforDLI.
11.3
RecommendedTreatmentofGvHD
AfterreducedͲintensityHCTfrom10/10antigenmatchedunrelateddonors,theincidenceofgradesII,III
and IV acute GvHD in patients with sustained engraftment has been 46%, 4% and 0%, respectively.
Acute GvHD has been readily controlled in most patients with high dose corticosteroids, but PUVA
(psoralen activated ultraviolet light) has been required on occasion. Chronic extensive GvHD has
occurredin34%ofpatients.AcuteGvHDandchronicGvHDwillbegradedaccordingtoestablished
criteria(AppendicesBandC).
11.3.1 PatientsdevelopingtGrade2acuteGvHD:
a.
CSP 7.5 mg/kg/day PO in two divided doses.  If there is concern of GI absorption, continue CSP
prophylaxisusingIVroute(1.5mg/kgQ12hours).
b.
Prednisone(upto2mg/kg/day)maybeaddedifsevereGvHDandnoGvHDresponseby72hoursto
oneweekaftertheadditionofCSP.
c.
PatientswithlifeͲthreateninggradeIIIorIVacuteGvHDand/orsteroidrefractoryacuteGvHDare
eligibleforinstitutionaltrialsofGvHDtherapy.
11.3.2 PatientswithclinicalextensivechronicGvHD:
LTFUconsultshouldbeobtainedforpatientswithchronicGvHDanddeterminationoftheappropriate
treatmentforchronicGvHDwillbebasedontheLTFUconsultteamrecommendations.
12.0 EVALUATIONS
12.1
PatientPreͲTransplantBaselineEvaluation
PatientworkͲupwillbeinaccordancewithStandardPracticePolicyManualEvaluationGuidelinesfor
MarrowTransplantPatients,withthefollowingadditionalrequirements:
a.
10ccbloodinoneredtoptube(10cc)labeled“Protocol2468”totheLab(D3Ͳ395,ThomasBuilding)
foranalysisofHAMA.
b.
CT scan of chest and abdomen for calculation of organ volumes (lungs, liver, spleen & kidneys).
Otherimagingstudiesasclinicallyindicated.
c.
Unilateralbonemarrowbiopsyandaspirateforpathologyandcytogenetics*within30dayspriorto
consentsigning/enrollment.
 
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d.
Dataforrelevantprognosticindices(e.g.,RelapsedAMLIndex,IPSS)willberecordedforallpatients.
*
CytogeneticstoincludeFISHpanelforAMLandMDSpatients;NPM1,CEBPA,FLT3mutationsfor
AMLpatientsonly.
Certain baseline data collected as part of standard clinical workͲup, including serum creatinine,
estimated creatinine clearance, bilirubin, AST, ALT, leukocyte count, blast count, or cytopenias chest
xͲrays,andpulmonaryfunctiontests,willalsoberecordedaspartoftheresearchrecord.
12.2
PatientEvaluationwithDOTAͲBC8Infusions
x
Vital signs:  prior to starting infusion, every 30 minutes (+/Ͳ 5 minutes) during first 2 hours of
infusion,hourly(+/Ͳ15minutes)forremainderofinfusion,andasclinicallyindicated.
x
Bloodsamples:
a.
Beforeandafterinfusion,3cclavendertoptubeforCBCwithdifferential,and6ccgreentop
tubeforrenalandliverfunctiontesting.
b.
6ccgreentoptubeforrenalandliverfunctiontestingonedayafterinfusion.
c.
10ccbloodinoneredtoptube(10cc)totheLab(roomD3Ͳ395,ThomasBuilding)forHAMA
onedaypriorto90YͲDOTAͲBC8Therapyinfusion.
d.
Samplesdrawnforpharmacokineticsasdescribedundersection12.3.
12.3
Pharmacokinetics(Pk)
12.3.1 Timing
ThefirstseveralpatientsenrolledonthestudywillundergocollectionofbloodandurinesamplesforPk
studies.InitialPksamplingwillbebasedontheassumptionthatthestudydrugwilldistributeaccording
toatwoͲcompartmentmodel.Althoughsamplingmaychangewithdataaccrual,theinitialsampleswill
becollectedbeforeandafter111In/90YͲDOTAͲBC8administrationasfollows:
x
Blood:2Ͳ5ccinpurpletoptubestakenpriortotreatment,andthenaftertreatmentat15minutes
(+/Ͳ5minutes)and1Ͳ2hours(+/Ͳ10minutes)postinfusion,andat3Ͳ5additionaltimepointswithin
thefirst72hourspostinfusion.
x
Urine:sampleswillbecollectedduringthefirst2Ͳ3daysfollowinginfusion,eitherasaliquotsfrom
individualvoidsorbasedon24Ͳhoururinecollection.
12.3.2 Handlingofspecimens
x
Bloodsamplestobeheldatcollectionlocationforpickupbythelabtechnician(refrigerationisnot
required).
x
Urinecollectionswillbemeasuredandrecorded,analiquotofuptoapproximately2ccremoved
andstoredatroomtemperature(unlessbeingheldovertheweekend,inwhichcaserefrigerationis
preferable),andtheremainderdoubleͲflusheddownthetoilet.
x
Itisimportanttoprovidethetimeofsamplecollectionsonthelabelsontubes
 
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12.4
PatientEvaluationsDuringConditioningandforFirst100DaysPostͲTransplant
See Standard Practice Policy Manual for "Evaluation Guidelines for Transplant Patients".  Data from
these standard laboratory studies, other clinically indicated studies, and clinical assessments by the
primary care team will be reviewed regularly to assess for regimenͲrelated toxicity, occurrence of
SeriousAdverseEvents,andotherpotentialpostͲtransplantcomplicationssuchasGvHDandinfections.
Thefollowingadditionalstudiesandtestswillbeperformed(Table5):
a.
Heparinized blood 10 cc to for quantitation of TͲcell, NKͲcell and granulocyte chimerism on
approximatelydays+28,+56(if<50%onday+28),and+84.
b.
Bonemarrowaspirate(andbiopsyifunabletoobtainadequateaspiratesample)topathologyon
approximately days +28 and +84.  Aspirate will be sent at each time point to cytogenetics, if
patient’sdiseasehasaknowncytogeneticabnormalityandwillalsobesentforotherinformative
diseasemarkers.
c.
ChronicGvHDscreeningbetweendays+80and+100postͲtransplant.

d.
10 cc blood in one red top tube (10 cc) to the lab (D3Ͳ395, Thomas Building) for HAMA on
approximatelyday+84.
12.5
PatientEvaluationsFollowing100DaysPostͲTransplant
Followingday+100ordischargefromtheSCCA,patientswillreturntotheirprimarycarephysicians
undertheguidanceoftheFHCRC/SCCALongͲTermFollowͲUpAfterHematopoieticStemCellorBone
Marrow Transplant General Guidelines for Referring Physicians.  PatientfollowͲupwillbeperformed
primarilybytheFHCRCLongͲTermFollowͲUpDepartmentundertheFHCRC/SCCAMasterProtocolfor
CollectionofClinicalDataandStorageofLeftoverSpecimensfromPatientsTreatedAccordingtoFHCRC
Protocols(Protocol#0999.209).Thefollowingdatacollectedthroughthismechanismwillberecorded
forpurposesofthisstudyat6,9,12,18and24monthspostͲtransplant(Table5).
1.
Survival.
2.
Diseasestatus.
3.
Selectedbloodcounts(WBC,hemoglobin,hematocrit,platelets).
4.
Renal (creatinine, BUN) and hepatic (Bilirubin, AST, ALT) laboratory values.  Estimated creatinine
clearancewillbecalculatedandrecordedaspartoftheresearchrecord.
5.
Presence/treatmentofchronicGVHD.
6.
Pulmonaryfunctiontests(12monthspostͲtransplant)
7.
ChestxͲrays(12monthspostͲtransplant)
8.
Secondarymalignancies.
AnyofthesedatathatareunavailablethroughstandardlongͲtermfollowͲupwillberequesteddirectly
fromthepatientorlocalphysician.AfterthetwoͲyearfollowͲuptimepoint,wewillcontinuetomonitor
anychangestosurvival,diseasestatus,andsecondarymalignanciesreportedunderthestandardlongͲ
 
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termfollowͲupprotocol,andwillrecordthisdataforlongͲtermanalysisandreporting.Followingrelapse
ordiseaseprogression,patientswillbefollowedannuallyforsurvivalanddevelopmentofsecondary
malignancies.Followingothersignificantdiagnosesand/ortherapiesthatwouldconfoundassessment
oftherelationshipbetweenthestudytreatmentandadverseevents(e.g.,furthertherapyintendedto
maintain disease remission), patients will be followed annually for disease status, survival, and
developmentofsecondarymalignancies.
TABLE5:GeneralScheduleofPatientEvaluations

Baseline
Days
Months
Annual
following2
years
+28
+56
+84
6
9
12
18
24

HAMA(PressLab)
භ


භ






CT(chest,abdomen)
භ









BoneMarrowBiopsy/Aspirateto:










Pathology
භa
භ

භ






Cytogenetics
භa
භb

භb






BloodtoHematopathology/CIL(Chimerism)
භc
භ
භd
භ






GVHDscreening



භe






Datatrackingforsurvival,diseasestatus,bloodcounts,renalandhepaticlabvalues,
presence/treatmentofchronicGVHD,seriousadverseevents,secondarymalignancies.
භ
භ
භ
භ
භ

Datatrackingforsurvival,diseasestatus,andsecondarymalignancies





භ
aBonemarrowbiopsy/aspiratewithin30dayspriortoenrollment.
bSampletocytogeneticsifpatient’sdiseasehasknowncytogeneticabnormality.
cBloodmaybedrawnpriortobaseline;e.g.,attimeofHLAtyping.
dChimerismatday+56onlyif<50%atday+28.
eGVHDscreeningbetweenday+80andday+100.
13.0 DEFINITIONS
Completeremission:completeresolutionofallsignsofmyelodysplasiaorleukemiaforatleastfour
weekswithallofthefollowing:
1.
Normalbonemarrowwithblasts<5%withnormalcellularity,normalmegakarypoiesis,morethan
15%erythropoiesisandmorethan25%granulocytopoiesis.
2.
Normalizationofbloodcounts(noblasts,platelets>100000/mm3,granulocytes>1500/mm3)
3.
Noextramedullarydisease.
Partialremission:
1.
Improvementofhematologicalparametersintheperipheralblood
2.
50% decline in marrow blasts from preͲtransplant level with >10% erythropoiesis and 25%
granulocytopoiesis.
 
