A Phase 1/2a Pilot Study of Intravesical TSD-001 for Treatment of Low-Grade, Stage Ta, Non Muscle Invasive Bladder Cancer
Phase: PHASE1
Conditions: Bladder Cancer Cell Transitional, Non-Muscle Invasive Bladder Cancer, Bladder Cancer, Urinary Bladder, Transitional Cell Carcinoma of the Bladder, Urinary Bladder Neoplasms, Urologic Neoplasms, Urogenital Neoplasms, Urinary Bladder Diseases, Urologic Diseases
Sponsor: Lipac Oncology LLC

APhase1/2aPilotStudyofIntravesicalTSD-001forTreatment
ofLow-Grade,StageTa,Non-MuscleInvasiveBladderCancer
StudyNumber:TD-001
NCT03081858

ProtocolVersion7.0
Date04FEB2020

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
1

CONFIDENTIAL



StudyProtocol





APhase1/2aPilotStudyofIntravesicalTSD-001forTreatmentof
Low-Grade,StageTa,Non-MuscleInvasiveBladderCancer








StudyNumber:

TD-001
Version


7.0
Date 


04FEB2020
StudyPhase: 

Phase1/2a
InvestigationalProduct:
TSD-001
InvestigationalNewDrug
(IND)/EudraCTNumber: 129419
Indication: 

Non-MuscleInvasiveBladderCancer(NMIBC)
Sponsor:


LIPACOncologyLLC
325SharonParkDrive,Suite739
MenloPark,CA94025-6805
















ComplianceStatement:Thisstudywillbeconductedinaccordancewiththeclinicalresearch
guidelinesestablishedbytheUSCodeofFederalRegulations(CFR)(Title21,Parts50
[includingSubpartD],54,56,and312),andtheregulationsandguidelinesoftheInternational
ConferenceonHarmonisation(ICH)GuidelinesforGoodClinicalPractice(GCP).Study
documentswillbemaintainedinaccordancewithapplicableregulations.
Confidential:Theinformationcontainedinthisprotocolisconfidentialandisintendedforthe
useofclinicalinvestigators.ItisthepropertyofLIPACoritssubsidiariesandshouldnotbe
copiedbyordistributedtopersonsnotinvolvedintheclinicalinvestigationofTSD-001,unless
suchpersonsareboundbyaconfidentialityagreementwithLIPACoritssubsidiaries.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
2

CONFIDENTIAL

PROTOCOLAPPROVALSIGNATUREPAGE
I,theundersigned,havereviewedthisstudyprotocol,andIagreetoconductthisstudyin
accordancewiththeInternationalConferenceonHarmonisation(ICH)guidelinesonGood
ClinicalPractice(GCP);theethicalprinciplessetforthintheDeclarationofHelsinki;theUnited
States(US)CodeofFederalRegulations(CFR)governingtheprotectionofhumansubjects
(21CFRPart50),financialdisclosurebyclinicalinvestigators(21CFRPart54),Institutional
ReviewBoards(21CFRPart56),andtheobligationsofclinicalinvestigators(21CFRPart312);
andotherapplicablelocalregulatoryrequirements.
TheprotocolmaynotbemodifiedwithoutwrittenapprovaloftheSponsor.Allchangestothe
protocolmustbesubmittedtotheapplicableregulatoryauthoritiesandInstitutionalReview
Board(IRB),andmustbeapprovedbytheIRBpriortoimplementationexceptwhennecessary
toeliminateimmediatehazardstothesubjectsorwhenthechange(s),asdeemedbytheSponsor,
involvesonlylogisticaloradministrativechanges.DocumentationofIRBapprovalmustbesent
totheSponsorimmediatelyuponreceipt.
IhavereadthisprotocolinitsentiretyandIagreetoallaspects.

Investigator(s)


______________________________
PrincipalInvestigatorSignature

InvestigatorPrintedName:_____________________________
Date:_______________

Institution/Location:





LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
4

CONFIDENTIAL
TABLEOFCONTENTS
PROTOCOLAPPROVALSIGNATUREPAGE...........................................................................2
TABLEOFCONTENTS.................................................................................................................4
LISTOFTABLES...........................................................................................................................7
LISTOFABBREVIATIONS..........................................................................................................8
1.
SYNOPSIS...................................................................................................................9
2.
SCHEDULEOFEVENTS.........................................................................................17
3.
INTRODUCTIONANDSTUDYRATIONALE......................................................24
4.
STUDYOBJECTIVES..............................................................................................26
5.
INVESTIGATIONALPLAN.....................................................................................28
5.1.
OverallDesignandPlanoftheStudy.........................................................................28
6.
SELECTIONOFSTUDYPOPULATION................................................................32
6.1.
InclusionCriteria........................................................................................................32
6.2.
ExclusionCriteria.......................................................................................................33
7.
TREATMENTS..........................................................................................................35
7.1.
DescriptionofTreatmentPreparation........................................................................35
7.1.1.
PackagingandLabeling..............................................................................................35
7.1.2.
StorageandAccountability.........................................................................................35
7.2.
StudyDrugDosingRules...........................................................................................35
7.3.
MethodofAssigningSubjectstoPart,Cohort,andDosingLevels...........................37
7.4.
Blinding......................................................................................................................37
7.5.
Prior/ConcomitantMedicationandTherapy..............................................................38
7.6.
ReliableMethodsofBirthControl.............................................................................38
7.7.
GeneralandDietaryRestrictions................................................................................38
7.8.
TreatmentCompliance................................................................................................39
8.
STUDYPROCEDURES............................................................................................40
8.1.
Screening....................................................................................................................40
8.1.1.
TURBT.......................................................................................................................41
8.1.2.
MarkerLesion(forPart2)..........................................................................................41
8.2.
StudyProcedures/Visits..............................................................................................42
8.2.1.
Enrollment..................................................................................................................42

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
5

CONFIDENTIAL
8.2.2.
Treatment....................................................................................................................42
8.2.3.
OtherStudyProcedures..............................................................................................44
8.3.
Exit/WithdrawalfromPart1/Part2............................................................................44
8.4.
Part3(Surveillance)Visits.........................................................................................45
8.5.
Unscheduled...............................................................................................................46
9.
EFFICACYANDSAFETYASSESSMENTS..........................................................47
9.1.
MethodsofAssessment/Evaluations..........................................................................47
9.1.1.
PrimaryEndpoint........................................................................................................47
9.1.2.
SecondaryEndpoints..................................................................................................47
9.2.
PharmacokineticParameters.......................................................................................47
9.3.
SafetyParameters.......................................................................................................48
9.3.1.
AdverseEvents...........................................................................................................48
9.3.2.
LaboratoryMeasurementsandVariables...................................................................51
9.3.3.
OtherSafetyParameters.............................................................................................52
9.4.
AppropriatenessofMeasurements.............................................................................53
10.
DATAQUALITYASSURANCE..............................................................................54
10.1.
DataCollection...........................................................................................................54
10.1.1.
Confidentiality/Property.............................................................................................54
10.1.2.
RetentionofRecords..................................................................................................54
10.1.3.
RoutineMonitoring....................................................................................................55
10.1.4.
SiteAudits..................................................................................................................55
10.2.
DatabaseManagementandQualityControl...............................................................56
11.
STATISTICALMETHODSANDDETERMINATIONOFSAMPLESIZE...........57
11.1.
StatisticalandAnalyticalPlan....................................................................................57
11.1.1.
GeneralConsiderations...............................................................................................57
11.1.2.
HandlingofMissingData...........................................................................................57
11.1.3.
AnalysisPopulations..................................................................................................58
11.1.4.
DemographyandBaselineCharacteristics.................................................................58
11.1.5.
EfficacyParameters....................................................................................................58
11.1.6.
SafetyParameters.......................................................................................................59
11.1.7.
PharmacokineticAssessments....................................................................................59
11.2.
InterimAnalyses.........................................................................................................59

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
6

CONFIDENTIAL
11.3.
DeterminationofSampleSize....................................................................................59
12.
ETHICALANDADMINISTRATIVERESPONSIBILITIES..................................60
13.
REFERENCES...........................................................................................................61
14.
APPENDICES............................................................................................................62
APPENDIX1. STUDYADMINISTRATIONANDETHICALCONSIDERATIONS............63
14.1.
InvestigatorsandStudyAdministrativeStructure......................................................63
14.2.
InstitutionalReviewBoard(IRB)Approval...............................................................63
14.3.
EthicalConductoftheStudy......................................................................................64
14.4.
SubjectInformationandConsent...............................................................................64
14.5.
SubjectConfidentiality...............................................................................................64
14.6.
StudyMonitoring........................................................................................................65
14.7.
CaseReportFormsandStudyRecords......................................................................65
14.8.
DataMonitoringCommittee.......................................................................................65
14.9.
TerminationoftheStudy............................................................................................65
14.10.
FinancialDisclosure...................................................................................................66
14.11.
PublicationandDisclosurePolicy..............................................................................66
APPENDIX2. INTERNATIONALPROSTATESYMPTOMSCORE(IPSS)........................67
APPENDIX3. OVERACTIVEBLADDERQUESTIONNAIRE(OAB-Q).............................70
APPENDIX4. DOSEESCALATIONRULES..........................................................................71






LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
7

CONFIDENTIAL
LISTOFTABLES
Table1:
Part1ScheduleofAssessments.................................................................................17
Table2:
Part2Cohort1ScheduleofAssessments..................................................................19
Table3:
Part2Cohort2ScheduleofAssessments..................................................................21
Table4:
SurveillanceScheduleofAssessments(Part3)..........................................................23
Table5:
Protocol-RequiredSafetyLaboratoryAssessments...................................................52



LISTOFFIGURES
Figure1:
OverviewofStudyDesign..........................................................................................29
Figure2:
DiagramoftheAdaptiveAcceleratedIndividualDose-escalationSchedule
forPart1andDoseAssignmentforPart2:................................................................36
Figure3:
DiagramoftheAdaptiveAcceleratedIndividualDose-escalationSchedule
forPart1andDoseAssignmentforPart2.................................................................71















LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
8

CONFIDENTIAL
LISTOFABBREVIATIONS

Abbreviationorspecialistterm
Explanation
AE
adverseevent
BCG
BacillusCalmette-Guérin
CFR
CodeofFederalRegulations
CIS
carcinomainsitu
CTCAE
CommonTerminologyCriteriaforAdverseEvents
DLT
dose-limitingtoxicity
ECG
electrocardiogram
eCRF
electroniccasereportform
FDA
FoodandDrugAdministration
HgbA1c
glycatedhemoglobin
ICH
InternationalConferenceonHarmonisation
IPSS
InternationalProstateSymptomScore
IRB
InstitutionalReviewBoard
LIPAC
LIPACOncologyLLC
MDD
maximumdeliverabledose
MITT
modifiedintent-to-treat(population)
MTD
maximumtolerateddose
NCI
NationalCancerInstitute
NMIBC
non-muscleinvasivebladdercancer
OAB-q
OveractiveBladderQuestionnaire
PK
pharmacokinetic(s)
PP
perprotocol(population)
SAE
seriousadverseevent
SAP
statisticalanalysisplan
SWFI
sterilewaterforinjection
Ta
noninvasivepapillarycarcinoma
TCC
transitionalcellcarcinoma
Tis
carcinomainsitu
TURBT
transurethralresectionofbladdertumor
US
UnitedStates
WHO
WorldHealthOrganization