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Nonresponder:Allpatientsnotqualifyingforcompleteorpartialremission.
Relapse:
1. AfterCR:>5%blastsinthebonemarrowand/orperipheralblood.Confirmationofrelapsebybone
marrowanalysiswithmorethan10%blasts.
2. AfterPR:increaseofblastscellsinthemarrowto>50%ofthoseduringPR.
3. Extramedullarydiseaseconfirmedcytologicallyorhistologically.
PersistentDisease:
1. >5%blastsinthebonemarrowbyhistology
2. presenceofaclonalpopulationofmyeloidcellsbyflow
3. persistence/recurrenceofapreviouslydocumentedcytogeneticabnormality
FullChimerism:>95%donorCD3+Tcells.
MixedChimerism:thedetectionofperipheralblooddonorTcells(CD3+)andgranulocytes(CD33+)asa
proportionofthetotalperipheralbloodTcellandgranulocytepopulation,respectively.
IncreasingDonorChimerism:anabsoluteincreaseof20%ofCD3+Tcellsoverthechimerismevaluation
ofthepreviousmonth.
DecreasingDonorChimerism:decreasingdonorchimerismisdefinedasanabsolutedecreaseofatleast
20%ofCD3+Tcellchimerismoverthepreviousmonth.
LowDonorChimerism:lowdonorchimerismisdefinedas<40%CD3+TcellsafterHSCT.Lowdonor
chimerismshouldalwaysbeconfirmedwithrepeatperipheralbloodTcellandgranulocytechimerism
analysis.
GraftFailure:Primarygraftfailureisdefinedasfailuretoachieveneutrophilengraftment(ANC>500/μL)
inpatientssurvivingatleast28days;secondarygraftfailureasneutrophilrecoveryfollowedbyadecline
inANCto<500/μLunresponsivetogrowthfactorstimulation.
14.0 TOXICITIESANDCOMPLICATIONS
14.1
111In/90YͲDOTAͲBC8
TwoseparatetypesoftoxicitiesareanticipatedwiththeuseofradiolabeledDOTAͲBC8:acutetoxicities
associatedwithmonoclonalantibodyinfusion,andlongertermtoxicitiesassociatedwithradiationdose.
14.1.1 AcutetoxicityassociatedwithDOTAͲBC8infusion
TheprimaryacutetoxicitiesassociatedwithadministrationoftheBC8Abareallergicreactions.Allergic
reactions to administration of foreign protein may result in fever, chills/rigors, hypotension, pruritis,
urticaria, allergic rhinitis, conjunctivitis, cough, chest or throat tightness, wheezing/bronchospasm,
dyspnea, anaphylaxis, Arthus reaction, vasculitis, and serum sickness.  Nausea, vomiting, diarrhea,
myalgia, arthralgia, headache, fatigue, and hand/foot skin reaction have also been observed with
administrationofBC8antibodyandarethereforesimilarlyexpectedwithDOTAͲBC8.Inaddition,rapid
 
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infusion of DOTAͲBC8 may produce pulmonary, renal or hepatic toxicity as a result of lysis or
agglutination of circulating cells.  Table 6 describes the grading of significant acute toxicities due to
DOTAͲBC8infusion.
TABLE6:GradingofAcuteToxicitiesDuetoDOTAͲBC8Infusion(fromNCICTCAEversion4.0).
Parameters
1(Mild)
2(Moderate)
3(Severe)
4(LifeͲ
Threatening)
Immunesystem
disorders:
Allergicreaction
Transientflushingor
rash;drugfever<38°C
(<100.4°F);
interventionnot
indicated
Interventionindicated;
respondspromptlyto
treatment
Prolongedrecurrenceof
symptoms;
hospitalizationindicated
LifeͲthreatening
consequences;
urgentintervention
indicated


Investigations:
1.Bilirubin
2.AST
3.Creatinine

>ULN–1.5×ULN
>ULN–2.5×ULN
>ULN–1.5×ULN

>1.5×ULN–3.0×ULN
>2.5×ULN–5.0×ULN
>1.5×ULN–3.0×ULN

>3.0×ULN–10.0×ULN
>5.0×ULN–20.0×ULN
>3.0×ULN–6.0×ULN

>10.0×ULN
>20.0×ULN
>6.0×ULN
Premedicationforandmanagementofpotentialacutesideeffectsaredescribedundersection9.3.1.5.
PatientsexperiencingacuteallergictypetoxicityduringDOTAͲBC8infusionwillhavetheinfusionslowed
orterminated.Ifgrade2allergictoxicityisencountered,theinfusionshouldbepaused,thepatient
treatedasindicatedundersection9.3.1.5,andtheinfusionnotrestarteduntilsymptomshavesubsided.
Ifgrade3allergictoxicityisencounteredanddoesnotresolveusingthemeasuresdescribed,theinfusion
mustbeterminatedandnotͲrestarted,andthepatientwillbeoffprotocol.Othergrade2or3acute
toxicitymaybetreatedandtheinfusionrestarted.Iftoxicitypersistsorprogresses,theinfusionwillbe
terminated.Patientswithgrade4acutetoxicitywillhavetheinfusionstoppedandfurtherparticipation
inthestudywillbeterminated.
Hepatic and/or renal toxicity will not be evident during the DOTAͲBC8 infusion but instead will be
determinedbylaboratorysamplesobtainedattheendofinfusionandthefollowingday.Ifapatient
experiencesgrade3hepaticorrenaltoxicityafterthefirstdose(associatedwiththebiodistributiondose
of radiolabeled DOTAͲBC8), determination of whether or not the patient can proceed to the therapy
dosewillbemadebythePIorhisdesigneeinconsultationwiththeattendingphysician,andwilldepend
inpartupontherateofrecoveryfromthelaboratoryabnormalities.Apatientexperiencinggrade4
hepaticorrenaltoxicityafterthefirstdosewillnotbeeligibletoreceivethenecessaryseconddose
associatedwiththetherapydoseofradiolabeledDOTAͲBC8,andwillbetreatedonanalternateprotocol.
14.1.2 ToxicityassociatedwithradiolabeledDOTAͲBC8
Theriskassociatedwith theadministrationof~5Ͳ10mCiof 111Inisestimatedtobelow.Anadverse
event of grade 4 hypotension has been reported as probably related to 111In administration in one
patientwithBCelllymphoma.Thepatientrequired2daysofhospitalizationuntilallsideeffectswere
resolved.
The radioisotope 111In is a relatively lowͲdose imaging agent that is widely used in clinical imaging
applications.111Inisusedasatracertofollowbiodistributionandtoestimatetheradiationabsorbed
 
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dosefor90Ybasedontheassumptionthatbothisotopesbehavesimilarlyinvivowhenstablycomplexed
byDOTAchelate.90YͲDOTAͲBC8thatdoesnotbindtocellularrecognitionsitesisexpectedtobecleared
rapidly by the kidneys, resulting in increased renal exposure to radiation.  All patients will receive
intravenoushydrationbefore,during,andaftertheinfusioninordertosupportadequaterenalfunction
andefficientclearanceofcirculating90YͲDOTAͲBC8.
Themajortoxicityassociatedwiththeuseof90YͲlabeledantibodiesismyelosuppression.Thiseffectis
partlyduetodissociationof90YfromtheDOTAmoleculeandsubsequentaccumulationoffree90Ymetal
ioninbonethatirradiatesthebonemarrow.Thedegreeofmyelosuppressionisafunctionofresidence
time in the blood, chelate stability, and the amount of 90Y administered.  In addition, DOTA ligand
complexesofM+3metals,includingyttrium,areknowntobekineticallyinert;therefore,releaseoffree
metal is expected to be minimal.  Patients will undergo further intended myelosuppression from
treatmentwithFLUandTBIpriortoHCT.
In previous studies using high doses of targeted radiation delivered via 131IͲBC8 in an allogeneic
transplant setting for leukemia and myelodysplastic syndrome, significant pulmonary toxicities that
were considered at least possibly related to the study drug occurred within the first 100 days postͲ
transplantin7ofthefirst74patientstreated(9%).TheseeventsincludedyspneaandhypoxiaatNCI
CTC/CTCAE Grade 3 and above, bronchiolitis obliterans organizing pneumonia (BOOP), and
pneumonitis/pulmonaryinfiltrates.Inthesamepatientpopulation,16of34(47%)patientssurviving
morethan100dayspostͲtransplanthadlaterreportsofpulmonaryeventsduringfollowͲup.Mostof
theseweremild(e.g.,cough),but4patientsshowedradiographicchangessuggestiveofpneumonitis
and/orfibrosis.
AdditionalradiationͲrelatedtoxicitiesmayincludedamagetovariousorganssuchastheskin,lungs,liver
orkidney.Radiationexposureisalsoassociatedwithariskofsecondarymalignancy.Thereisararerisk
of venoͲocclusive disease (VOD), which causes abnormal liver function, body swelling from water
retentionandpainintherightsideoftheabdomen.Patientswillbeinformedaboutthesepotentially
fatalrisks.
14.2
Fludarabine
14.2.1 Description
Fludarabine monophosphate is a purine antimetabolite that, after administration, undergoes rapid
conversioninplasmatothenucleoside2ͲfluoroaraͲA(FͲaraA).FͲaraAsubsequentlyenterscellswhereit
isphosphorylatedtoFͲaraATPandthemonophosphateFͲaraAMP.Onceactivated,FͲaraATPinhibits
DNApolymeraseandribonucleotidereductase.ThemonophosphateFͲaraAMP,onceincorporatedinto
DNA,isaneffectiveDNAchainterminator.FollowingIVadministration,thedrugismetabolizedto2ͲFͲ
araA and widely distributed in tissues. 2ͲFͲaraA is excreted primarily in urine and has a terminal
eliminationhalfͲlifeof7Ͳ12hr.
14.2.2 Storageandadministration
Fludarabinemonophosphateiscommerciallyavailableasa50mg/vialwhichisreconstitutedwith2ml
ofsterilewater,resultingina25mg/mlsolution.Thedesireddoseisfurtherdilutedtoconcentrationsof
 