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
9

CONFIDENTIAL
1.
SYNOPSIS
Sponsor:
NameofMedicalProduct:
ActiveIngredient:
LIPACOncologyLLC
TSD-001
PaclitaxelUnitedStates
Pharmacopeia(USP)
StudyTitle:APhase1/2aPilotStudyofIntravesicalTSD-001forTreatmentofLow-Grade,
StageTa,Non-MuscleInvasiveBladderCancer
StudyCenter(s):ThisisamulticenterstudythatwillbeconductedintheUnitedStates.
StudyDuration:
StudyPhase:
Part1– upto20weeks(upto4-weekscreeningperiod,
10-weektreatmentperiod,and6-weekfollow-upperiod)
Part2Cohort1–upto17weeks(upto4-weekscreening
period,5-weektreatmentperiod,and8-weekfollow-upperiod).
Part2Cohort2–upto20weeks(upto4-weekscreening
period,7-weektreatmentperiod,and9-weekfollow-upperiod).
Part3–Standard-of-carecystoscopicsurveillanceevery
3monthsforupto24monthsfrominitialinstillation.
1/2a
(phase1portionisfirstin
human)
StudyObjectives:
Theprimaryobjectiveofpart1istoestablishthemaximumtolerateddose(MTD),definedas
thedoseimmediatelyprecedingthedoseatwhichdose-limitingtoxicity(DLT)occursorwhen
amaximumdeliverabledose(MDD)isdetermined.
Thesecondaryobjectivesofpart1aretodeterminepaclitaxelpharmacokinetic(PK)
concentrationsintheurineandtheperipheralbloodatallTSD-001doses.
Exploratoryobjectivesofpart1includeevaluationofthechangefrombaselinetoWeek16in
InternationalProstateSymptomScore(IPSS)(menonly)andOveractiveBladder
Questionnaire(OAB-q).
Theprimaryobjectiveofpart2istoassessthemarkerlesionresponserateusingthe
MTD/MDDestablishedinpart1.
Thesecondaryobjectivesofpart2areto:1)determinepaclitaxelPKconcentrationsinthe
peripheralbloodbeforeandafterthethirdintravesicalexposuretoTSD-001;and
2)characterizetheseverityandfrequencyofadverseevents(AEs)followingintravesical
administrationofTSD-001attheMTD/MDDestablishedinpart1,asdefinedaccordingtothe
NationalCancerInstitute(NCI)CommonTerminologyCriteriaforAdverseEvents(CTCAE)
Version5.0.
Exploratoryobjectivesofpart2includechangefrombaselinetotheendofthetreatmentpart
inIPSS(menonly)andOAB-qscoresandpaclitaxellevelsinvoidedurinesamplesat24,48,
and72hoursafterthethirdinstillationofTSD-001.
Theexploratoryobjectiveofpart3(surveillance)istodetermineratesofdisease-free(i.e.,no
histologicaltissuediagnosisevidenceofrecurrence)survivalofsubjectsexposedtoTSD-001
inpart1orpart2.Histologicaltissuediagnosisevidenceisidentificationofanyurothelial
carcinoma(i.e.,transitionalcellcarcinoma[TCC]),includingallgradesandstages.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
10

CONFIDENTIAL
Cystoscopicsurveillancewillbeperformedasstandardofcareapproximatelyevery3months
fromlastendoscopicassessmentinpart1orpart2until24months(frominitialinstillation).
Methodology:
Thisisasingle-arm,phase1/2astudyofformulatedpaclitaxelinsubjectswithlow-grade,
noninvasivepapillarycarcinoma(stageTa)ofthebladder.Subjecteligibilitywillbe
determinedduringthescreeningperiod,andwillenrolllow-grade,stageTanon-muscle
invasivebladdercancer(NMIBC).Followingscreening,part1ofthestudywillenroll
6subjects(3percohort)withlow-grade(WHO,2004)(i.e.,grade1[G1]andorgrade2[G2],
[WHO,1973]),uni-ormultifocal,stageTaTCCofthebladderwhowillreceiveescalating
dosesofpaclitaxelformulatedasTSD-001every2weeksfor6treatments.Part2cohort1of
thestudywillenrollatleast5subjectswithlow-grade,stageTaTCCofthebladderwhowill
receiveweeklyTSD-001for6administrationsatthehighestnontoxicdoseestablishedin
part1ofthestudy.Part2cohort2ofthestudywillenrollupto10subjectswithlow-grade,
stageTaTCCofthebladderwhowillreceiveweeklyTSD-001for8administrationsatthe
highestnontoxicdoseestablishedinpart1ofthestudy.Subjectswhoreceiveatleasttwo
treatmentsinpart1orpart2maybefollowedfurtherwithstandard-of-carecystoscopic
surveillanceinpart3.Theobjectiveofpart3istodetermineratesofdisease-free(no
histologicaltissuediagnosisevidenceofrecurrence)survivalofsubjectsexposedtoTSD-001
inpart1orpart2.
Thestudyhasatotalof17plannedclinicvisitsforpart1and14plannedclinicvisitsfor
part2cohort1subjectsand16plannedclinicvisitsforpart2cohort2subjects.Part3hasan
additional7plannedclinicvisits.
Potentialsubjectswillundergoscreeningandoncequalifiedwillthenreceiveintravesical
instillationsofTSD-001.Inpart1,TSD-001exposurewillbeginnosoonerthan12days
(±2days)afterthetransurethralresectionofbladdertumor(TURBT)procedure.Inpart2,
TSD-001exposurewillbeginimmediately(≤120minutes)aftercompletionofTURBToras
scheduledforsubjectsnotundergoingTURBT(i.e.,solitarytumorsubjects).
PaclitaxelPKconcentrationsinurineandperipheralbloodwillbeobtainedat
15(±15)minutespre-instillationand2hours±10minutespost-instillationforeachTSD-001
intravesicalexposureaccordingtothescheduleofevents.
Forpart2cohort1subjects,themarkerlesionresponseratewillbedetermined12weeks
(±7days)afterDay1(i.e.,7weeks[±7days]afterthelastintravesicalinstillation),via
cystoscopy,cytology,andbiopsyundergeneral/regionalanesthesia.ForPart2cohort2
subjects,themarkerlesionresponseratewillbedetermined15weeks(±7days)afterDay1
(i.e.,8weeks[±7days]afterthelastintravesicalinstillation).Completemarkerlesion
responserequiresnoevidenceofTCConcystoscope-directedbiopsy.Partialresponseisat
leasta30%decreaseinmarkerlesionsize(Eisenhaueretal.,2009).
TheseverityandfrequencyofAEswillbeassessedintheweeksfollowingTSD-001
administrationanddefinedaccordingtotheCTCAE(Version5.0).
Forpart1ofthetrial,anadaptivetitrationdesignwithanintra-subjectdoseescalationscheme
willbeusedtoestablishtheMTD.Forthefirst3subjects,theinitialdosewillbe10mgin

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
11

CONFIDENTIAL
sterilewaterforinjection(SWFI).UnlessDLTisobserved,subsequentintravesicaldoseswill
beincreasedevery14daysaccordingtothefollowingschedule:25,50,75,100,150mg.The
startingdoseforallsubsequentstudysubjectswillbedeterminedbasedontheMTD/MDD
observedinsubjectsexposedtoTSD-001;MTDisestablishedbythepresenceorabsenceof
DLT(seeSection7.2fordetails).
Ifgrade2toxicityisobservedandresolvesorimprovestograde1,theintravesicaldosetobe
administered14dayslaterinthesubjectwithgrade2toxicitywillbereducedaccordingtothe
rulesestablishedinSection7.2.
TheconcentrationofpaclitaxelinTSD-001isdynamicoverthecourseofintravesicaldwell
timebasedontherateofurineproductionandonthereconstitutioninstructionsforeachdose.
Theprimaryendpointofpart1istodeterminetheMTD,definedasthedoseimmediately
precedingthedoseatwhichDLToccursorwhenaMDDisdeterminedinthedoseescalation
schemedescribedbelowwithoutanyDLT.
Dose-limitingtoxicityisdefinedasanytoxiceffectpotentiallyrelatedtodrugthatis
consideredunacceptableandlimitsfurtherdoseescalation.Specifically,DLTwillbedefined
byanygrade3or4(G3orG4)orprolonged(greaterthan14days)grade2CTCAEtoxicity
relatedtostudydrug.IfnoG3orG4(orprolongedgrade2)CTCAEtoxicityrelatedtostudy
drugisobserved,MTDwillbedefinedbythedosejustbeforethedoseatwhich˃33%ofthe
studysubjectsexperienceG2CTCAEtoxicityrelatedtostudydrug.IfnoDLTisobservedin
thefirst6subjectsaftertitration,then360mgwillbethedoserecommendedforpart2ofthe
study,asthispaclitaxelconcentrationissubstantiallyhigherthanthehalf-maximalinhibitory
concentration(IC50)observedinbladdercancercelllinesexposedtoTSD-001.
Subjectsinpart2cohort1willreceiveintravesicalinstillationsofTSD-001viasterileurethral
catheterizationoftheurinarybladderattheMTD/MDDestablishedinpart1atweekly
intervalsfor6consecutiveweeks.Subjectsinpart2cohort2willreceiveintravesical
instillationsofTSD-001atweeklyintervalsfor8consecutiveweeks.Thefirstinstillationof
TSD-001willbeimmediately(≤120minutes)post-TURBTorasscheduledforsubjectsnot
undergoingTURBT(i.e.,solitarytumorsubjects).Theinstillationwillberetainedinthe
bladderfor2hours(1hourormorewillbeacceptable,dependingonsubject’stolerabilityof
theprocedure).WhenlocalAEsoccur,treatmentmaybedelayed(upto14days)and/orthe
dosereduced(perrulesdetailedinSection7.2)attheinvestigator’sdiscretion.
PaclitaxelPKconcentrationmeasurementsofperipheralbloodduringpart2willbeobtained
2hours(±10minutes)afterthefirstintravesicalinstillation,and15minutes(±15minutes)
beforeand2hours(±10minutes)afterthethirdintravesicalinstillation.Paclitaxellevelswill
alsobemeasuredinvoidedurinesamplesat24,48,and72hoursafterthethirdinstillationof
TSD-001.
Subjectquestionnaires(IPSS[menonly]andOAB-q)willbeadministeredatbaseline
enrollment,dayoflasttreatment,andattheendofthetreatmentpart.Safetyanalyseswillbe
performedondatacollectedthroughoutthestudy.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
12

CONFIDENTIAL
DiagnosisandInclusionCriteria:
Thesecriteriaapplytostudyentryintopart1orpart2.Subjectshavetomeetallofthe
followinginclusioncriteria:
1. 18to85yearsofageattimeofstudyenrollment.
2. Abletomeettherequirementsofthestudy;givevoluntary,writteninformed
consent;andadheretodosingandvisitschedules.
3. Hasadiagnosisoflowgrade(WHO,2004)(i.e.,G1orG2[WHO,1973]),
uni-ormultifocalpapillary-appearingbladdertumor,stageTa.Inpart2,a
subjectmeetsthisinclusionwithoutthishistologicaltissuediagnosisifon
cystoscopicassessmenttheyhaveasolitarypapillarytumor(≥0.5cmand
≤2.0cmindiameter).
4. Forpart1,subjectwillhave≥1and≤5tumors(priortoTURBT),noneof
whichexceeds3.0cmindiameter;forpart2,patientwillhave≥2and
≤5tumors(priortoTURBT),noneofwhichexceeds3.0cmindiameter
(resectionloop~1cm),OR,forpart2,subjectmeetsthisinclusioncriterion
ifoncystoscopicassessmenttheyhaveasolitarypapillarytumor(≥0.5cm
and≤2.0cmindiameter).
5. SubjectissurgicalcandidateforTURBTaspartofnormalNMIBCtreatment
plan.Forpart1,successfulcompletionofTURBTprocedure.Forpart2,
successfulcompletionofcystoscopicassessment/TURBTprocedurewith
onemarkerlesionleftintact;themarkerlesionshouldbe≥0.5cmand≤2.0cm
indiameter.
6. EasternCooperativeOncologyGroup(ECOG)performancestatusof0or1.
7. Peripheralneuropathygrade1orless(NCICTCAEVersion5.0).
8. Adequatehematological,hepatic,andrenalparameters;i.e.,hemoglobin
>10g/dL,creatinine<3.5mg/dL,bilirubin<1.5mg/dL,aspartate
aminotransferase<50U/L,alanineaminotransferase<50U/L,andalkaline
phosphatase<130U/L.
9. Allsexuallyactivesubjectsofreproductivepotentialarerequiredtouseor
startusingareliablemethodofbirthcontrolatleast2weekspriortostudy
enrollment,throughoutthetreatmentpart,andforatleast3monthsfollowing
completionofstudydrugtreatment.Areliablemethodofbirthcontrolis
definedinSection7.6.
10.Femalesofchildbearingpotentialmusthaveanegativepregnancytestwithin
30dayspriortoenrollment.Femaleswhoarepostmenopausalforatleast
1year(definedasmorethan12monthssincelastmenses)oraresurgically
sterilizeddonotrequirethistest.
11.Adequatevenousaccesstoallowcollectionofbloodsamplesby
venipuncture.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
13

CONFIDENTIAL
12.Formalesubjects,thedigitalrectalexaminationmustnotbesuspiciousfor
carcinomaoftheprostate.
13.Abletoretainbladderinstillationsforupto120minutes(±15minutes).
Thesecriteriaapplytostudyentryintopart1orpart2.Potentialstudysubjectswillbe
excludedifone(ormore)ofthefollowingexclusioncriteriaispresent:
1. Hasanactiveconcurrentmalignancy/life-threateningdisease.Ifthereisa
historyofpriormalignancies/life-threateningdiseases,thesubjectistobe
diseasefreeforatleast5years.Subjectswithotherpriormalignancieslessthan
5yearsbeforestudyentrymaystillbeenrollediftheyhavereceivedtreatment
resultingincompleteresolutionofthecancerandcurrentlyhavenoclinical,
radiologic,orlaboratoryevidenceofactiveorrecurrentdisease.Subjectswill
notbeexcludedforrecurrentNMIBC,basalorsquamouscellskincancers,or
noninvasivecancerofthecervix.
2. Haspositiveurinecytologyforurothelialmalignancy(i.e.,high-grade)at
screening.
3. HasCisorT1transitionalcellcarcinoma(TCC).
4. HasBacillusCalmette-Guérin(BCG)-refractoryTCC.
5. Hasanactiveuncontrolledinfection,includingaurinarytractinfection,
underlyingmedicalcondition(e.g.,systolicbloodpressure≥160mmHg
and/ordiastolicbloodpressure≥92mmHg),orotherseriousillnessthat
wouldimpairtheabilityofthesubjecttoreceiveprotocoltreatment.
6. Previousintravesicaltherapy(e.g.,BCG,mitomycinC,chemotherapeuticagent)
within6monthsofstudyentry.
7. Participatedinapreviousclinicaltrialorusedanyinvestigationaldrugs,
biologics,ordeviceswithin90dayspriortostudytreatmentorplanstouse
anyoftheseduringthecourseofthestudy.
8. Hashadanypreviousexposuretopaclitaxelordocetaxelinthelast5years.
9. Hasorhaseverhad:uppertractTCC;urethraltumor(prostaticurethra
included);anyinvasivebladdertumor(T2orgreater);anyevidenceoflymph
nodeordistantmetastasis;anybladdertumorwithhistologyotherthanTCC.
10.Hasatumorinabladderdiverticulum.
11.Concurrenttreatmentwithanychemotherapeuticagent.
12.Historyofvesicoureteralreflux.
13.Anindwellingureteralstent.
14.Hasreceivedanypelvicradiotherapy(includingexternalbeamand/or
brachytherapy).
15.Hasableedingdisorderorascreeningplateletcount<100×109/L.
16.Hasanyunstablemedicalconditionthatwouldmakeitunsafetoundergo

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
14

CONFIDENTIAL
TURBTorreceiveinstillation(e.g.,presenceofuncontrolledgross
hematuria).Subjectexperiencedanyprocedure-relatedadverseeffectduring
TURBTthat,intheopinionoftheinvestigator,wouldputthesubjectat
unacceptablerisktoreceiveintravesicaltreatmentorparticipateinthestudy
(e.g.,bladderperforation).
17.Hasanactivediagnosisofinterstitialcystitis.
18.Forsubjectswithrecurrenttumor,thesubjectdidnothaveatleasta6-month
cystoscopicallyconfirmedtumor-freeintervalbetweenthelasttumor
recurrenceandscreeningcystoscopicexamination.
19.Femalesofchildbearingpotentialwhoarenursing,pregnant,intendingto
becomepregnant,orintendingtonurseduringthetimeofthestudy,orwho
haveapositivepregnancytestatbaseline.
20.Currentlyseekingtofatherachildorisseekingfertilitywithinoneyearof
trialparticipation.
21.Presenceofpoorlycontrolleddiabetesmellitus(glycatedhemoglobin
[HgbA1c]>9.0%).
22.Clinicallysignificantco-morbidconditionsthatwouldinterferewiththe
subject’sparticipationorcompromisethesubject’ssafety.
23.Anysignificanthistoryofallergyand/orsensitivitytothedrugproductsor
theirexcipients,includinganyhistoryofsensitivitytopaclitaxel.
24.Undergonesurgeryorhadamedicalconditionthatinthejudgmentofthe
principalinvestigatorplacesthesubjectatunacceptablerisktoparticipatein
thestudy.
25.Anycontraindicationtobloodsampling.
26.Intenttohaveanelectivesurgicalprocedure(otherthanTURBT)duringthe
courseofthetrial.
27.Donatedbloodorbloodproductsorhadasignificantlossofbloodwithin
90daysbeforedosing.
28.Donatedbonemarrowwithin6monthsbeforedosing.
29.Positiveurinedrugscreenorhistoryofdrugoralcoholabuseinthepast
6months.
30.Anyconditionthattheinvestigatorbelieveswouldinterferewiththeintentof
thisstudyorwouldmakeparticipationnotinthebestinterestsofthesubject.
NumberofSubjects(planned):Anenrollmentofupto21subjectsisplanned,with
6subjectsinpart1andupto15additionalsubjectsinpart2(atleast5incohort1andupto
10incohort2).Anysubjectthatreceivesatleasttwotreatmentsinpart1orpart2iseligible
forsurveillanceinpart3.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
15

CONFIDENTIAL
TestProduct,Dose,andModeofAdministration:
ThetestproductisTSD-001(PaclitaxelUSP)administeredviaintravesicalinstillation.In
part1,thestudydrugstartingdoseforthefirstthreesubjects(cohort1)willbe10mg,and
increasedaccordingtotheschedule(25,50,75,100,150mg)every2weeks,oruntilDLTis
reached,foratotalof6intravesicalinstillationsviaurethralcatheterization.Thestudydrug
startingdoseforthenextthreesubjectsinpart1(cohort2)willbe90mg,andincreased
accordingtotheschedule(180,270,360,450,540mg).Thestudydrugdosewillbeup-or
down-titratedperprotocol(seeSection7.2).Forsubjectsinpart2cohort1,theMTDorMDD
willbeadministeredevery7daysfor6consecutiveintravesicaladministrationsviaurethral
catheterization.Forsubjectsinpart2cohort2,theMTDorMDDwillbeadministeredevery
7daysfor8consecutiveadministrations.
CriteriaforEvaluation:
Theprimaryendpointforpart1istheMTD,definedasthedoseimmediatelyprecedingthe
doseatwhichdose-limitingtoxicity(DLT)occursorwhenamaximumdeliverabledose
(MDD)isdetermined.TheseverityandfrequencyofAEswillbeassessedintheweeks
followingTSD-001administration,anddefinedaccordingtoCTCAE.
Thesecondaryendpointsforpart1aretodeterminepaclitaxelconcentrationsintheurineand
theperipheralbloodatallTSD-001doses.
Exploratoryendpointforpart1includeevaluationofthechangefrombaselinetoWeek16in
IPSS(menonly)andOAB-qscores.
Theprimaryendpointofpart2isthemarkerlesionresponserateusingtheMTD/MDD
establishedinpart1.
Thesecondaryendpointsofpart2areto:1)determinepaclitaxelPKconcentrationsinthe
peripheralblood;and2)characterizetheseverityandfrequencyofAEsfollowingintravesical
administrationofTSD-001attheMTD/MDDestablishedinpart1,asdefinedaccordingto
CTCAE.
Exploratoryendpointsofpart2includechangefrombaselinetotheendofthetreatmentpart
inIPSS(menonly)andOAB-qscoresandpaclitaxellevelsinvoidedurinesamplesat24,48,
and72hoursafterthethirdinstillationofTSD-001.
Theexploratoryendpointofpart3(surveillance)willbedisease-freesurvivalofsubjects
exposedtoTSD-001inpart1orpart2.Theendpointwillbeatimetoevent(recurrence)
aftertheTURBT(Day-12inPart1)oraftercompleteresponseorWeek12TURBTinPart2.
Cystoscopicsurveillanceasperstandardofcarewillbeperformedapproximatelyevery
3monthsfromlastendoscopicassessmentinpart1orpart2until24months(frominitial
instillation).Disease-freesurvivalwillbedefinedasnohistologicaltissuediagnosisevidence
ofrecurrence.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020
LIPACOncologyLLC
16

CONFIDENTIAL
StatisticalMethods:
Allefficacyanalyseswillbeconductedbasedonthemodifiedintent-to-treat(MITT)
populationaswellastheperprotocol(PP)population.Allsafetyanalyseswillbeconducted
onthesafetypopulation.Additionalexploratoryanalysesofthedatamaybeconductedas
appropriate.Unlessotherwisestated,alltestsofsignificancewillbeperformedatalpha=0.05,
two-sided.Allstudydata,includingdatanotappearingintables,willbepresentedin
by-subjectdatalistings.Descriptivestatistics(numberofsubjects,mean,standarddeviation,
standarderrorofthemean,coefficientofvariation,minimum,median,andmaximumvalues)
willbepresentedforcontinuousvariablesbytreatmentgroupandtimepoint(ifapplicable).
Categoricalvariableswillbesummarizedusingnumberandpercentageofsubjectspercategory
foreachtreatmentgroupandtimepoint(ifapplicable).



LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
17

CONFIDENTIAL

2.
SCHEDULEOFEVENTS
Table1:
Part1ScheduleofAssessments
Visit
Screening
Day
-12
Day
1
Day
8
Week
1
Day
15
Week
2
Day
22
Week
3
Day
29
Week
4
Day
36
Week
5
Day
43
Week
6
Day
50
Week
7
Day
57
Week
8
Day
64
Week
9
Day
71
Week
10
Day
78
Week
11
Day
99
Week
14
Day
106
Week
15
Day
113
Week
16
VisitWindow

≤28days
beforeDay1
±2
days
N/A
±1
day
±1
day
±1
day
±2
days
±2
days
±2
days
±2
days
±2
days
±2
days
±2
days
±2
days
±7
days
±7
days
±7
days
Informedconsent
X
















Subjectdemographics
X
















Eligibilitycriteria
X
X
X














Medical/surgicalhistory
X
















HemoglobinA1c
X
















Weightandheight
X















X
Drugscreen
X















X
UrinalysiswithpH1
X

X

X

X

X

X

X



X
Pregnancytest(urine)2
X

X













X
12-leadECG1
X















X
Vitalsigns(BP,HR,RR,BT)1
X

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physicalexamination1
X















X
Chemistrypanel(fasted
≥2hours)1
X





X









X
Hematologypanel1
X

X
X
X
X
X
X
X
X
X
X
X
X


X
Prior/concurrentmedication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopicassessment3
X7
X8











X9



Enrollment


X














Administerstudydrug4


X

X

X

X

X

X




Adverseevents
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Paclitaxellevelplasma5


X

X

X

X

X

X




Paclitaxellevelurine6


X

X

X

X

X

X




IPSS,OAB-q
X











X



X
Treatmentexit10
















X

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
18

CONFIDENTIAL

BP=bloodpressure;BT=bodytemperature;ECG=electrocardiogram;HR=heartrate;IPSS=InternationalProstateSymptomScore(menonly);N/A=not
applicable;OAB-q=OveractiveBladderQuestionnaire;RR=respiratoryrate;TURBT=transurethralresectionofbladdertumor
1. Mayalsobeperformedatprincipalinvestigator’sdiscretionatanyvisit(includingunscheduledvisits).
2. Forwomenofchildbearingpotential.
3. EndoscopicassessmentincludesTURBT(Day-12),voidedcytology(screening/Day78),and/orcystoscopy(screening/Day78).
4. Studydrugisadministeredintravesicallyusingsterileurethralcatheter.Intravesicaldwelltime=2hours(1hourormorewillbeacceptable,dependingon
subject’stolerabilityoftheprocedure).Forstudydoseescalation,studydrugreconstitution,andadministrationinstructions,seeSection7andSection8.
5. Peripheralvenousbloodwillbeobtained15±15minutesbefore,and2hours±10minutesafter,intravesicalinstillationofTSD-001.
6. Urine(duplicatealiquotsviacatheterizedorvoided)willbeobtained15±15minutesbefore,and2hours±10minutesafter,intravesicalinstillationof
TSD-001.UrinepHwillbemeasuredbyurinepHteststripsateachtimepoint.Selectsiteswillmakeobservationsonurineappearance(turbidityand
precipitation).
7. Voidedcytologyandcystoscopywillbeperformedatscreeningvisit.Positivecytologyfindingwillresultinscreenfailure.
8. TURBTtobeperformedonDay-12.
9. Voidedcytologyandcystoscopyperformedinofficeasbladdertumorstandard-of-careatscreeningandDay78±2days.Acystoscopeandvoidedurine
cytologyshouldbeperformedatanyearlytreatmentpartwithdrawalvisitpriortoDay78.
10. Endtreatmentpart,beginsurveillanceportionofstudy(part3).





LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
19

CONFIDENTIAL

Table2:
Part2Cohort1ScheduleofAssessments
Visit
Screening
Day1
Day8
Week1
Day15
Week2
Days
16,17,18
Day22
Week3
Day29
Week4
Day36
Week5
Day43
Week6
Day64
Week9
Day85
Week12
Day92
Week13
VisitWindow

≤28days
beforeDay1
N/A
±1day ±2days

±2days ±2days ±2days ±2days ±7days ±7days ±7days
Obtaininformedconsent
X











Subjectdemographics
X











Eligibilitycriteria
X
X










Medical/surgicalhistory
X











HemoglobinA1c
X











Weightandheight
X










X
Drugscreen
X










X
UrinalysiswithpH1
X
X
X
X

X
X
X



X
Pregnancytest(urine)2
X
X









X
12-leadECG1
X










X
Vitalsigns(BP,HR,RR,BT)1
X
X
X
X
X
X
X
X
X
X
X
X
Physicalexamination1
X










X
Chemistrypanel(fasted≥2hours)1
X










X
Hematologypanel1
X
X
X
X

X
X
X
X


X
Prior/concurrentmedications
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopicassessment3
X7
X8








X9,10

Enrollment

X










Administerstudydrug4

X
X
X

X
X
X




Adverseevents
X
X
X
X
X
X
X
X
X
X
X
X
Paclitaxellevelplasma5

X

X








Paclitaxellevelurine6



X
X







IPSS,OAB-q
X






X



X
Treatmentexit11











X
BP=bloodpressure;BT=bodytemperature;ECG=electrocardiogram;HR=heartrate;IPSS=InternationalProstateSymptomScore(menonly);N/A=not
applicable;OAB-q=OveractiveBladderquestionnaire;RR=respiratoryrate;TURBT=transurethralresectionofbladdertumor
1. Mayalsobeperformedatprincipalinvestigator’sdiscretionatanyvisit(includingunscheduledvisit).
2. Forwomenofchildbearingpotential.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
20

CONFIDENTIAL

3. EndoscopicassessmentincludesTURBT(Day1formultipletumorsubjects),voidedcytology(screening/Day85),cystoscopy(screening/Day85),and/or
biopsyorTURBT(Day85).
4. Studydrugisadministeredintravesicallyusingsterileurethralcatheter.Intravesicaldwelltime=2hours(1hourormorewillbeacceptable,dependingon
subject’stolerabilityoftheprocedure).Forstudydoseescalation,studydrugreconstitutionandadministrationinstructionsseeSection7.
5. Peripheralvenousbloodsampleswillbeobtained2hours±10minutesafterthefirstintravesicalinstillationofTSD-001.Peripheralvenousbloodwill
alsobeobtained15±15minutesbefore,and2hours±10minutesafterthethirdintravesicalinstillationofTSD-001.
 Urine(duplicatealiquotsviacatheterizedorvoided)willbeobtained15±15minutesbefore,and2hours±10minutesafter,thethirdintravesical
instillationofTSD-001only.UrinepHwillbemeasuredbyurinepHteststripsateachtimepoint.Selectsiteswillmakeobservationsonurine
appearance(turbidityandprecipitation).Additionalurinesamplesshouldbeobtainedondays16,17,and18(24,48,and72hours,respectively,
followingthethirddoseofTSD-001).
7. Voidedcytologyandcystoscopywillbeperformedatscreeningvisit.Positivecytologyfindingwillresultinscreenfailure.
8. TURBTtobeperformedonDay1forsubjectsnotmeetingsolitarytumoreligibility;alltumorsexceptthemarkerlesiontumorwillberemovedonDay1.
9. TURBTperformedifevidenceoflesionispresent.
10. OnDay85,ifthereisnocystoscopicevidenceofbladdertumor,biopsymarkerlesionsiteandobtainurinecytology.PerformedatDay85oranyearly
treatmentpartwithdrawalbeforeweek12.
11. Endtreatmentpart,beginsurveillanceportionofstudy(part3).



LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
21

CONFIDENTIAL

Table3:
Part2Cohort2ScheduleofAssessments
Visit
Screening
Day1
Day8
Week1
Day15
Week2
Days16,
17,18
Day22
Week3
Day29
Week4
Day36
Week5
Day43
Week6
Day50
Week7
Day64
Week9
Day85
Week12
Day106
Week15
Day113
Week16
VisitWindow

≤28days
beforeDay1
N/A
±1day ±2days

±2days ±2days ±2days ±2days ±2days ±7days ±7days ±7days ±7days
Obtaininformedconsent
X













Subjectdemographics
X













Eligibilitycriteria
X
X












Medical/surgicalhistory
X













HemoglobinA1c
X













Weightandheight
X












X
Drugscreen
X












X
UrinalysiswithpH1
X
X
X
X

X
X
X
X
X



X
Pregnancytest(urine)2
X
X











X
12-leadECG1
X












X
Vitalsigns(BP,HR,RR,BT)1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physicalexamination1
X












X
Chemistrypanel(fasted
≥2hours)1
X












X
Hematologypanel1
X
X
X
X

X
X
X
X
X
X


X
Prior/concurrentmedications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopicassessment3
X7
X8










X9,10

Enrollment

X












Administerstudydrug4

X
X
X

X
X
X
X
X




Adverseevents
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Paclitaxellevelplasma5

X

X










Paclitaxellevelurine6



X
X









IPSS,OAB-q
X








X



X
Treatmentexit11













X
BP=bloodpressure;BT=bodytemperature;ECG=electrocardiogram;HR=heartrate;IPSS=InternationalProstateSymptomScore(menonly);N/A=not
applicable;OAB-q=OveractiveBladderquestionnaire;RR=respiratoryrate;TURBT=transurethralresectionofbladdertumor
1. Mayalsobeperformedatprincipalinvestigator’sdiscretionatanyvisit(includingunscheduledvisit).
2. Forwomenofchildbearingpotential.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
22

CONFIDENTIAL

3. EndoscopicassessmentincludesTURBT(Day1formultipletumorsubjects),voidedcytology(screening/Day106),cystoscopy(screening/Day106),and/or
biopsyorTURBT(Day106).
4. Studydrugisadministeredintravesicallyusingsterileurethralcatheter.Intravesicaldwelltime=2hours(1hourormorewillbeacceptable,dependingon
subject’stolerabilityoftheprocedure).Forstudydoseescalation,studydrugreconstitutionandadministrationinstructionsseeSection7.
5. Peripheralvenousbloodsampleswillbeobtained2hours±10minutesafterthefirstintravesicalinstillationofTSD-001.Peripheralvenousbloodwill
alsobeobtained15±15minutesbefore,and2hours±10minutesafterthethirdintravesicalinstillationofTSD-001.
6. Urine(duplicatealiquotsviacatheterizedorvoided)willbeobtained15±15minutesbefore,and2hours±10minutesafter,thethirdintravesical
instillationofTSD-001only.UrinepHwillbemeasuredbyurinepHteststripsateachtimepoint.Selectsiteswillmakeobservationsonurine
appearance(turbidityandprecipitation).Additionalurinesamplesshouldbeobtainedondays16,17,and18(24,48,and72hours,respectively,
followingthethirddoseofTSD-001).
7. Voidedcytologyandcystoscopywillbeperformedatscreeningvisit.Positivecytologyatscreeningwillresultinscreenfailure.
8. TURBTtobeperformedonDay1forsubjectsnotmeetingsolitarytumoreligibility;alltumorsexceptthemarkerlesiontumorwillberemovedonDay1.
9. TURBTperformedifevidenceoflesionispresent.
10. OnDay106,ifthereisnocystoscopicevidenceofbladdertumor,biopsymarkerlesionsiteandobtainurinecytology.PerformedatDay106oranyearly
treatmentpartwithdrawalbeforeWeek15.
11. Endtreatmentpart2,beginsurveillanceportionofstudy(part3).





LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
23

CONFIDENTIAL

Table4:
SurveillanceScheduleofAssessments(Part3)
Visit1
Treatmentpart
exit
Month6
(Day181)
Month9
(Day271)
Month12
(Day366)
Month15
(Day456)
Month18
(Day546
Month21
(Day636)
ExitMonth24
(Day731)
VisitWindow


±7days
±7days
±7days
±7days
±7days
±7days
±7days
Obtaininformedconsent2
X







Cystoscopy

X
X
X
X
X
X
X
Prior/concurrentmedications3
X
X
X
X
X
X
X
X
Adverseevents4/Seriousadverseevents
X
X
X
X
X
X
X
X
Studysurveillanceexit







X
AE=adverseevent;eCRF=electroniccasereportform
1. Visittimingisfrominitialinstillationinprevious(treatment)part(e.g.Month6isapproximately6monthsfromDay1ofpreviouspart).
2. Ifnotpreviouslyobtainedinpart1orpart2,obtaininformedconsentforpart3attreatmentexitvisitorfirstavailablevisitinpart3.
3. OnlyrecordedineCRFiftheyrelatetoanAEcontinuingfrompart1orpart2oratreatmentforarecurrence.
4. AEscontinuedfrompart1orpart2,butnonewAEswillberecorded.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
24

CONFIDENTIAL
3.
INTRODUCTIONANDSTUDYRATIONALE
Morethan74,000newpatientswillbediagnosedwithbladdercancerin2015,ofwhom
approximately16,000willdie(Greenleeetal.,2001).Currentlythereareapproximately
600,000survivorsofbladdercancerintheUnitedStates(Devesaetal.,1995).Non-muscle-
invasivebladdercancer(NMIBC),includingcarcinomainsitu(Tis)aswellasstagesTa
(confinedtourothelium)andT1(invasiveintolaminapropria),accountsforapproximately
70%ofcases(Abel,1988).Whiletheprimarymethodofnon-muscle-invasivebladdertumor
treatmentcontinuestobetransurethralresection,intravesicaltherapyhasbecomeanintegral
componentinthemanagementofNMIBC(FairWR,1993).
Superficialbladdercanceraccountsfor70%to80%ofnewlydiagnosedbladdercancers.
Recurrenceratesafterinitialtreatmentrangefrom30%to85%,withgradeprogressionoccurring
in10%to30%andstageprogressionin4%to30%ofcases(Abel,1988,Devesaetal.,1995).
Theprimarytreatmentforpapillarybladdertumorsthatdonotinvadethemuscularlayer
(stageTaorT1transitional-cellcarcinoma[TCC])istransurethralresectionofthebladdertumor
(TURBT).Resection,fulguration,andlasercoagulationofthesetumorscanbeperformedwith
minimalmorbidity.
Despitecompleteeradicationoftheprimarytumor,approximatelytwo-thirdsofpatientswill
developtumorrecurrenceswithinthefirst5yearsoffollow-up(FairWR,1993).
MostbladdercancersareTCCs.Low-gradetumorshavelesspotentialtoprogresstoinvasive
cancers,buttheyhavea50%to70%chanceofrecurrence.High-gradetumorshavean
approximately20%higherchanceofprogressiontomuscle-invasivediseasethanlow-grade
cancers(FairWR,1993).Thishighrateofrecurrence(andpotentiallyprogression)canbe
reducedwithintravesicaltherapy,althoughnotherapyhasresultedinanimprovementinoverall
survival.
Thegoalofintravesicaltherapyistoreducediseaserecurrenceanditsprogressionto
muscle-invasivebladdercancer.T1tumors,whichinvadethelaminapropria,areanindication
forintravesicaltreatmentbecausepatientswiththesetumorshavea25%to30%riskof
progressiontomuscle-invasivedisease(Leeetal.,2012).Tumorpenetrationintothemuscularis
mucosaisassociatedwitha54%riskofprogression,comparedwitha7%riskwithpenetration
ofthelaminapropria(Sylvesteretal.,2004).ThisisstillconsideredtobeaT1cancer,but
clearlyitcarriesaworseprognosis.Carcinoma-in-situ(CIS)representshigh-gradeanaplasiaof
thesurfacemucosaandisvirtuallyalwaysassociatedwithadjacentlow-gradecancers.Inonly
10%ofcasesisitanisolatedpathologicfinding.Thepotentialfordevelopmentof
muscle-invasivediseaseis42%to83%incasesofCISassociatedwithpapillarytumorsversus
20%to34%whenCISisanisolatedfinding(Cooksonetal.,2012).TheriskofinvasionofCIS
isincreasedifthereiswidespreaddisease.BacillusCalmette-Guérin(BCG)isthemosteffective
regimenforthemanagementofsuperficialdisease,includingCIS.Inalargerandomizedclinical
trial,theuseofmaintenancetherapywithBCGwasshowntodecreasesubsequentrecurrences,
butwithsomeincreaseinsideeffects(Soloway,1988).Todate,BCGhasnotbeen
demonstratedtoprolongoverallsurvivalofpatientswithsuperficialdisease.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
25

CONFIDENTIAL
Patientswhodonotrespondtothisagentrepresentasignificantchallenge.Cliniciansneed
optionstotreatpatientswhodonotrespondtoBCG.Mostrecommendacystectomy,butmany
patientsarenotsurgicalcandidateseitherbecauseofcomorbidconditionsorbecausetheyrefuse
theprocedure.NochemotherapyagenttodatehasproventohaveactivityequivalenttoBCG,
andnoagenthasbeenverysuccessfulintreatingpatientswhodonotrespondtoBCG.
Valrubicinisanintravesicalchemotherapeuticagentthatpossessesminimalactivity,andmore
activealternativesareneeded.
Anadditionalmatteristhelevel1evidenceofreducedrecurrenceafterasinglepostoperative
intravesicalinstillationinlow-grade,stageTadisease(Sylvesteretal.,2004).Inaddition,a
singlepostoperativeinstillationisbothcosteffectiveandenhancesquality-adjustedlife-years
(QALYs)(Leeetal.,2012).Despitetheseadvantages,nointravesicalagentisapprovedfor
immediatepostoperativeinstallationandphysicianadherencetoNationalComprehensiveCancer
Network(NCCN),AmericanUrologicalAssociation(AUA),orEuropeanAssociationof
Urology(EAU)guidelinesismarginal.
ForboththeBCG-recurrentNMIBCpopulationandtheimmediatepostoperativeinstillationof
low-andintermediate-riskNMIBCpatients,aclearneedexistsformoreactivealternatives.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
26

CONFIDENTIAL
4.
STUDYOBJECTIVES
Thisisaphase1/2astudytoevaluatethesafetyofTSD-001,thelocalandsystemicpaclitaxel
pharmacokinetic(PK)concentrationsafterintravesicalexposuretoTSD-001,andthemarker
lesionresponserateafterTSD-001treatmentinsubjectswithlow-grade,stageTaNMIBC.
Theprimaryobjectiveforpart1istoestablishthemaximumtolerateddose(MTD),definedas
thedoseimmediatelyprecedingthedoseatwhichdose-limitingtoxicity(DLT)occursorwhena
maximumdeliverabledose(MDD)isdetermined.Theseverityandfrequencyofadverseevents
(AEs)willbeassessedintheweeksfollowingTSD-001administration,anddefinedaccordingto
theNationalCancerInstitute(NCI)CommonTerminologyCriteriaforAdverseEvents
(CTCAE)Version5.0.
Thesecondaryobjectivesforpart1aretodeterminethelocal(bladderurine)andsystemic
(peripheralblood)paclitaxelPKconcentrationsbeforeandafterintravesicalexposureto
TSD-001atalldoses.Bloodandurinesampleswillbecollected15±15minutesbeforeand
2hours(±10minutes)aftereachinstillation.
Exploratoryobjectivesforpart1includeevaluationofthechangefrombaselinetoWeek16in
InternationalProstateSymptomScore(IPSS)(menonly)andOveractiveBladderQuestionnaire
(OAB-q)scores.
Theprimaryobjectiveforpart2istoassessthemarkerlesionresponserateusingthe
MTD/MDDestablishedinpart1.Forsubjectsincohort1,theassessmentwilloccur12weeks
(±7days)afterDay1(i.e.,7weeks[±7days]afterlastintravesicalTSD-001instillation)atthe
MTD/MDDestablishedinpart1.Subjectsincohort2willhavethemarkerlesionresponserate
determined15weeks(±7days)afterDay1(i.e.,8weeks[±7days]afterthelastintravesical
instillation).
CompletemarkerlesionresponserequiresnoevidenceofTCConcystoscope-directedbiopsy.
Partialresponseisatleasta30%decreaseinmarkerlesionsize(Eisenhaueretal.,2009).
Thesecondaryobjectivesofpart2areto:1)determinethesystemic(peripheralblood)
paclitaxelPKconcentrationsbeforeandafterthethirdintravesicalexposuretoTSD-001atthe
MTD/MDD;and2)characterizetheseverityandfrequencyofAEsattheMTD/MDDfollowing
TSD-001administration,anddefinedaccordingtoCTCAE.
PaclitaxelPKconcentrationmeasurementsofperipheralbloodduringpart2willbeobtained
2hours(±10minutes)afterthefirstintravesicalinstillation,and15minutes(±15minutes)
beforeand2hours(±10minutes)afterthethirdintravesicalexposureofTSD-001atthe
MTD/MDD.
Exploratoryobjectivesofpart2includechangefrombaselinetotheendofthetreatmentpartin
IPSS(menonly)andOAB-qscoresandpaclitaxellevelsinvoidedurinesamplesat24,48,and
72hoursafterthethirdinstillationofTSD-001.
Part1and2safetyassessmentswillbeevaluatedbyanalyzingresultsofAE,laboratorytest,
vitalsigns,electrocardiogram(ECG),andphysicalexaminationassessments.
Theexploratoryobjectiveofpart3(surveillance)istodetermineratesofdisease-freesurvivalof
subjectsexposedtoTSD-001inpart1orpart2.Cystoscopicsurveillancewillbeperformedas
standardofcareapproximatelyevery3monthsfromlastendoscopicassessmentinpart1or

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
27

CONFIDENTIAL
part2until24months(frominitialinstillation).Disease-freesurvivalwillbedefinedasno
histologicaltissuediagnosisevidenceofrecurrence.Histologicaltissuediagnosisevidenceis
anydiagnosisofurothelialcarcinoma(i.e.,TCC),includingallgradesandstages.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
28