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0.04Ͳ1mg/mlinnormalsalineor5%dextrose(50Ͳ100ml)forinjectionandadministeredbyIVinfusion.
FludarabinewillbeadministeredbyIVinfusionover30minutesinadoseof30mg/m2/dayondaysͲ4to
Ͳ2.
14.2.3 Sideeffectsandtoxicity
Clinicaltoxicitiesoffludarabinemonophosphateinclude:myelosuppression,primarilylymphopeniaand
granulocytopenia, alopecia, rash, dermatitis, nausea, vomiting, anorexia, stomatitis, diarrhea,
somnolence,fatigue,peripheralneuropathy,mentalstatuschanges,corticalblindness,hepatocellular
toxicitywithelevationinserumtransaminases,andinterstitialpneumonitis.Theseeffectsarereversible
whenthedrugisdiscontinued.Immunosuppressionobservedwiththeuseoffludarabineincreasesthe
riskofinfectionwhichcanbelifeͲthreatening.
14.3
Cyclosporine(CSP)
SeeSCCAstandardpracticemanualforinformationaboutadministration,toxicityandcomplications.
14.4
MycophenolicAcidMofetil(MMF)
14.4.1 Description
MMFisthemorpholinylethylesterprodrugoftheactiveimmunosuppressantmycophenolicacid(MPA).
This active metabolite is a noncompetitive, reversible inhibitor of inosine monophosphate
dehydrogenase,particularlythetypeIIisoformthatismoreprominentinactivatedlymphocytes.Asa
resultoftheinhibitionofdenovopurinesynthesis,proliferationofTͲandBͲlymphocytesisblockedand
antibody production is inhibited.  There are no pharmacokinetic interactions with ganciclovir,
cotrimoxazole,oralcontraceptivesorcyclosporine.
14.4.2 Storageandadministration
MMF is commercially available in an oral and an intravenous formulation. The oral formulation is
supplied in 250 mg hard gelatin capsules and can be stored at room temperature. MMF for i.v.
administrationissuppliedasalyophilizedpowderinaglassvialcontainingtheequivalentof500mg.
14.4.3 Sideeffectsandtoxicity
Side effect profiles include diarrhea, leukopenia, sepsis, allergic reactions, and vomiting. MMF use
duringpregnancycarriesasignificantriskofmiscarriageorbirthdefects.Anincreaseincertaintypesof
infectionmainlyfromtheherpesvirusfamily(CMV,HSV&VZV)andcandidahasbeenreported.There
havebeenreportsofprogressivemultifocalleukoencephalopathy(PML),sometimesfatal,andofPure
RedCellAplasia(PRCA)inpatientsreceivingMMFaspartofanimmunosuppressiveregimen.MMFhas
notbeenstudiedextensivelyinpatientsafterHCT.Mostcommonsideeffectsknownfromstudiesin
patients with solid organ transplants are hematologic (decline in WBC and hematocrit) and
gastrointestinal(nausea,vomiting,diarrhea,G.I.bleeding).Experiencehasshownthatnauseacanbe
successfullytreatedwithantiͲemetics,andthatsideeffectsoftenrespondtoadecreaseindose.Several
etiologicfactorsmaycausealterationsinG.I.andhematologicparametersinthesettingofHCT.MMF
doseadjustmentswillthereforebemadewhenclinicallyindicatediftheresponsiblephysicianruledout
otherpossiblecauses.Doseadjustmentsshouldbediscussedwiththeprincipalinvestigator.Withthe
 
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exceptionofhypophosphatemiathereseemstobenodifferenceinsideeffectsbetweeni.v.andoral
MMFadministrationandefficacyisthesamewithbothadministrationroutes.
15.0 ADVERSEEVENTREPORTING
15.1
AdverseEventDefinitions
x
AdverseEvent
AnAdverseEvent(AE)isanyuntowardmedicaloccurrenceinaclinicalinvestigationsubject
administeredamedicinalproduct;theeventdoesnotnecessarilyhaveacausalrelationshipwith
studydrugadministrationorusage.Anadverseeventcanthereforebeanyunfavorableand
unintendedsign(includinganabnormallaboratoryfinding),symptom,ordiseasetemporally
associatedwiththeuseofamedicinalproduct,whetherornotconsideredrelatedtothemedicinal
product.
x
SeriousAdverseEvent
Aseriousadverseevent(SAE)isdefinedasanuntowardmedicaloccurrencethatresultsinanyof
thefollowingoutcomes:
o
Death.
o
LifeͲthreateningsituation(i.e.,withanimmediateriskofdeathfromtheeventasitoccurredbut
notincludinganeventthat,haditoccurredinamoreseriousform,mighthavecauseddeath).
o
InͲpatienthospitalizationorprolongationofexistinghospitalization.Inpatienthospitalization
comprisesformaladmissiontoahospitalformedicalreasons,foranylengthoftime,whetheror
nothospitalizationextendsovernight.However,hospitaladmissionsforadministrationofthe
studydrug,proceduresrequiredbythestudyprotocol,ortumorͲrelateddiagnosticprocedures
arenotconsideredserious.
o
Persistentorsignificantdisability/incapacityorsubstantialdisruptionoftheabilitytoconduct
normallifefunctions.
o
Congenitalanomaly/birthdefect.
o
Animportantmedicaleventthatrequiresinterventiontopreventoneoftheaboveoutcomes.
x
UnexpectedAdverseEvent
Anunexpectedadverseeventisdefinedasaneventthathasanatureorseverity,orfrequencythat
isnotconsistentwiththeapplicableinvestigatorbrochure.“Unexpected,”asusedinthisdefinition,
referstoanadversedrugexperiencethathasnotbeenpreviouslyobservedandreportedrather
thananexperiencethathasnotbeenanticipatedbasedonthepharmacologicalpropertiesofthe
studydrug.

15.2
MonitoringandRecordingAEs
Adverseeventswillbeassessedbytheinvestigatororqualifieddesigneeanddesigneeandrecordedin
theCRFs.Theinvestigatorshouldattempttoestablishadiagnosisoftheeventonthebasisofsigns,
symptomsand/orotherclinicalinformation.Insuchcases,thediagnosisshouldbedocumentedasthe
adverseeventand/orseriousadverseeventandnotdescribedastheindividualsignsorsymptoms.The
followinginformationshouldberecorded:
x
Descriptionoftheadverseeventusingconcisemedicalterminology
x
Descriptionastowhetherornottheadverseeventisserious
 
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x
Thestartdate(dateofadverseeventonset)
x
Thestopdate(dateofadverseeventresolution)
x
Theseverity(grade)oftheadverseevent
x
Adescriptionofthepotentialrelatednessoftheadverseeventtostudydrugorastudyprocedure
x
Theactiontakenduetotheadverseevent
x
Theoutcomeoftheadverseevent.

15.3GradingoftheSeverityofanAdverseEventAEswillbegradedinseverityaccordingtotheNCI
CommonTerminologyCriteriaforAdverseEvents(CTCAE)Version4.0
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).IfaCTCAEcriteriondoesnotexist,theinvestigator
shouldusethegradeoradjectives:Grade1(mild),Grade2(moderate),Grade3(severe),Grade4(lifeͲ
threatening),orGrade5(fatal)todescribethemaximumintensityoftheadverseevent.However,the
BearmanScaleofRegimenͲRelatedToxicitywillbeusedfordecisionsregardingdoseescalation/deͲ
escalationandinvocationofstoppingrules.

15.4AttributionofAdverseEventAssociationorrelatednesstothestudyagentwillbeassessedby
theinvestigatorasfollows:
•
Definite:Theeventfollowsareasonabletemporalsequencefromexposuretotheinvestigational
agent,hasbeenpreviouslydescribedinassociationwiththeinvestigationalagent,andcannot
reasonablybeattributedtootherfactorssuchasthepatient’sclinicalstate,othertherapeutic
interventionsorconcomitantmedications;ANDtheeventdisappearsorimproveswithwithdrawal
oftheinvestigationalagentand/orreͲappearsonreͲexposure(e.g.,intheeventofaninfusion
reaction).
•
Probable:Theeventfollowsareasonabletemporalsequencefromexposuretotheinvestigational
agentandhasbeenpreviouslybeendescribedinassociationwiththeinvestigationalagentOR
cannotreasonablybeattributedtootherfactorssuchasthepatient’sclinicalstate,other
therapeuticinterventionsorconcomitantmedications.
•
Possible:Theeventfollowsareasonabletemporalsequencefromexposuretotheinvestigational
agent,butcouldbeattributabletootherfactorssuchasthepatient’sclinicalstate,other
therapeuticinterventionsorconcomitantmedications.
•
Unlikely:Toxicityisdoubtfullyrelatedtotheinvestigationalagent(s).Theeventmaybeattributable
tootherfactorssuchasthepatient’sclinicalstate,othertherapeuticinterventionsorconcomitant
medications.
•
Unrelated:Theeventisclearlyrelatedtootherfactorssuchasthepatient’sclinicalstate,other
therapeuticinterventionsorconcomitantmedications.

ForgeneralAEassessment,anAEisconsideredrelatedifitisassessedasdefinitely,probably,or
possiblyrelated;unrelatedifitisassessedasunlikelyrelatedorunrelated.FordeterminationofIND
safetyreporting,AEattributionwillbeassessedaccordingtothesuspectedadversereactiondefinition
describedin21CRF312.32asanAEforwhichthereisareasonablepossibilitythatthedrugcausedthe
adverseeventwhere“reasonablepossibility”meansthereisevidencetosuggestacausalrelationship
 
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betweenthedrugandtheAE.Suspectedadversereactionsthatarebothseriousandunrelatedwillbe
reportedtotheFDAasanINDsafetyreport,inaccordancewithregulationsunder21CFR312.32.

15.5AdverseEventReportingPeriod
AEswillbemonitoredandrecordedinstudyͲspecificcasereportforms(CRFs).Fromthetimeoffirst
exposuretoaninvestigationalagent(i.e.,thestartofthe111InͲDOTAͲBC8infusion)throughday+100
postͲtransplantorthroughdischargepriortothatdatefromtheSCCAsystemtocareofthepatient’s
primaryphysician,nonͲhematologicadverseeventsofшgrade3,possiblyrelatedeventsofgrade2that
havenotpreviouslybeenobservedwithcomponentsofthestudyregimen,andallseriousadverse
eventswillbecapturedinprotocolͲspecificcasereportforms.Gradeч4hematologictoxicityisexpected
andwillonlyberecordedastimetoengraftment.Beyondday+100,diseaseprogression,development
ofsecondarymalignancies,andsurvivalonlywillbecollected.AEswithanonsetdatepriortothefirst
exposuretoaninvestigationalproductwillnotberecorded,exceptinthecaseofclinicallysignificant
worseningoftheAEduringthespecifiedmonitoringtimeframe.Asubjectwithdrawnfromthestudy
becauseofanadverseeventmustbefolloweduntiltheclinicaloutcomefromtheadverseeventis
determined.

ThefollowingeventsarenotidentifiedasAEsinthisstudy:
x
Diseaseprogressionorrelapse.However,clinicaleventsassociatedwithprogression/relapsemay
bereportableasAEs.
x
Hospitalizationforthepurposeoffacilitatingconditioningand/orstemcellinfusionisnot
consideredanAE.AnyAErequiringprolongationofthishospitalizationwillberecordedandsubject
toapplicableSAEreporting.
x
Medicalorsurgicalproceduresinandofthemselves,includingthosethatrequirehospitalization
(e.g.,surgery,endoscopy,biopsyprocedures)arenotconsideredAEs.However,aneventor
conditionrequiringsuchproceduresmaybeanAE.