CONFIDENTIAL
5.
INVESTIGATIONALPLAN
5.1.
OverallDesignandPlanoftheStudy
Thisisasingle-arm,phase1/2astudyofintravesicalproliposomalformulatedpaclitaxel
(TSD-001)insubjectswithlow-grade(WHO,2004),stageTa,NMIBC.Anenrollmentofupto
21subjects(6inpart1andupto15inpart2)isplanned.Anysubjectthatreceivesatleast
twotreatmentsinpart1orpart2iseligibleforsurveillanceinpart3.Subjecteligibilitywill
bedeterminedduringthescreeningperiodbasedonthesubjectmeetingalloftheinclusionand
noneoftheexclusioncriteria.
Figure1presentsadiagramdepictinganoverviewofthestudydesign.Thestudy,foreach
subject,comprisesascreeningperiod,asix-doseescalationsafetyandpaclitaxelPK
concentrationassessment(part1),andastabledosingphaseassessingthemarkerlesion
responserate,safety,and(inpart2)apaclitaxelPKconcentrationassessmentafterthefirstand
thirdintravesicalinstillations.Studypart1willincludeacystoscopyabout13weeks(±7days)
afterTURBT.Studypart2cohort1willincludeacystoscopyandbiopsy(orTURBT)under
general/regionalanesthesia12weeks(±7days)afterDay1.Part2cohort2willincludea
cystoscopyandbiopsy(orTURBT)undergeneral/regionalanesthesia15weeks(±7days)after
Day1.
Thestudyhasatotalof17plannedclinicvisitsforpart1and14plannedclinicvisits(part2
cohort1)or16plannedclinicvisits(part2cohort2),includingofficevisitsineachpartfor
studydrugadministrationandadditionalofficevisitsforsafetyandpaclitaxelconcentration
assessments.Part3hasanadditional7plannedclinicvisits.
Figure2presentsadiagramoftheadaptiveindividualdose-escalationscheduleforpart1and
doseassignmentforpart2.Forthefirst3subjects(cohort1)inpart1,studydrugwillbe
administeredevery2weeksatastartingdoseof10mgTSD-001andadjustedevery2weeksfor
atotalof6intravesicaltreatments.Thestudydrugstartingdoseforthenextthreesubjectsin
part1(cohort2)willbe90mg,andincreasedaccordingtotheschedule(180,270,360,450,
540mg).Inpart1,peripheralbloodandurinesampleswillbecollectedforpaclitaxel
concentrations15minutes(±15minutes)beforeand2hours(±10minutes)aftereach
instillation.Thirteenweeks(±7days)afterTURBT,anofficecystoscopywillbeperformed.
Duringpart2,upto15additionalsubjectswithlow-grade,stageTaNMIBCwillhaveweekly
intravesicalinstillationsofTSD-001atthehighestnontoxicdose(MTD/MDD)establishedin
part1.PaclitaxelPKconcentrationmeasurementsofperipheralbloodduringpart2willbe
obtained2hours(±10minutes)afterthefirstintravesicalinstillation,and15minutes(±15
minutes)beforeand2hours(±10minutes)afterthethirdinstillationofTSD-001.Allsubjects
inpart2willalsohaveadditionalurinesamplescollectedaftertheirthirdintravesical
instillation.Voidedurinepaclitaxellevelswillbedeterminedforurinesamplestakenat24,48,
and72hoursafterinstillationofTSD-001asanexploratoryendpoint.Forpart2cohort1,the
markerlesionresponseassessmentwillbeperformedatWeek12(i.e.,7weeks[±7days]after
thelastTSD-001intravesicalinstillation).Forpart2cohort2,themarkerlesionresponse
assessmentwillbeperformedatWeek15(i.e.,8weeks[±7days]afterthelastintravesical
instillation).Subjectswillreporttothestudysitepreparedtoundergocystoscopyandbladder

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
29

CONFIDENTIAL
biopsyundergeneralanesthesia.CompletemarkerlesionresponserequiresnoevidenceofTCC
oncystoscope-directedbiopsy.Partialresponseisatleasta30%decreaseinmarkerlesionsize.
Beforeeachoftheplannedintravesicaltreatmentvisitsinpart2,thesubjectswillreporttothe
studysiteasdirected.Intravesicalinstillationofstudydrugwillbeperformedwithdwelltimeof
2hours(1hourormorewillbeacceptable,dependingonsubject’stolerabilityoftheprocedure).
SubjectswillbeobservedwithinthestudysiteforanyAEsduringthe2-hourintravesicaldwell
andfor30minutesaftercompletingintravesicaladministration.
Subjectquestionnaires(IPSS,OAB-q)willbeadministeredatbaselineenrollment,dayoflast
treatment,andattheendofthetreatmentpartonDay92(Week13)forpart2cohort1or
Day113(Week16)forpart2cohort2.
SafetyanalysiswillbeperformedondatacollectedthroughWeek16ofpart1,Week13of
part2cohort1,andWeek16ofpart2cohort2.
Uponoraftercompletionofpart1orpart2(treatmentpart)ofthestudy,thesubjectmaybe
enteredintopart3(surveillance).Inpart3,subjectswillbefollowedfordisease-freesurvival
andreceivecystoscopicassessmentsapproximatelyevery3monthsaspartofstandardcare
followingtreatmentoflow-gradeNMIBC.Subjectswillreceivenointravesicaladministrations
ofTSD-001duringpart3.
Ifthereisevidenceofrecurrenceuponcystoscopicexaminationduringpart3,thensubjectswill
haveadditionalstandardcare.Ifknown,thedeterminationofgrade,stage,andresultsofurine
cytologywillberecordedintheelectroniccasereportform(eCRF).Inaddition,anytreatments
administeredaspartofstandardcarefortheNMIBCrecurrencewillberecordedasconcomitant
medication(s).Duringpart3,AEscontinuedfrompart1orpart2willbefolloweduntil
resolutionorstabilizationbutnonewAEswillberecorded.
StudyassessmentswillbeperformedasnotedintheschedulesofeventsprovidedinSection2.
Figure1:
OverviewofStudyDesign 
 


LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
30

CONFIDENTIAL




LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
31

CONFIDENTIAL

MDD=maximumdeliverabledose;MTD=maximumtolerateddose;PK=pharmacokinetics;
TURBT=transurethralresectionofbladdertumor

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
32

CONFIDENTIAL
6.
SELECTIONOFSTUDYPOPULATION
6.1.
InclusionCriteria
Potentialstudysubjectshavetomeetallofthefollowinginclusioncriteriatobeenrolled(prior
toTURBT).Thesecriteriaapplytostudyentryintopart1orpart2.Subjectsareeligiblefor
inclusioninpart3iftheyreceivedatleasttwoeligibletreatmentsinpart1orpart2and
providedinformedconsenttosurveillanceprocedures.
DiagnosisandInclusionCriteria:
1. 18to85yearsofageattimeofstudyenrollment.
2. Abletomeettherequirementsofthestudy;givevoluntary,writteninformedconsent;and
adheretodosingandvisitschedules.
3. Hasadiagnosisoflow-grade(WHO,2004)(i.e.,G1orG2(WHO,1973)),uni-or
multifocalpapillary-appearingbladdertumor,stageTa.Inpart2,asubjectmeetsthis
inclusionwithoutthishistologicaltissuediagnosisifoncystoscopicassessmenttheyhave
asolitarypapillarytumor(≥0.5cmand≤2.0cmindiameter).
4. Forpart1,subjectwillhave≥1and≤5tumors(priortoTURBT),noneofwhich
exceeds3.0cmindiameter;andforpart2subjectwillhave≥2and≤5tumors(priorto
TURBT),noneofwhichexceeds3.0cmindiameter(resectionloop~1cm),OR,for
part2,subjectmeetsthisinclusioncriterionifoncystoscopicassessmenttheyhavea
solitarypapillarytumor(≥0.5cmand≤2.0cmindiameter).
5. SubjectissurgicalcandidateforTURBTaspartofnormalNMIBCtreatmentplan.For
part1,successfulcompletionofTURBTprocedure.Forpart2,successfulcompletion
ofcystoscopicassessment/TURBTprocedurewithonemarkerlesionleftintact;the
markerlesionshouldbe≥0.5cmand≤2.0cmindiameter.
6. EasternCooperativeOncologyGroup(ECOG)performancestatusof0or1.
7. Peripheralneuropathygrade1orless(NCICTCAEVersion5.0).
8. Adequatehematological,hepaticandrenalparameters;i.e.,hemoglobin>10g/dL,
creatinine<3.5mg/dL,bilirubin<1.5mg/dL,aspartateaminotransferase<50U/L,
alanineaminotransferase<50U/L,andalkalinephosphatase<130U/L.
9. Allsexuallyactivesubjectsofreproductivepotentialarerequiredtouseorstartusinga
reliablemethodofbirthcontrolatleast2weekspriortostudyenrollment,throughoutthe
treatmentpart,andforatleast3monthsfollowingcompletionofstudydrugtreatment.A
reliablemethodofbirthcontrolisdefinedSection7.6.
10.Femalesofchildbearingpotentialmusthaveanegativepregnancytestwithin30days
priortoenrollment.Femaleswhoarepostmenopausalforatleast1year(definedasmore
than12monthssincelastmenses)oraresurgicallysterilizeddonotrequirethistest.
11.Adequatevenousaccesstoallowcollectionofbloodsamplesbyvenipuncture.
12.Formalesubjects,thedigitalrectalexaminationmustnotbesuspiciousforcarcinomaof
theprostate.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
33

CONFIDENTIAL
13.Abletoretainbladderinstillationsforupto120minutes(±15minutes).

6.2.
ExclusionCriteria
Thesecriteriaapplytostudyentryintopart1orpart2.Potentialstudysubjectswillbe
excludediftheymeetoneormoreofthefollowingexclusioncriteria:
1. Hasanactiveconcurrentmalignancy/life-threateningdisease.Ifthereisahistoryofprior
malignancies/life-threateningdiseases,thesubjectistobediseasefreeforatleast5years.
Subjectswithotherpriormalignancieslessthan5yearsbeforestudyentrymaystillbe
enrollediftheyhavereceivedtreatmentresultingincompleteresolutionofthecancerand
currentlyhavenoclinical,radiologic,orlaboratoryevidenceofactiveorrecurrent
disease.SubjectswillnotbeexcludedforrecurrentNMIBC,basalorsquamouscellskin
cancers,ornoninvasivecancerofthecervix.
2. Haspositiveurinecytologyforurothelialmalignancy(i.e.,high-grade)atscreening.
3. HasCisorT1transitionalcellcarcinoma(TCC).
4. HasBCG-refractoryTCC.
5. Hasanactiveuncontrolledinfection,includingaurinarytractinfection,underlying
medicalcondition(e.g.,systolicbloodpressure≥160mmHgand/ordiastolicblood
pressure≥92mmHg),orotherseriousillnessthatwouldimpairtheabilityofthesubject
toreceiveprotocoltreatment.
6. Previousintravesicaltherapy(e.g.BCG,mitomycinC,chemotherapeuticagent)within
6monthsofstudyentry.
7. Hasparticipatedinapreviousclinicaltrialorusedanyinvestigationaldrugs,biologics,or
deviceswithin90dayspriortostudytreatmentorplanstouseanyoftheseduringthe
courseofthestudy.
8. Hashadanypreviousexposuretopaclitaxelordocetaxelinthelast5years.
9. Hasorhaseverhad:uppertractTCC;urethraltumor(prostaticurethraincluded);any
invasivebladdertumor(T2orgreater);anyevidenceoflymphnodeordistantmetastasis;
anybladdertumorwithhistologyotherthanTCC.
10.Hasatumorinabladderdiverticulum.
11.Concurrenttreatmentwithanychemotherapeuticagent.
12.Historyofvesicoureteralreflux.
13.Anindwellingureteralstent.
14.Hasreceivedanypelvicradiotherapy(includingexternalbeamand/orbrachytherapy).
15.Hasableedingdisorderorascreeningplateletcount<100×109/L.
16.HasanyunstablemedicalconditionthatwouldmakeitunsafetoundergoTURBTor
receiveinstillation(e.g.,presenceofuncontrolledgrosshematuria).Subjectexperienced
anyprocedure-relatedadverseeffectduringTURBTthat,intheopinionofthe