15.6AdverseEventReportingRequirements
15.6.1ResearchSiteReportingRequirements
ClassificationofaneventasseriousornonͲserious(seeSection15.1)determinesthereporting
procedurestobefollowedbythesiteforreportingtheeventtotheINDSponsor.Theinvestigatormust
reporteventstotheFredHutchIRBinaccordancewiththepoliciesoftheIRB.

TABLE7:PItoINDSponsorReportingRequirementsforAdverseEvents
Classification
ReportingTime
ReportingAction
ContactInformation
Serious
Adverse
Event(SAE)
FatalorlifeͲ
threatening
Within24hoursofresearch
teamawareness
EmailnotificationtoIND
Sponsor’sMedicalMonitor&
ISIOCAdministrator
MedicalMonitoremail:
tillb@fredhutch.org
ISIOCemail:
ISIOC@fredhutch.org
AllSAEs
Within2businessdaysof
researchteamawareness
Submitcompleted
InstitutionͲSponsoredIND
SAEReportingFormsigned
byPIordesignatedsubͲ
ISIOCFax:
206Ͳ667Ͳ6068
ISIOCemail:
 
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Investigator
ISIOC@fredhutch.org
NonͲseriousAdverseEvent
PerCRFcompletion
guidelines
Recordinformationon
appropriateCRFs
N/A
*Researchteamisdefinedastheindividualslistedonthedelegationofauthoritylog.Physicianslistedonthestudy’sdelegation
ofauthoritylogastransplantserviceattendingphysiciansdelegatedauthoritytoadministerinformedconsentwillnotbe
consideredpartoftheresearchteamunlessadditionalresponsibilitiesrelatedtotheconductofthestudyhavebeendelegated
tothembythePrincipalInvestigator.
TheinformationintheInstitutionͲSponsoredINDSAEReportingFormmustmatchorbereconciledwith
theinformationrecordedintheadverseeventssectionoftheCRFandstudydatabase.Forexample,the
sameadverseeventtermshouldbeusedonbothforms.
TheinvestigatormustreporteventstotheFredHutchIRBinaccordancewiththepoliciesoftheIRB.The
INDsponsorassumesresponsibilityforINDsafetyreportingtotheFDAandparticipatinginvestigators,in
accordancewithregulationsunder21CFR312.32.
15.6.2FredHutchINDSponsorReportingRequirements
ThesponsorassumesresponsibilityforINDsafetyreportingtotheFDAandparticipatinginvestigators,in
accordancewithregulationsunder21CFR312.32.
EachseriousadverseeventreportreceivedfromtheinvestigatorwillbeevaluatedbytheMedical
Monitorwhowillassesstheseriousnessoftheevent(seeSection15.1),theexpectednessoftheevent
(seeSection15.1),andtherelationshiptoparticipationinthestudy(seeSection15.4).Forregulatory
reportingpurposes,theINDSponsorwilldetermineexpectednessrelatingtotheinvestigationalproduct
usingsafetyinformationspecifiedintheInvestigatorBrochure.Aneventwillbeclassifiedasrelatedif
eithertheinvestigatorortheINDSponsordeterminesthattheeventmayberelatedtothestudydrug.

TheINDSponsororitsdesigneewillprovideallinvestigatorswithasafetyletternotifyingthemofan
eventthatmeetsFDAINDSafetyReportingcriteria.Investigatorswillberequestedtoprovidewritten
notificationofsafetyreporttotheFredHutchIRBassoonasispractical,consistentwithIRB
requirements.
15.7
SAESAssociatedwithHematopoieticCellTransplantation(HCT)
CertaineventsthatarecommonlyobservedasSAEsfollowingHCTaredescribedinAppendixEinorder
to facilitate assessments of attribution.  SAEs that are identified as routinely experienced in the
allogeneictransplantsettingwouldtypicallybeassessedasunrelatedtoelementsoftheinvestigational
regimenusedinthisprotocol.SymptomsassociatedwithGvHDaredescribedunderAppendicesBand
C.
16.0 DOSEESCALATION
16.1
DosetoNormalOrgan
Doseescalationwillbeconductedbythe“twoͲstage”approachintroducedbyStorer.79TheMTDwillbe
definedasthedosethatisassociatedwithatrueDLTrateof25%.ADLTwillbedefinedasaGradeIII/IV
 
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regimenͲrelatedtoxicity(Bearmanscale)occurringwithin30dayspostͲtransplant.Patientsateither
stage are considered evaluable after survival of 30 days postͲtransplant, or earlier if Grade III/IV
regimenͲrelatedtoxicity(RRT)occursbeforethattime.
Inthisstudyaninitialconservative90Ystartingdosehasbeenselectedtodeliveranestimated6Gyto
thenormalorganthatreceivesthehighestdose.Thisstartingdoseisbasedondatathatutilized90YͲ
ibritumomabtiuxetan(Zevalin®)antiͲCD20RITaspartofahighͲdosetherapyregimeninthesettingof
autologousHCTfornonͲHodgkinlymphoma(NHL).Thesegroupshaveshownthatemployingstandard
(0.4mCi/kg)dosesof 90YͲibritumomabtiuxetanbasedapproachaspartofaHCTregimenisfeasible,
efficacious and safe, without a negative impact on engraftment.80Ͳ81  Additional investigators have
explored the use of escalating doses of 90YͲibritumomab tiuxetan in combination with highͲdose
chemotherapyandautologousHCTforNHL.82Ͳ86Thesestudieshavesafelydeliveredш0.5mCi/kgwith
dosesestimatedtodeliver>15Gytocriticalorgans(liverinmostcases)whencombinedwithhighͲdose
chemotherapyandautologousHCT.Inaddition,theestimatedMTDofradiationdeliveredtothenormal
organ receiving the highest dose of 131IͲBC8 Ab on our Phase I study (Protocol #1432) was 24 Gy
deliveredtotheliver.GiventhedifferencesinradionuclidesutilizedbetweenProtocol#1432andthis
study,combinedwithpriorexperiencesusing90YͲibritumomabtiuxetan,weanticipatethatadoseof6
Gydeliveredby90YͲDOTAͲBC8willrepresentaconservativestartingpointresultinginlesstoxicitythan
hasbeenobservedusing24Gydeliveredby131IͲBC8Aborusinghigherdosesof90Yasreportedbyother
groups.
Singlepatientswillbeenteredonthefirststage,andescalationby2Gyincrements(intheradiation
dosedeliveredtothenormalorganreceivingthehighestdose;seeTable4)willoccuruntilapatient
experiencesaGradeIII/IVregimenͲrelatedtoxicity(Bearmanscale)orDLT,atwhichpointthesecond
stagewillbeginatthenextlowerdoselevel.Ifthefirstpatient(i.e.,atthestartingdoselevel)hasDLT,
deͲescalationwilloccurby2GyincrementsuntilthefirstdoseatwhichapatientdoesnothaveDLT,at
whichpointthesecondstagewillbeginatthatdoselevel.
Inthesecondstage,patientswillbeenteredincohortsof4evaluablepatients.Ifthecurrentcohortis
treatedatdoselevelk,thenextcohortwillbetreatedaccordingtothefollowing:levelkͲ1if2DLT’sare
encounteredamongthe4orfewerpatientsinthecohort;levelkif1DLTisobservedwithinthecurrent
cohort;levelk+1if0DLT’sareseeninthecurrentcohort.Theserulesarefolloweduntilaminimumof
20evaluablepatientshavebeentreatedatthesecondstageandhavebeenevaluatedforDLTsthrough
day 100 following transplant.  It is possible that a patient will be entered on the protocol before a
patient currently enrolled on Stage 1 or all 4 patients in a cohort in Stage 2 have been followed
sufficiently long to evaluate toxicity (30 days postͲtransplant).  Such patients will be treated at the
currentdoselevelandwillbeusedforpurposesoffittingthedoseͲresponsecurveuponcompletionof
thesecondstage.However,thesepatientswillnotbeusedforpurposesofdosemodificationunless
requiredintheinterestsofpatientsafetybasedontheclinicaljudgmentoftheprincipalinvestigator,
norwilltheybecountedtowardstherequirednumberofpatientsforcompletionofthesecondstage.
Followingthecompletedobservationofthefinalpatient,atwoͲparameterlogisticmodelwillbefitto
thedata,therebygeneratingadoseͲresponsecurvebasedontheobservedtoxicityrateatthevarious
 
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doselevelsvisited.Basedonthisfittedmodel,theMTDisestimatedtobethedosethatisassociated
withatoxicityrateof25%.
16.2
DosetoBoneMarrowandGraftFailure
Initiallynopatientwillreceiveadoseof90Yestimatedtodelivermorethan43Gytothemarrow(5Gy
lessthanthe48Gyfrom131IͲBC8AbtoleratedonProtocol#1432).Patientsforwhomtheamountof90Y
required to deliver the stipulated dose to liver would result in the delivery of more than 43 Gy to
marrowwillhavethe90Ydoselimitedtotheamountwhichwoulddeliver43Gytomarrow.If0of3,or
nomorethan1of6patientstreatedatthisestimateddosetomarrowexperiencesgraftfailure,wewill
then escalate in increments of 5 Gy to marrow in those patients as allowed by the marrow:liver
radiationabsorbeddoseratio(i.e.,withoutexceedingintendedestimatedradiationabsorbeddoseto
liver).TheMTDofradiationdosetomarrowwillbeestimatedtobethedosebelowanydosewhere>2
patientsofupto6treatedexperiencegraftfailure.
16.3
DoseLimitstoOtherNormalOrgans
AlthoughtheRITapproachisintendedtodelivermyeloablativedosesofabsorbedradiationtositesof
disease,itwillbeimportanttoensurepatientsafetyandminimizetheriskofradiationtoxicityinnormal
organs.  In this study the total radiation dose will be limited to ensure that critical organs receive
radiationabsorbeddosesbelowknowntolerancelimits.Thetotaldoseincludescontributionsfromboth
external and internal radiation sources.  The internal radiation component is the absorbed dose to
normalorgansfrom 90YͲDOTAͲBC8. Theexternalradiationdoseinthisstudyis200cGyofTBI.For
patientswhohavepreviouslybeentreatedwithexternalbeamradiotherapy,thepriorradiationdose
deliveredwillalsobefactoredintodeterminationofthemaximumradiationdosepermittedforthat
individual.  Although there are several published standards for the tolerance limits for radiation
absorbeddosesforcriticalnormalorgans,themostwidelyquotedarethoseestablishedbyEmamietal.
for high dose rate, external gamma radiation therapy delivered by a linear accelerator.87  While the
Emamietal.valuesmaynotdirectlyequatetotolerancelimitsforradiationabsorbeddosestocritical
normalorgansdeliveredbyverylowdoserateinternalradiationtherapyusingbetaͲparticleemitting
radionuclides, we will adopt them as a conservative approach to patient safety.  Table 8 shows the
functionaldoselimitsthatwewillfollow.

TABLE8:FunctionalDoseLimitstoNormalOrgans
Organa
MaximumwholeorganTD
5/5limit(cGy)87
Radiationtobe
deliveredviaTBI
(cGy)
Maximumradiationdose
permissiblefromYͲ90(cGy)
Kidneys
2300
200
2100
Bladderwall
6500
200
6300
Brain
4500
200
4300b
Heart
4000
200
3800
Stomach
5000
200
4800
Smallintestine
4000
200
3800
Upperlargeintestine
4500
200
4300
 
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Organa
MaximumwholeorganTD
5/5limit(cGy)87
Radiationtobe
deliveredviaTBI
(cGy)
Maximumradiationdose
permissiblefromYͲ90(cGy)
Lowerlargeintestine
6000
200
5800
Liver
3000
200
2800c
a Lungs are not accessible and are not measured using standard dosimetric methods due to rib
attenuation.
bMaximumYͲ90radiationdosetobraininpatientswithpriorevidenceofCNSleukemicinvolvement
maybefurtherdecreasedbasedonanticipatedexternalcranialorcranialͲspinalirradiationasdescribed
undersection10.10.
cActualdosetoliverisexpectedtobelower,reflectingdoseescalationschemadescribedundersection
16.1.
16.4
AdditionalClinicalDoseLimitsandModifications
Insomepatients,theamountof90Yrequiredtodeliverthetargetdosetonormalorgan,asdetermined
by biodistribution studies, may be deemed clinically inappropriate by the investigator (e.g., if the
amount of 90Y activity (mCi) is significantly higher than has been previously delivered in a clinical or
researchsetting).Inthisevent,thepatientmaybetreatedatalowerdosebasedonuseofapriordose
leveloruseofanalternatedosedeterminationmechanism,suchasmCi/kgormCi/m2,atthediscretion
oftheinvestigatorinconjunctionwiththeattendingphysicianandaNuclearMedicinerepresentative.
17.0 STATISTICALCONSIDERATIONS
The primary objective of this study is to estimate the MTD of 90YͲDOTAͲBC8 when combined with a
reducedintensityconditioningregimen.TheMTDwillbedefinedasthedoseof90YͲDOTAͲBC8usedin
combinationwiththereducedͲintensityHCTconditioningregimenthatisassociatedwithaGradeIII/IV
RRTortrueDLTrateof25%.InthisprotocolforpatientswithadvancedAML,ALL,orhighͲriskMDS,the
doseadjustmentschemaisdesignedtotargeta25%rateofGradeIII/IVRRTsincethesepatientsareat
such highͲrisk of relapse postͲtransplant and could benefit from the delivery of maximum radiation
dosestoleukemiccellsinBMandspleen.DetailsofthedoseͲmodificationalgorithmarecontainedin
section16.1.
A secondary objective of this study is to determine if engraftment can be achieved safely among
patientswithhighͲriskhematologicmalignancieswhoundergoHCTusingDOTAͲBC8RIT.Althoughwe
havenotseenrejectioninanyofourpriorradiolabeledBC8Abstudies,in thisprotocolifsufficient
evidence exists suggesting that the true rate of graft rejection exceeds 20%, the protocol will be
suspended and reviewed by the investigators and other experts/committees as appropriate to
determine whether the trial should be terminated, continued without change, or continued with
revisions.  Sufficient evidence will be taken to be a lower limit of the appropriate 80% oneͲsided
confidence interval associated with the estimated proportion of rejections in excess of 0.20.  These
proportions and associated confidence intervals will be calculated after every 5th patient enrolled is
evaluable.Operationally,graftrejectionatanyofthefollowingobservedproportionswouldtriggera
suspension:3/5,4/10,5/15,6/20,8/25,9/30,10/35,or11/40.
 
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Inadditiontograftrejection,thestudywillbesuspendedifthereissufficientevidencetosuggestthat
thetruerateofgradesIIIͲIVacuteGvHDatday+100isexcessive(gradedaccordingtotheestablished
criteria at the FHCRC).  Sufficient evidence for grades IIIͲIV GvHD will be taken to be an observed
proportion of GvHD whose lower limit to the associated oneͲsided 80% confidence interval exceeds
35%.Aswithrejection,theseproportionswillbeevaluatedafterevery5thenrolledpatientbecomes
evaluable.  Operationally, any of the following observed proportions of GvHD would lead to study
suspension:4/5,6/10,8/15,10/20,12/25,14/30,16/35,or18/40.
Eachsuspensionrulewillbeevaluatedamongallpatientsenrolled,regardlessofthedoseof90YͲDOTAͲ
BC8administered.
Table 9 summarizes the operating characteristics of each of these rules, each rule considered
independentoftheother.

TABLE9:CharacteristicsofSuspensionRules
Numberof
patients
Truerateof
graftrejection
Probabilityof
suspension1
Truerateof
GVHD
Probabilityof
suspension2
20
.15
.12
.25
.04
35
.15
.13
.25
.05
20
.35
.80
.50
.66
35
.35
.90
.50
.83
1 Representsestimateoftheprobabilityofstudysuspensionbyassociatednumberofpatientsdueto
excessgraftrejection.
2 Representsestimateoftheprobabilityofstudysuspensionbyassociatednumberofpatientsdueto
excessGvHD.
 Eachestimatedfrom5,000MonteCarlosimulations.
Because the antiͲleukemic effect of 90YͲDOTAͲBC8 combined with this reducedͲintensity regimen is
unknown,butlikelytoincreaseathigherdoselevels,wewillfollowdiseaseresponseanddurationof
remission,butratesofrelapsepostͲtransplant,orfailuretoenterremission,willnothaltthestudy.
 
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18.0 TARGETED/PLANNEDENROLLMENT
EthnicCategory
Sex/Gender

Females
Males
Total
HispanicorLatino
1
1
2
NotHispanicorLatino
13
15
28
EthnicCategoryTotalofAllSubjects*
14
16
30
RacialCategories
AmericanIndian/AlaskaNative
0
1
1
Asian
1
1
2
NativeHawaiianorOtherPacificIslander
1
1
2
BlackorAfricanAmerican
1
1
2
White
11
12
23
TotalofAllSubjects
14
16
30
19.0 TERMINATIONOFSTUDY
Individualpatientsmaychoosetodiscontinuetreatmentatanytime.Treatmentmayalsobeterminated
at the discretion of the Principal Investigator if continuation of treatment is deemed to pose
unacceptabletoxicitytothepatient.Specificreasonsforwithdrawalmayinclude:
a.
Patientrequest.
b.
Unacceptabletoxicityduringdosimetryantibodyinfusion(seesections14.0,4.3,and17.0for
completetoxicitydescriptionsandstoppingrules).
c.
DevelopmentofantiͲmouseantibodies.
ThePIandINDsponsormayterminatethestudyatanytime.TheIRBandFDAalsohavetheauthorityto
terminatethestudyshoulditbedeemednecessary.Stoppingrulesassociatedwithlackofefficacyand
excessivetoxicityaredetailedinthestatisticalsection.
20.0 DATAANDSAFETYMONITORINGPLAN
Thisisasingleinstitutiontrialwhereallpatientsarefollowedcloselybytheinvestigators.Additionally,
thetrialdesignprovidesrulesfordoseescalationdependingupontherateofdevelopmentofGrade
III/IVRRT(BearmanScale).Thisdesignmandatesongoingreviewoftheoutcomeofpreviouspatients
treatedonstudysothattheappropriateDoseLevelforthecurrentpatientcanbeassigned.The
principalinvestigator,primaryresearchnurse,andstudydatacoordinatorcommunicateroutinely
(typicallyweekly)toreviewrecentlyacquireddata,stoppingrules,andadverseevents.Thedata
recordedwithintheresearchchartsandprotocoldatabaseiscomparedwiththeactualdatathatis
availablefromthemedicalrecordand/orclinicalhistories.Datadetailedintheresearchcasereport
formsincludesthenatureandseverityofallsignificanttoxicities,whicharealsoreportedasdescribed
above.Allinvestigatorsontheprotocolhavereceivedformaltrainingintheethicalconductofhuman
research.
InstitutionalsupportoftrialmonitoringwillbeinaccordancewiththeFHCRC/UniversityofWashington
CancerConsortiumInstitutionalDataandSafetyMonitoringPlan(DSMP).Undertheprovisionsofthis
 
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plan,FHCRCClinicalResearchSupportcoordinatesdataandcompliancemonitoringconductedby
consultants,contractresearchorganizations,orFHCRCemployeesunaffiliatedwiththeconductofthe
study.Independentmonitoringvisitsoccuratspecifiedintervalsdeterminedbytheassessedrisklevel
ofthestudyandthefindingsofpreviousvisitspertheinstitutionalDSMP.

Inaddition,protocolsarereviewedatleastannuallyandasneededbytheConsortiumDataandSafety
MonitoringCommittee(DSMC),FHCRCScientificReviewCommittee(SRC)andtheFHCRC/Universityof
WashingtonCancerConsortiumInstitutionalReviewBoard(IRB).Thereviewcommitteesevaluate
accrual,adverseevents,stoppingrules,andadherencetotheapplicabledataandsafetymonitoringplan
forstudiesactivelyenrollingortreatingpatients.TheIRBreviewsthestudyprogressandsafety
informationtoassesscontinuedacceptabilityoftheriskͲbenefitratioforhumansubjects.Approvalof
committeesasapplicableisnecessarytocontinuethestudy.
Thetrialwillcomplywiththestandardguidelinessetforthbytheseregulatorycommitteesandother
institutional,stateandfederalguidelines.
21.0 DATAMANAGEMENT/CONFIDENTIALITY
Theinvestigatorwillensurethatdatacollectedconformtoallestablishedguidelines.Eachsubjectis
assignedauniquesubjectnumbertoassuresubjectconfidentiality.Subjectswillnotbereferredtoby
thisnumber,byname,orbyanyotherindividualidentifierinanypublicationorexternalpresentation.
Thelicensedmedicalrecordsdepartment,affiliatedwiththeinstitutionwherethesubjectreceives
medicalcare,maintainsalloriginalinpatientandoutpatientchartdocuments.Additionalclinicaldata
maybemadeavailablefromtheFredHutchcoredatabase(Gateway),whichismanagedandverified
independentoftheresearchgroup. 
TheresearchteamwillmaintainCaseReportForms(CRF)andassociatedresearchdocumentationfor
eachpatienttreatedundertheprotocol.ThisdocumentationincludesbothclinicaldataandstudyͲ
specificdocumentsforeachpatient.AdditionalstudyͲspecificdocumentsandradiologicdataare
maintainedbytheUWDivisionofNuclearMedicine.ThePrincipalInvestigatororadesigneewillverify
completedCRFsagainstsourcedocumentationonanongoingbasisastheyarecompletedforindividual
patients.CRFsshouldbecompleteanddataenteredintothestudydatabasewithin120daysof
transplant.Datarequiredforanalysisofpatientstreatedonthisprotocolwillbemaintainedina
passwordͲprotectedstudyͲspecificdatabase.DatafromtheCRFsarekeyeddirectlyintothedatabaseby
authorizedresearchstaffandverifiedonanongoingbasis.
22.0 REFERENCES
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2001;98(3):565Ͳ572.
 