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
34

CONFIDENTIAL
investigator,wouldputthesubjectatunacceptablerisktoreceiveintravesicaltreatment
orparticipateinthestudy(e.g.,bladderperforation).
17.Hasactivediagnosisofinterstitialcystitis.
18.Forsubjectswithrecurrenttumor,thesubjectdidnothaveatleasta6-month
cystoscopicallyconfirmedtumor-freeintervalbetweenthelasttumorrecurrenceand
screeningcystoscopicexamination.
19.Femalesofchildbearingpotentialwhoarenursing,pregnant,intendingtobecome
pregnantorintendingtonurseduringthetimeofthestudy,orwhohaveapositive
pregnancytestatbaseline.
20.Currentlyseekingtofatherachildorisseekingfertilitywithinoneyearoftrial
participation.
21.Presenceofpoorlycontrolleddiabetesmellitus(glycatedhemoglobin[HgbA1c]>9.0%).
22.Clinicallysignificantco-morbidconditionsthatwouldinterferewiththesubject’s
participationorcompromisethesubject’ssafety.
23.Anysignificanthistoryofallergyand/orsensitivitytothedrugproductsortheir
excipients,includinganyhistoryofsensitivitytopaclitaxel.
24.Undergonesurgeryorhadamedicalconditionthatinthejudgmentoftheprincipal
investigatorplacesthesubjectatunacceptablerisktoparticipateinthestudy.
25.Anycontraindicationtobloodsampling.
26.Intenttohaveanelectivesurgicalprocedure(otherthanTURBT)duringthecourseofthe
trial.
27.Donatedbloodorbloodproductsorhadasignificantlossofbloodwithin90daysbefore
dosing.
28.Donatedbonemarrowwithin6monthsbeforedosing.
29.Positiveurinedrugscreenorhistoryofdrugoralcoholabuseinthepastsixmonths.
30.Anyconditionthattheinvestigatorbelieveswouldinterferewiththeintentofthisstudy
orwouldmakeparticipationnotinthebestinterestsofthesubject.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
35

CONFIDENTIAL
7.
TREATMENTS
7.1.
DescriptionofTreatmentPreparation
TSD-001isdeliveredsterilely,intravesicallyviaurethralcatheter.Afterpassageoftheurethral
catheter,thesubject’sbladderwillbecompletelyemptied.Pleasenote,asrequiredaccordingto
thescheduleofevents,urinemayberequiredforPKanalysis.
TheproliposomalTSD-001lyophilizedpowderwillbereconstitutedwithsterilewaterfor
injection(SWFI),mixed,andtheninstilledintravesicallyviathesterileurethralcatheterunder
gentleplungerpressure.Thecatheterandattachedsyringewillthenberemovedanddiscarded
accordingtousualbiohazardprecautions.Formoreinformationonreconstitutionprotocol,refer
tothepharmacymanual.
Thedwelltimewillbe2hours(1hourormorewillbeacceptable,dependingonsubject’s
tolerabilityoftheprocedure).
FormoredetailedinformationonTSD-001anditsexcipients,refertotheInvestigatorBrochure.
7.1.1.
PackagingandLabeling
PackagingandlabelingwillbecarriedoutinaccordancewiththerequirementsofAnnex13of
theGoodManufacturingPractice(GMP)guidelines,ICHGCP/ISO14155requirements,LIPAC
andvendor-approvedstandardoperatingprocedures,andallapplicableUSlaws.
7.1.2.
StorageandAccountability
TSD-001shouldbestoredatcontrolledrefrigeratortemperature(2to8ºC)inthesupplied
packaging.
Thestudysitemustmaintainaccurateinvestigationalproductrecords,includingdatesand
amountofstudydrugdispensed(subject-by-subjectaccounting),andaccountsofanystudydrug
accidentallyordeliberatelydestroyed.
Unlessotherwisenotified,allstudydrugproductsincludingtheemptypackaging,ifapplicable,
mustbesavedforstudydrugaccountability.  Duringandattheendofthestudy,reconciliation
mustbemadebetweentheamountofstudydrugsupplied,dispensed,andreturnedfor
destruction.Anydiscrepanciesinremainingstudydrugwillberecordedandtheinvestigator
notifiedifanydiscrepanciesarefound.Awrittenexplanationwillbeprovidedforany
discrepanciesandtheremainingsupplieswillbereturnedtoadesignatedlocationfordestruction.
7.2.
StudyDrugDosingRules
Forpart1,intravesicaladministrationofTSD-001willbeginnosoonerthan12days(±2days)
afterTURBT.Forthisphase1trial,anadaptivetitrationdesignwithanintra-subjectdose
escalationschemewillbeusedtoestablishtheMTD.Figure2presentsthestudydrugdosing
rulesandadiagramoftheadaptiveindividualdose-escalationscheduleforpart1anddose
assignmentforpart2.Additionalinformationonthedoseescalationandde-escalationplanis
includedbelowandinAppendix4.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
36

CONFIDENTIAL
Figure2:
DiagramoftheAdaptiveAcceleratedIndividualDose-escalationSchedule
forPart1andDoseAssignmentforPart2:

DLT=dose-limitingtoxicity;MDD=maximumdeliverabledose;MTD=maximumtolerateddose
Part1:
Forthefirst3subjects(cohort1)enrolled,theinitialdosewillbe10mginSWFI.IfDLTdoes
notdevelop,intravesicalinstillation14dayslaterwillbetitratedupaccordingtotheschedule
(25,50,75,100,150mginSWFI)untilDLT(definedasanygrade3or4toxicityorprolonged
[greaterthan14days]grade2toxicity)isobserved.
IfnoDLTisobservedinthefirst3subjectsaftertitration,cohort2(subjects4,5,and6)will
startdosingat90mgandthenevery14daysatthefollowingdoses:180,270,360,450,540mg
oruntilDLTisobserved.
IfDLTisobservedinthefirst3subjectsaftertitration,cohort2(subjects4,5,and6)willnotbe
requiredinthestudydesign.Enrollmentwillcontinuetopart2ofthestudy(upto15additional
subjects).
IfnoDLTisobservedinthefirst6subjectsaftertitration,then360mgwillbethedose
recommendedforpart2ofthestudy,asthispaclitaxelconcentrationissubstantiallyhigherthan
thehalf-maximalinhibitoryconcentration(IC50)observedinbladdercancercelllinesexposedto
TSD-001.Additionalsubjectsmaybeenrolledatthediscretionofthesponsortodetermine
appropriateDLTandMTD.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
37

CONFIDENTIAL
TheconcentrationofpaclitaxelinTSD-001willvaryasafunctionofurineproductionoverthe
2-hourintravesicaldwelltime.TheMDD,therefore,willbedefinedbyDLT(i.e.,MTD)orper
protocol(i.e.,thehighestconformingdoseinstilledpertheadaptiveacceleratedtitrationdesign).
Theprimaryendpointinthisphase1trialistodefinetheMTD,whichisdefinedasthedose
immediatelyprecedingthedoseatwhichDLToccursorwhenaMDDisdeterminedinthedose
escalationschemedescribedbelowwithoutanyDLT.
TheMTDorMDDwillbetherecommendeddoseforthephase2studydescribedbelow.
Part2:
Inpart2,thedosewillbeselectedastheMTD(highestnontoxicdose)orMDDestablishedin
part1andprovidedweeklyviatheintravesicalroute.
Duringpart2,upto15additionalsubjectswillreceiveintravesicalinstillationsofTSD-001via
urethralcatheterizationoftheurinarybladderattheMTDorMDDestablishedinpart1at
weeklyintervals.Subjectsinpart2cohort1willreceive6weeklyinstillationsandsubjectsin
part2cohort2willhave8weeklyinstillations.TSD-001willberetainedinthebladderfor
2hours(1hourormorewillbeacceptable,dependingonsubject’stolerabilityoftheprocedure).
Thedecelerationplanfordosetitrationfollowingstudy-relatedlow-gradetoxicityisdetailedin
Appendix4.
Part3:
Inpart3,subjectswillbefollowedfordisease-freesurvivalafterparticipationinthetreatment
partofthestudy(part1orpart2).Subjectsinpart3willreceivecystoscopicassessments
approximatelyevery3monthsaspartofpartofstandardcarefollowingtreatmentoflow-grade
NMIBC.
SubjectswillreceivenointravesicaladministrationsofTSD-001duringpart3.
7.3.
MethodofAssigningSubjectstoPart,Cohort,andDosingLevels
SubjectswillbeassignedonDay1intothenextavailablestudypart,cohort,andstartingdosing
levelbasedonacentraldoseassignmentlistkeptbyLIPAC.Screeningmaybeopenedorclosed
incoordinationwithparticipatinginvestigatorsinordertoensurescreenedsubjectswillhavethe
nextavailabledoseassignment.Accordingly,subjectsmaybeinscreeningduringcompletionof
thepreviouscohortandbeplannedtoenterthenextavailablecohortassignment.Additionally,
subjectsthatstarttreatmentinpart2cohort1willbere-assignedtocohort2priortocompletion
oftreatmentadministrationvisits(i.e.,Week5)afterinstitutionalreviewboard(IRB)written
approvalofthepart2cohort2scheduleandtheassociatedprotocolversion.
Subjectswillbeenteredintopart3(surveillance)uponoraftercompletionoftheirpart1or
part2visitsandinformedconsenttosurveillanceprocedures.Subjectswhoreceiveatleast
twotreatmentsinpart1orpart2maybeenteredintopart3.
7.4.
Blinding
Notapplicabletothissingle-armstudy.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
38

CONFIDENTIAL
7.5.
Prior/ConcomitantMedicationandTherapy
Allmedicationstakenbysubjectsduringthecourseofthestudywillberecorded.Continuation
ofexistingmedicationsisallowedwiththeexceptionoftheprohibitedmedicationsdefined
below,providedtheuseofthesemedicationsremainsstableduringthestudy.Duringthe
treatmentperiod,subjectsshouldcontacttheinvestigatoriftheyneedtotakeanewdrugormake
changestothedrugstheyweretakinguponstudyentry.Theinvestigatormustdiscussthese
changesinmedicationwiththeMedicalMonitorasspecifiedinthestudymanual.
ChangesinmedicationsandnewmedicationsshouldonlyberecordedintheeCRFduringthe
surveillanceportion(part3)ofthestudyiftheyrelatetoanAEcontinuingfrompart1or
part2oratreatmentforarecurrence.
Thefollowingdrugsareprohibitedwithin6monthsbeforethefirstdoseofstudydrugand
duringthetreatmentperiod: 
• Anyintravesicalimmunotherapyorchemotherapy(e.g.,BCGormitomycinC)
• Systemicchemotherapy,biologicaltherapy,orimmunotherapy(e.g.,cisplatin,
bevacizumab)
7.6.
ReliableMethodsofBirthControl
Areliablemethodofbirthcontrolisrequiredforwomenofchildbearingpotential.Womenof
childbearingpotentialaredefinedasanyfemalewhohasexperiencedmenarcheandwhoisNOT
permanentlysterileorpostmenopausal.Postmenopausalisdefinedas12consecutivemonths
withnomenseswithoutanalternativemedicalcause.Reliablebirthcontrolisdefinedasoneof
thefollowing:
• oralorinjectablecontraceptives
• intrauterinedevice
• contraceptiveimplants
• tuballigation
• adouble-barriermethod(diaphragmwithspermicidalfoamorjelly,oracondom)
• abstinence
• vasectomy
• hysterectomy.
7.7.
GeneralandDietaryRestrictions
Consumptionoffoods,beverages,orsupplementscontainingthefollowingsubstanceswillbe
prohibitedasindicated:
• Alcohol:Nomorethan3unitsperdayofalcoholicbeveragesfromthebeginningof
screeningthroughtheendofthestudy.Aunitisdefinedas4oz.ofwine,8oz.of
beer,or1.5oz.ofhardliquor.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
39