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44.BurkeJM,CaronPC,PapadopoulosEB,etal.CytoreductionwithiodineͲ131ͲantiͲCD33antibodies
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2001;7(8):2254Ͳ2262.
 
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69.Chakraverty R, Peggs K, Chopra R, et al. Limiting transplantationͲrelated mortality following
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2002;99(3):1071Ͳ1078.
70.NiederwieserD,MarisM,ShizuruJA,etal.LowͲdosetotalbodyirradiation(TBI)andfludarabine
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donorsandpostgraftingimmunosuppressionwithcyclosporineandmycophenolatemofetil(MMF)
can induce durable complete chimerism and sustained remissions in patients with hematological
diseases.Blood.2003;101(4):1620Ͳ1629.Epub2002Oct1623.
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Blood.2003;102(6):2021Ͳ2030.Epub2003Jun2025.
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tumoreffects.Blood.2001;97(11):3390Ͳ3400.
73.Gyurkocza B, Storb R, Storer B, et al. Nonmyeloablative Allogeneic Hematopoietic Cell
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2008;112(11).
74.Kahl C, Storer BE, Sandmaier BM, et al. Relapse risk in patients with malignant diseases given
allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood.
2007;110(7):2744Ͳ2748.
75.LaportGG,SandmaierBM,StorerBE,etal.ReducedͲintensityconditioningfollowedbyallogeneic
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myeloproliferativedisorders.BiolBloodMarrowTransplant.2008;14(2):246Ͳ255.
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patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPD) (except
chronicmyelogenousleukemia).Blood.2002;102:185a[Abstract].
77.Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after
conditioningwith131IͲantiͲCD45antibodyplusfludarabineandlowͲdosetotalbodyirradiationfor
elderly patients with advanced acute myeloid leukemia or highͲrisk myelodysplastic syndrome.
Blood. 2009;114(27):5444Ͳ5453. Prepublished on 2009/09/30 as DOI 10.1182/bloodͲ2009Ͳ03Ͳ
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1993;49(4):1117Ͳ1125.
 
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80.KrishnanA,NademaneeA,FungHC,etal.PhaseIItrialofatransplantationregimenofyttriumͲ90
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Oncol.2008;26(1):90Ͳ95.Prepublishedon2007/11/21asDOI10.1200/jco.2007.11.9248.
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highͲdose BEAM chemotherapy and autologous stem cell transplantation for chemoͲrefractory
aggressive nonͲHodgkin's lymphoma. Exp Hematol. 2007;35(4):534Ͳ540. Prepublished on
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2005;106(8):2896Ͳ2902.
83.WinterJN,InwardsDJ,SpiesS,etal.YttriumͲ90ibritumomabtiuxetandosescalculatedtodeliverup
to 15 Gy to critical organs may be safely combined with highͲdose BEAM and autologous
transplantation in relapsed or refractory BͲcell nonͲHodgkin's lymphoma. J Clin Oncol.
2009;27(10):1653Ͳ1659.
84.DevizziL,GuidettiA,TarellaC,etal.HighͲdoseyttriumͲ90ͲibritumomabtiuxetanwithtandemstemͲ
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10.1200/jco.2008.16.8294.
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Prepublishedon2007/11/06asDOI10.2967/jnumed.107.044016.
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10.1111/j.1365Ͳ2141.2007.06869.x.
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APPENDIXA:
BEARMANCRITERIAFORREGIMENͲRELATEDTOXICITY
Thecriteriafortoxicityweredevelopedtoconveythefollowingconsiderationsaboutthetoxicityofthe
preparativeregimen.Itistheresponsibilityoftheprincipalinvestigatortotryanddistinguishtoxicities
duetothepreparativeregimenfromtheseduetootherfeaturesoftransplantation.
Grade1
Development of transient chemical abnormalities which are not of major clinical
consequenceandwhichreversewithoutrequiringmajormedicalinterventions.Ingeneral,
the intent of this toxicity scale is to observe transient target organ toxicity which is
reversible.
Grade2
Developmentofchemicalorlaboratoryabnormalitieswhicharepersistentandwhichmay
representtargetorgandamagewhichmaynotbereadilyreversed.Itisanticipatedthatat
thisdoseofdrug,thetoxicityobtainedwouldbemanageablebyclinicalmethodsbutmay
interferewithothertherapies.
Grade3
Development of major clinical, chemical or laboratory abnormalities which represent
maximumtoxicitieswithoutbeingfatal.Thisgradeoftoxicityisdesignedtobethedose
limitingtoxicity.Further,thedevelopmentofthisdegreeoftoxicitycannotbeconsideredto
be a regular acceptable but rather an occasional toxicity (<20%), acceptable given the
severityofthedisease.Includedinthiswouldbetheneedforlifesupporttechniquessuch
asrenaldialysisandventilationtherapy.
Grade4
Fatal.
A.
Cardiac
Grade1
EKGvoltagedecreaseby25%orless,restingtachycardiawithweightgainbutresponsiveto
diuretictherapy.
Grade2
EKG voltage decrease by 25Ͳ50%, congestive heart failure responsive to diuretic therapy,
arrhythmiasmanageablewithmedicaltherapy.
Grade3
SymptomaticCHFunresponsivetodiuretictherapy,decreaseinEKGvoltagebymorethan
50%,lifeͲthreateningarrhythmia.
Grade4
Fataltoxicity.
B.
Bladder
Grade1
Microscopichematuriaformorethan7days.
Grade2
Macroscopichematuria.
Grade3
Hemorrhagic cystitis requiring transfusion and placement of an indwelling catheter to
removeclots,orcystoscopywithorwithoutinstallationofsclerosingagents.
Grade4
Fataltoxicity.
 
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C.
Renal
Grade1
Increaseincreatinineuptotwicebaselinevalue.
Grade2
Increaseincreatinineabovetwicebaselinevaluebutnotrequiringdialysis.
Grade3
Requirementofdialysis.
Grade4
Fataltoxicity.
D.
Pulmonary
Grade1
DecreaseinpO2ordyspneawithoutaninfiltrateor,atmost,atransientpatchyinfiltrate.
Grade2
Transient interstitial pneumonia (either idiopathic or unbiopsied) that does not require
ventilatorysupport).
Grade3
Interstitialpneumoniarequiringventilatorysupport.
Grade4
Fataltoxicity.
E.
Hepatic
Grade1
TransientelevationsinliverfunctiontestslessthanthoselistedasGrade2toxicity.
Grade2
Hepaticdysfunctionwithbilirubinelevationgreaterthan5,SGOTincreasegreaterthanfiveͲ
foldorascites.
Grade3
Hepatic failure including hepatoͲrenal syndrome, hepatic encephalopathy, bilirubin
elevationgreaterthan20,orGrade3VODasdefinedbyShulmanetal.
Grade4
Fataltoxicity.
F.
CentralNervousSystem
Grade1
Transientsomnolence.
Grade2
Somnolencemorethan36hoursorothersignsofCNStoxicity.
Grade3
Seizuresorcoma.
Grade4
Fatal.
G.
Stomatitis
Grade1
Ulcerationorpainbutnotprohibitingoralintake.
Grade2
Painfululcerationprohibitingoralintake.
Grade3
Severeulcerationrequiringintubation.
Grade4
Fatal.
H.
Gastrointestinal
Grade1
Waterystools,butlessthan6stools/day.
 
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Grade2
Watery stools more than 6Ͳ12 stools/day, or hemorrhagic enterocolitis not requiring
transfusion,ortransientileus.
Grade3
Hemorrhagicenterocolitisrequiringtransfusion,orileusrequiringnasogastricsuction.
Grade4
Fatal.

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APPENDIXB:
ACUTEGVHDASSESSMENT

StagingbyIndividualOrganInvolvement

SKIN:
measuredbyrashfirstappearinggenerallybetween10and70daysaftertransplant.
(excludesrashesofknownviralorotherorigin)

Stage
Description
1
Maculopapularrash<25%BSA
2
Maculopapularrash25–50%BSA
3
Generalizederythroderma
4
Generalizederythrodermawith
bullousformationanddesquamation

LIVER*:
measuredbytotalserumbilirubin

Stage
Description
1
2.0–2.9mg/dL
2
3.0–5.9mg/dL
3
6.0–14.9mg/dL
4
>15.0mg/dL

GUT**:
includesonlydiarrheaoccurringafterDay+21

Score
Adult
Pediatric***
1
upperGI(anorexia,nausea,vomiting)
withdiarrheaof<1000mL/day
upperGI(anorexia,nausea,vomiting)
withdiarrheaof<555mL/m2/day
2
1000–1499mL/daydiarrhea
556Ͳ833mL/m2/daydiarrhea
3
>1500mL/daydiarrhea
>833mL/m2/daydiarrhea
4
severeabdominalcramping,bleedingorileuscausedbyGVHD

*
Incaseswhereanothercauseofhyperbilirubinemiaantedatedtheonsetofrash,theliverscore
shouldbedecreasedbyonestage.
** IncaseswherepeakGIsymptomsareexacerbatedbyacauseotherthanGVHD,thegutscore
shouldbedecreasedbyonestage.
***Pediatricpatients<17yearsofage

 
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OverallGrade

ThedeterminationofanoverallGVHDgradeshouldbebasedontheorganstage,responsetotreatment
andwhetherGVHDwasamajorcauseofdeath.

Overall
Grade
OrganStage
QualifyingConditions
AdditionalQualifyingConditions
I
Stage1Ͳ2skin
Noliverorgut
Indicatesthattheprophylactic
immunosuppressiveregimenwasnot
sufficienttopreventallmanifestationsof
aGVHD.
II
Stage3skin

or
Stage1liver

or
Stage1gut
N/A
Indicatesthattheprophylactic
immunosuppressiveregimenwasnot
sufficienttopreventallmanifestationsof
aGVHD,butglucocorticoidtreatmentafter
theonsetofGVHDwasgenerallysufficient
tocontrolthedisease.
III
Stage4skin

or
Stage2Ͳ4liver

or
Stage2Ͳ4gut

withoutGVHDasamajor
contributingcauseofdeath


Indicatesthattheprophylactic
immunosuppressiveregimenwasnot
sufficienttopreventallmanifestationsof
aGVHDandthatadditionaltreatmentafter
theonsetofGVHDdidnotreadilycontrol
thedisease.
IV
Stage4skin

or
Stage2Ͳ4liver

or
Stage2Ͳ4gut

withGVHDasamajor
contributingcauseofdeath


GVHDwasresistanttoboththe
prophylacticimmunosuppressiveregimen
andanyadditionaltreatmentafterthe
onsetofthedisease.
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APPENDIXC:
CHRONICGVHDGRADING*
Inallcases,concomitantprocesses(i.e.infectionsordrugreactions)mustberuledout.Karnofskyor
LanskyClinicalPerformancescores,60%,>15%weightloss,andrecurrentinfectionsareusuallysignsof
clinical extensive chronic GVHD. Abnormalities that could indicate chronic GVHD are categorized by
organsystemsaslistedbelow.

Skin
Erythema,dryness,pruritus,pigmentarychanges (i.e. hyperpigmentation,vitiligo),
mottling, papulosquamous plaques, nodules, exfoliation, macularͲpapular or
urticarialrash,scleroderma,morphea(oneorseveralcircumscribed,induratedand
shinylesions)
Nails
Ridging,onychodystrophy,onycholysis
Hair
Prematuregraying,(scalphair,eyelashes,eyebrows),thinningscalphair,alopecia,
decreasedbodyhair
Mouth
Dryness,burning,gingivitis,mucositis,striae,atrophy,erythema,lichenoidchanges,
ulcers, labial atrophy or pigmentary changes, tooth decay, tightness around the
mouth
Eyes
Dryness,burning,blurring,grittyeyes,photophobia,pain
Vagina/vulva
Dryness,dyspareunia,strictureorstenosis,erythema,atrophyorlichenoidchanges
notincluded
Liver
Elevated liver function tests not due to other causes (alkaline phosphatase t 3x
upperlimitofnormal,ASTorALTt4xupperlimitofnormalortotalserumbilirubint
2.5;intheabsenceofchronicGVHDinvolvingotherorgans,liverbiopsyisrequired
toconfirmdiagnosis)
Lung
Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, dyspnea on
exertion,historyofrecurrentbronchitisorsinusitis
GI
Anorexia,nausea,vomiting,weightloss,dysphasia,odynophagia,malabsorption
Fasciitis
Stiffnessandtightnesswithrestrictionofmovement,occasionallywithswellingpain,
cramping,erythemaandinduration,mostcommonlyaffectingforearms,wristsand
hands,ankles,legs,andfeet,inabilitytoextendwristswithoutflexingthefingersor
theelbows,contractures
Serositis
Chestpainorcardiopulmonarycompriseduetopericarditisorpleuritis
Muscle
Proximalmuscleweakness,cramping
Skeletal
Arthralgiaoflargeproximalgirdlejointsandsometimessmallerjoints
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LaboratorytestinganddiagnosticindicatorsofchronicGVHD*
Eye
Schirmer’s test with a mean value d 5mm at 5 minutes, or symptomatic with
valuesof6Ͳ10mmorkeratitisdetectedbyslitlampexamination
Liver
Elevated liver function tests not due to other causes (see definition of clinical
limitedandextensivechronicGVHD)
Lung
NewobstructivelungdefectdefinedasFEV1<80%ofpredictedwitheitheran
FEF 25Ͳ75 <65% of predicted or RV >120% of predicted, or a decrease of
FEV1/FVC by > 12% within a period of less than 1 year. A diagnosis of
bronchiolitis
obliterans
requires
negative
microbiological
tests
from
bronchoalveolar lavage and evidence of air trapping by high resolution endͲ
expiratory and endͲinspiratory CAT scans o the chest. A thoracoscopic lung
biopsy may be necessary in order to confirm the diagnosis of bronchiolitis
obliterans in patients who have obstructive lung disease without air trapping
whenchronicGVHDinvolvingotherorgansisabsent
Esophagus
Esophageal web formation, stricture or dysmotility demonstrated by barium
swallow,endoscopyormanometry
Muscle
ElevatedCPKoraldolase,EMGfindingsconsistentwithmyositis
Blood
Thrombocytopenia
(usually
20,000Ͳ100,000/Pl),
eosinophilia,
hypogammaglobulinemia, hypergammaglobulinemia, and autoantibodies occur
insomecases

*FromStandardPracticeGuidelinesfor“ChronicGraftͲversusͲHostDiseaseClassificationatthetimeof
presentation”developedbyLongTermFollowͲUpattheFHCRC
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APPENDIXD:
METHODSUSEDTOCALCULATERADIATIONABSORBED
DOSESTOPATIENTS
a. ScientificBasisforInternalDosimetryCalculations
Radiationabsorbeddoseswillbecalculatedforeachpatient’snormalorgansandtissuesandthewhole
bodyusingstandardmethodsrecommendedbytheMedicalInternalRadiationDose(MIRD)Committee
ofTheSocietyofNuclearMedicine(Loevingeretal.,1991).TheMIRDmethodsaccountforboththe
penetrating gamma and the nonͲpenetrating beta radiation (electrons) emitted by radioactivity
distributed throughout the body.  The pharmacokinetics and biodistribution of the radiolabeled
antibodywillvaryfromonepatienttothenext.Therefore,intheMIRDschema,dosimetrycalculations
are based on a series of direct measurements of the organ biodistribution of radiolabeled antibody.
TheseincludegammaͲcameraimagesandquantitativeactivitymeasurementsoftheradionuclideused
(111In as a surrogate for yttriumͲ90Ͳlabeled antibody) in the major imageable source organs, tumor
tissue,redmarrow,andthetotalbodyatvarioustimeͲpointspostͲinfusion.Marrowtissuebiopsiesare
weighedandcountedtodeterminetheactivityconcentrationinmarrowatspecifictimepoints.When
available,thepatientͲspecificorganmassesareusedforinternaldosecalculationsratherthangeneric
modelvalues.ThemathematicalfoundationsforapplicationofthesemethodstocriticalorgansinhighͲ
doseradioimmunotherapyarewellͲestablished(Fisher1994,2000;Fisheretal.2009).
b. Rationale for the Use of IndiumͲ111 to Predict YttriumͲ90 Biodistribution for Deciding the
AdministeredactivityofTherapy
Because 90YisapurebetaͲemitter,itcannotbeimagedaccuratelyorconvenientlyinthepatient,and
activityovertimeintheindividualorganscannotbeeasilydelineated.ThephotonͲemittingindiumͲ111
labelstheantibodytoshowthebiodistributionof90YͲantibody.Weassumethatthebiodistributionof
thetraceͲlabeled 111Inantibodyfaithfullyrepresentsthebiodistributionof 90Yantibodyinthecancer
patient.Preclinicalstudiesbyothersconfirmthatthebiodistributionof111Inantibodyusuallycorrelates
with 90Y antibody biodistribution (Fisher et al. 2009). Therefore, it is common practice to use 111In
antibodymeasurementdatatopredictthebiodistributionof90YͲantibodyduringtherapy.Inabsolute
terms,thiscorrelationmaynotbecompletelycorrect,however,becausepartialdissociationof90Yand
111Infromtheimmunoconjugatemayoccurinvivo;someofthefree90Ymaydepositonbonesurfaces,
andsomeofthe111Inmaypreferentiallygotothetestesduetonaturaluptakeofindiumbygermcells.
During radiolabeling, quality control usually allows less than 2% unbound
111In in the
radioimmunoconjugate.  We will not measure the unbound fraction in serum after injection.  For
dosimetry calculations, however, we will assume that the biodistributions of 111InͲ and 90YͲlabeled
antibody are equivalent, recognizing that without further correction this assumption may, in some
cases, lead to minor underestimates of 90Y dose to bone surfaces and red marrow, and to minor
overestimatesof90Ydosetothetestes.
c. DirectMeasurementsinPatients
(i)ConjugateͲviewquantitativeplanarimagingwithanteriorandposteriormeasurementsisthemost
widelyusedmethodforassessingsourceͲorganactivityinpatients.Theconjugateviewmethoddoes
notrequireknowingthedepthofthesourceregionanddoesnotdependonassumptionsinherentin
 
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singleͲviewphantomsimulations,butdoesincorporatecorrectionforbackground,scatter,andphoton
attenuation.
(ii)BiodistributionImaging
After a tracer quantity of 111In (usually 111 to 222 MBq or 3 to 6 mCi) labeled to DOTAͲBC8 is
administered, the patient is imaged using collimated anterior and posterior planar gammaͲcamera
imaging.Biodistributionimagingbeginsimmediatelyafterinfusionof111IntraceͲlabeledDOTAͲBC8on
day0.Anuclearmedicinecamerawithamediumenergycollimator,withphotopeaksettingsat171and
245keV,andasymmetric15%windowaroundeachphotopeak,isusedforimaging.Imagesinclude
chestwithupperhumeriandthyroid,abdomen,andpelviswithupperfemurs.Regionsofinterestare
alwaysselectedforthemajorsourceorgansthatvisualizeabovebackground,whichmayinclude,but
arenotlimitedto,theliver,spleen,heartvolume,redmarrowspace,lungs,kidneys,thyroid,andtestes.
Normalorgansandtumorsarevisualizedwhenconcentrationsof111Inantibodyintheorganortumor
are greater than those in the surrounding tissue.  Background regions are drawn for each organ or
regionofinterestsimilartothemethodsdescribedabove.Inaddition,attenuationcorrectionfactorsare
determinedforthechestandabdomenusingthemethodsdescribedbelow.Wemayimagetumorsites
thathavewellͲdefineduptakesandretentionof 111InͲradiopharmaceuticals,allowingustodetermine
the percent of administered activity per gram of tissue for all cancerous areas selected for dose
assessment.Imagingofselectedtumorsmaybeconductedforvarioustimepoints,andtimeͲactivity
curvesmaybeconstructedandintegratedfortumordoseassessments.
Measurementsarealsomadeofrepresentativebackgroundtissueandofanimagingstandardwithout
the patient in the camera fieldͲofͲview.  The outlines for the regions of interest are drawn by a
technologistfromtheacquiredimages,andcountsareobtainedfromtheselectedregions.Thecounts
aredecayͲcorrectedtothe 111Inimagingstandard.Thegeometricmeanoftheanteriorandposterior
countsisobtainedforeachregionofinterest.Countsarethencorrectedforattenuation,decay,and
background.TotalͲbodymeasurementsareobtainedusingwholeͲbodygammacameraimagesinboth
anteriorandposteriorprojections,toquantifythetotal111Inactivityremaininginthepatient,overtime,
asafractionofthetotaladministeredactivity.
(iii)Attenuation
Priortoantibodyinfusion,allpatientswillhavemeasurementmadeoftheirabdomenattenuationby
transmissionscans.Afluidfilledsheetsource,largeenoughtocovertheentireusefulfieldofviewof
thecamera,isloadedwithapproximately0.5–0.7mCiof 111In.Uniformdistributionoftheisotope
throughout the sheet source is ensured.  The source is placed on the lower detector, and with the
patientonthescanningtableandtheirabdomeninthefieldofview,theupperdetectorisloweredinto
place.  A five minute transmission image is acquired.  Without moving the detectors and with the
scanningtablealonebetweenthem,anotherfiveminuteimage(flood)isacquired.Theobservedratio
ofcountsinthefloodsourceactivitycountedwithandwithoutthepatientoverlyingistheattenuation
correctionfactorforthevariousorgansofinterest.
 
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(iv)SamplingTimes
Selecting an appropriate number of imaging/counting times requires tradeͲoffs between having
sufficientdataandeconomizingtheimagingcostsandminimizingpatientinconvenience.Ourobjective
istoselectthefewestdataͲcollectiontimepointsthatwillstillprovideareasonableevaluationofthe
correctmathematicalfunctionthatbestdescribestheactivityͲtimecurve.Aminimumofthreetofour
datameasurementpointswilltypicallyberequiredfor 111InͲDOTAͲBC8imaging.Imagingincludesone
setofmeasurementsimmediatelypost111InͲDOTAͲBC8infusion,followedbyanadditionaltwotothree
imagingtimepointsonDays1and2postinfusion.Forexample,apatientcouldhaveimagesperformed
duringthemorningandafternoonofDay1,andtheafternoonofDay2,postinfusion.Theseanalyses
providedatatoestimateofthefractionoftheadministeredactivitythatresidesineachsourceorgan
andinthetotalbodyateachmeasurementtimepostͲinfusion.
d. TimeͲActivityCurves
Thesequentialmeasurementdataareplottedtodeterminethecumulatedactivityandresidencetimes
for each source organ.  We plot the fractions of the total administered activity observed at each
measurementtimepoint.Weplottheeffectivedata(asmeasured),ratherthanthevaluesthatwere
decayͲcorrectedfromaradionuclidestandard,becauseinternaldosesarecalculatedfromtheintegral
areasundertheeffectivetimeͲactivitycurves.Wethenselectanappropriatemathematicalfunction
(equation)withparametersthatbestrepresentthedata,andwedeterminetheequationparametersby
leastͲsquareslinearregression.WethenintegratethebestͲfitequationstoinfinitetimetodetermine
theresidencetimes(W,hours)foreachsourceorgan,tumor,theredmarrow,andthewholebody.We
usuallyfitthebiodistributiondatatoanexponentialorsumofexponentials.Anestimateoftheslope
ofthelongͲtermtailofthetimeͲactivitycurvemaybemadebyfittinganexponentialfunctiontothelast
twopoints.
e. ResidenceTimeCalculations:IntegratingtheTimeͲactivityCurves
The residence time (BqͲsec/Bq or PCiͲhr/PCi administered) for a source organ is the fraction of the
administeredactivityinasourceorganovertimetocompletedecay,obtainedbyintegratingthetimeͲ
activitycurvetoinfinity,asdescribedinthepreviousparagraph.Residencetimevaluesarethebasic
inputnumberrequiredbysoftwarepackages(MIRDOSE2andMIRDOSE3computerprograms,OakRidge
Associated Universities, Oak Ridge, Tennessee) and OLINDAͲEXM (Vanderbilt University, Nashville,
Tennessee)thatimplementtheMIRDdosimetryschema.WewilluseOLINDAͲEXMforpatientdose
assessmentonthisprotocol.
f.
PatientͲspecificDosimetry
Sinceorgandoseisapproximatelyproportionaltotheinverseoftargetmass,acorrectionshouldbe
made for patient weight and organ mass when actual organ weights are obtained by CTͲimaging
(Rajendranetal.,2004).TheresidencetimesforeachsourceorganwillbecorrectedinOLINDAͲEXM
using actual organ mass and patient weight.  Actual patient weights and organ sizes vary among
patients,butwecancorrectforthosedifferencesusingactualorganmassesfromCTvolumetrics.
 
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g. EstimateofDosetoTestes
Werecognizethatfree111Inmaydepositinthetestesduetonaturalbiokineticprocesses,butthat90Y
maynot.Therefore,wewillbecarefulnottoattributecountsfrom 111Ininthetestesto 90Yduring
therapy.
h. EstimateofDosetotheBoneMarrow:
Redmarrowdosimetryisalwayschallenginginradioimmunotherapybecauseitisdifficulttoassessthe
highly variable concentration of radioactivity in marrow and the mass of red marrow in the patient.
Commonapproachestomarrowdosimetryoftenrelyonunreliableestimatesofradiolabeledantibody
concentrationinredmarroworinredmarrowrelativetotheconcentrationincirculatingbloodorblood
plasma.Ratherthanmeasurebloodplasmaactivityandmakeuncertainassumptions,wewillemploy
quantitativeimagingof 111Inindefinedmarrowspaces(acetabulum,sacrum,femoralhead,orlumbar
vertebrae) by direct imaging.  We will also obtain and count a representative bone marrow biopsy
specimeninastandardwellͲtypecounter.WewillplotatimeͲactivitycurvefromthemarrowimaging,
andthenwewillnormalizedthecurvestheknownvaluefromthebiopsyspecimen.Wewillobtaina
residence time by integrating the mathematical function represented by the normalized exponential
obtainedbyleastͲsquaresregressionanalysis.

REFERENCES:APPENDIXD
LoevingerR,BudingerTF,WatsonEEetal.MIRDPrimerforAbsorbedDoseCalculations(revised).New
York:TheSocietyofNuclearMedicine,1991.
FisherDR."RadiationDosimetryforRadioimmunotherapy:AnOverviewofCurrentCapabilitiesand
Limitations."Cancer73(3Suppl):905Ͳ911;1994.
Fisher,DR.“InternalDosimetryforSystemicRadiationTherapy.”Sem.inRad.Oncol.10(2):123Ͳ132;
2000.
FisherDR,MeredithRF,andShenS.“MIRDDoseEstimateReportNo.20:RadiationAbsorbedDose
Estimatesfor111InͲand90YͲIbritumomabTiuxetan(ZevalinTM).”JNuclMed.44(3):465Ͳ474;2009.
RajendranJG,FisherDR,GopalAK,DurackLD,PressOW,andEaryJF.“HighͲdose 131IͲTositumomab
(antiͲCD20)RadioimmunotherapyfornonͲHodgkin'sLymphoma:adjustingradiationabsorbeddoseto
actualorganvolumes.”J.Nucl.Med.45(6):1059Ͳ1064;2004.

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APPENDIXE
PotentialAdverseEventsAssociatedorExpectedwithHematopoieticCellTransplantation

1.Graftversushostdisease:GVHDisamajortoxicityassociatedwiththeinfusionofallogeneicdonor
stemcells.GVHDmaybeacuteorchronicandmayaffectmultipleorgansystems,includingtheskin,
liver,andGItract.

2.Opportunisticinfections,includingviralandfungalinfections,canresultinseverepulmonary,
neurologic,hepaticandotherorgandysfunction,andpossibledeath.

3.Gastrointestinaltoxicity.Nauseaandvomitingcanbeanticipatedduringtheentirecourseofablative
therapy.Mucositisanddiarrheashouldbeexpected.PrednisonecancauseGIbleeding.

4.Cardiactoxicity.Cardiotoxicity(congestiveheartfailure,pericardialeffusion,EKGchanges)is
uncommonlyassociatedwiththechemotherapyagentsandTBIusedintheregimenandthesesequelae
mayprovelethal.

5.Pulmonarytoxicity.Diffuseinterstitialpneumonitisofunknownetiologyanddiffusealveolar
hemorrhageoccurswithsomeregularityafterBMTandinterstitialfibrosisoccursmuchmorerarely.
BotharewellͲdescribedcomplicationsofintensivechemotherapyandTBIregimensandmayprove
lethal.

6.Hepatictoxicity.VenoͲocclusivediseaseoftheliverisacommontoxicityofhighͲdose
chemoradiotherapyandmayresultindeath.CalcineurininhibitorsmaycauseelevationofALT/AST.

7.Renaldysfunction.Chemoradiotherapymayuncommonlycauserenaldysfunction.Morecommonly,
nephrotoxicityresultsfromcalcineurininhibitorsandgenerallyrespondstodosereduction.Rarely,
idiopathicorcalcineurininhibitorͲassociatedhemolyticͲuremicsyndromemayoccurandmaybe
progressiveandfatal.Asyndromeofmoderaterenalinsufficiencyandhemolysishasbeenseen5Ͳ7
monthspostHSCTafterintensivemultiͲagentconditioningplusTBI.

8.Hemorrhagiccystitis,manifestedeitherasgrossormicroscopichematuria,isacommontoxicityafter
highͲdosechemoradiotherapy,butusuallyassociatedwithregimensthatincludecyclophosphamide.
HemorrhagiccystitismaypredisposetoalongͲtermincreasedriskofbladdercancer.

9.Centralnervoussystemtoxicity.RadiationandchemotherapycancauseCNStoxicity,including
seizures,depressedmentalstatus,orleukoencephalopathy.Calcineurininhibitorscancauseseizuresor
otherCNStoxicity.

10.Marrowaplasia.Severeneutropenia,thrombocytopenia,andanemia,isexpectedtooccurfora
periodof7to42daysafterthepretransplantconditioningregimen.Transfusionofplateletsandred
 
IRB Approved 
Document Release Date:12/13/2017
Printed on 12/17/2017


FHCRC Protocol 2468.00 
Page62of62
bloodcellsisexpectedassupportivecare.Transfusionofbloodproductsmaybeassociatedwith
acquisitionofHIVorahepatitisvirus.Neutropeniamayincreasetheriskforacquiringseriousinfection.
ThrombocytopeniamayincreasetheriskoflifeͲthreateninghemorrhage.Hemorrhagicorinfectious
complicationsduringtheexpectedperiodofaplasiamayresultindeath.

11.Miscellaneous.Alopeciaandsterilityareexpectedcomplicationsoftheprogramasawhole.Cataract
developmentispossibleafterTBIand/orsteroids.Deficienciesofgrowthhormone,thyroidhormone,
andsexhormonesarepossibleafterTBI.Calcineurininhibitorscancausetransientgingivalhyperplasia,
tremor,seizure,hypertension,headache,dysesthesiaandhirsutism.Steroidtherapycanalsocontribute
tofluidretention,easybruising,hypertension,asepticnecrosisofboneandincreasedsusceptibilityto
infection.MMFcancausespontaneousabortionsandbirthdefects.Hospitalizationduringconditioning
andrecoveryperiodisexpectedtobe5Ͳ9weeksinduration.

 
IRB Approved 
Document Release Date:12/13/2017
Printed on 12/17/2017