CONFIDENTIAL
• Marijuana(cannabinoids)
• Illicitdrugs(e.g.,cocaine,opiates,barbiturates,amphetamines,andbenzodiazepines).
7.8.
TreatmentCompliance
Treatmentcompliancewillbedocumentedbythestudysitepersonnelontheinstillationand
dwelltimeeCRF.Deviationsfromtheplannedtreatmentproceduresshouldbedocumentedfor
Sponsorreview.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
40

CONFIDENTIAL
8.
STUDYPROCEDURES
8.1.
Screening
Whenapotentiallyeligiblecandidateisidentified(e.g.,fromamongtheoutpatientscomingto
thesitefordiagnosticvisitsorafterTURBT),theinvestigatorordesignatedhealthcare
professionalwillasktheprospectivesubjectabouthis/herwillingnesstobeincludedinthe
clinicalstudy.Theprospectivesubjectistobeinformedverballyandinwritingaboutthenature,
risks,benefits,andexpectationsofparticipatingintheclinicalstudyandacopyofthesubject
informedconsentform(ICF)istobeprovidedintheappropriatelanguage.Allprospective
subjectswillhavethestudyexplainedinnon-technicaltermsandwillbeinformedofthestudy
restrictions.Priortostudyinitiation,acknowledgementofthereceiptofthisinformationandthe
subject’sinformedconsentwillbeobtainedinwritingasdescribedinSection14.4.Thesubject
willbegivenacopyoftheICF.TheICFistobesignedbythesubjectandcountersignedbythe
attendinginvestigatorpriortoproceedingwithanystudy-relatedprocedures.
Subjectswillhavetomeetallinclusioncriteriaandnoexclusioncriteriabeforebeingenrolledin
thestudy.Subjectsthatdonotmeeteligibilitycriteriamayberescreenedifinclusioncriteriaare
metandnoexclusioncriteriaaremetinthesecondscreeningperiod.
Thefollowingprocedureswillbeperformedduringthescreeningperiod:
• Collectionofdemographicdata
• Determinationofeligibility(meetingallinclusionandnoexclusioncriteria)
• Documentationofmedicalandsurgicalhistory
• Glycatedhemoglobin(HgbA1c)determination
• Weight(kilograms)andheight(centimeters)measurements
• Drugandalcoholscreens
• UrinalysiswithpH
• Urinepregnancytestforwomenofchildbearingpotential
• 12-leadECG
• Vitalsigns
• Physicalexamination
• Clinicallaboratorytests(hematology,serumchemistry)
• Cystoscopicassessment(tobecompletedduringscreeningorwithin30dayspriorto
startofscreeningaspartofstandardcare)
• IPSS(menonly)andOAB-q
Anysubjectnotmeetingenrollmentinclusioncriteriaand/ormeetingenrollmentexclusion
criteriawillbeconsideredascreenfailure.Forbothstudypart1andpart2,subjectscreening
willbecompleted≤28dayspriortoStudyDay1.Ascheduleofeventsforthescreeningvisit
andStudyDay1areprovidedinSection2andTable1.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
41

CONFIDENTIAL
8.1.1.
TURBT
Transurethralresectionofabladdertumor(TURBT)withpathologyconfirminglow-grade,
stageTaTCCofthebladderisnecessarybeforestudyenrollmentinpart1.Forpart1,eligible
subjectsmusthavelow-grade,stageTaNMIBC(transitionalcellhistology)withnomorethan
5tumors,noneofwhichcanbelargerthan3.0cmindiameter.Asaguidefortumorsize,use
theresectionloop(~1cm)asaguide.Forpart1,allvisibletumorsmustbesurgicallyremoved,
theremustnotbeanyevidenceofCIS,andurinecytologymustbenegativeforcancer.
Furthermore,thesubjectwillbeineligibleforstudyenrollmentifbladderperforationoccurs
duringTURBT.Forpart1,itispossibleforprospectivesubjectstobeidentifiedafterTURBT.
IfaprospectivesubjectisidentifiedafterTURBT,pleaseensurethescreeningproceduresare
completedinthe12days(±2days)priortoDay1andalleligibilitycriteriaaremet.
Forpart2,twodifferentsubjectpresentationsmaybeeligible.
First,forsubjectswithmultipletumors,TURBTwilloccurafterenrollmentintothestudyon
Day1.Eligiblesubjectsmusthavelow-grade,stageTaNMIBC(transitionalcellhistology)with
atleast2andnomorethan5tumors,noneofwhichcanbelargerthan3.0cmindiameter.For
subjectsthatundergoTURBT,afinalpathologyreportconfirminglow-grade,stageTaNMIBC
isrequiredforadditionalsubjecttreatments(intravesicaladministrations2throughfinal).
Furthermore,thesubjectwillbeineligibleforstudytreatmentifbladderperforationoccurs
duringTURBT.
Second,subjectsareeligibleifoncystoscopicassessmenttheyhaveasolitarypapillarytumor
(≥0.5cmand≤2.0cmindiameter),andnegativeurinecytology.Thecystoscopicassessment
shouldbecompletedduringscreeningorwithin30dayspriortostartofscreening(aspartof
standardcare).Forsubjectswithidentifiedsolitarytumorsthecystoscopicassessmentisnot
requiredtobeperformedagainonDay1.
ForallsubjectstheremustbenoevidenceofCIS,urinecytologymustbenegativeforcancer,
andthereshouldbenouncontrolledgrosshematuria.Thetumorsmustbepapillary.Asaguide
fortumorsize,theresectionloopis~1cm.Forpart2,thetumorselectedtobethemarker
lesionshouldbeapproximately1cm(useresectionloopasguideforsize)butmaybe≥0.5cm
(5mm)and≤2.0cmindiameter,andappearpapillary.Sessile,invasive-appearingtumors
shouldnotbeselectedasthemarkerlesiontumor.
8.1.2.
MarkerLesion(forPart2)
Markerlesionisatermusedtodesignateasinglebladdertumordeliberatelyleftunresectedfor
laterapplicationofastudiedagentorchemo-resection(Gofritetal.,2010).Inthisstudy,the
laterapplicationistheintravesicalinstillationofthestudydrug,TSD-001.Theuseofthis
markerlesionmethodprovidesclearopportunitytoobservetheeffectoftheagentonthetumor
inameasurablefashion.
Markerlesionstudieshavebeenusedfortheevaluationofanticancertherapiesasearlyasthe
early1980s.Theyaremostappropriateforsubjectswithmultiple,noninvasive,low-grade
tumorsrepresentinglowtointermediaterisk(Gofritetal.,2010).
Forpart2,thefirstmethodologytobefollowedforthisstudyisforsubjectswith≥2and
≤5tumorstohaveallbutoneofthesetumorsresectedusingstandardresection(e.g.,electric

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
42

CONFIDENTIAL
loop)proceduresviacystoscopy.Onemarkertumorwillbeleftintact,untouchedbecauseany
damagetothesupplyofbloodmaycauseinvolution.Asanyresectionofthemarkertumor
wouldmakethesubjectineligible,ifthisoccursduringthesurgery,thetumorshouldberesected
completelyandthesubjectwillbeconsideredineligiblefortreatmentandwithdrawnfromthe
study.
InvestigatorscanidentifytypicallylowgradepapillaryNMIBCtumorsusingcystoscopy.
CystoscopycorrectlypredictsTa,lowgradebladdertumorswithanaccuracyof93%.
CystoscopyalongwithanegativecytologyaccuratelypredictsstageTa,lowgradeNMIBCwith
anaccuracyof99%(Herretal,2002).
Inaddition,ithasbeenshownthatactivesurveillancewithdelayedinterventionrepresentsasafe
strategyforpatientswithrecurrentlowriskbladdercancer(Gorinetal,2015).
Ofnoteisthatthemarkerlesionisneverbiopsied;itisinferredtobehistologicallysimilartothe
othersynchronoustumors.
Thus,thesecondmethodologyiscystoscopicconfirmation(withoutbiopsy)ofasolitary
papillarybladdertumor.Thismethodologyisconsistentlydependentonexcludingsubjectswith
positiveurinecytologyforurothelialmalignancy(i.e.,high-grade)oruncontrolledgross
hematuria.Themarkerlesionforbothmethodologiesshouldappearpapillaryandbe≥0.5cm
and≤2.0cmindiameter.
8.2.
StudyProcedures/Visits
Oncethescreeningproceduresarecompleted,thesubjectwillbepreparedforStudyDay1.
8.2.1.
Enrollment
OnStudyDay1,thefollowingstudyprocedureswillbeconductedpriortostudydrug
preparations:
• UrinalysiswithpHbasedonvoidedurinesample
• Urinepregnancytestforwomenofchildbearingpotential
• Vitalsigns(bloodpressure,heartrate,respiratoryrate,bodytemperature)
• Documentationofanychangestopreviouslyrecordedpriorand/orconcurrent
medications
• Finaldeterminationofsubjecteligibilityforenrollmentandtreatment
8.2.2.
Treatment
TreatmentpreparationinstructionsfromSection7.1shouldbefollowedtoprepareTSD-001
proliposomalformulationdilutedwithSWFI.
TheproliposomalTSD-001lyophilizedpowderwillbereconstitutedwithSWFI,mixed,and
theninstilledintravesicallyviathesterileurethralcatheterundergentleplungerpressure.The
catheterandattachedsyringewillthenberemovedanddiscardedaccordingtousualbiohazard
precautions.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
43

CONFIDENTIAL
Ifthereisanyevidenceofanactive,untreatedurinarytractinfection,thetreatmentshouldbe
postponed.
Iftheprotocolrequiresapredoseperipheralvenousbloodorurinesample,itshouldbeobtained
15minutesbeforeintravesicalinstillationofTSD-001.
Forpart1,administrationofTSD-001willoccurapproximately2weeksafterTURBT,after
enrollmentonDay1.
Forpart2,thesubjectwillbeenrolledpriortoTURBT(forsubjectsnotmeetingsolitarytumor
requirements).Forthesesubjects,thefirststudyadministrationofTSD-001willbegin
immediately(≤120minutes)followingTURBT,eitherwiththesubjectstillanesthetizedinthe
operatingroomorinapost-surgeryrecoverysuite.SubjectsnotundergoingTURBT(i.e.,
solitarytumorsubjects)willbetreatedasscheduledandasecondcystoscopicassessmentisnot
requiredonDay1.Peripheralvenousbloodsamplesandscheduledurinesamplesshouldalsobe
takenduringtheprotocol-requiredtimeperiods.
Inpart2,ifthesubjectneedstobemovedafterTURBTandtheinitialinstillationofTSD-001,
careshouldbetakentomaintaintimerecordstoensurecompliancewithprotocol-requiredtime
ofinstillationandsubsequentbloodandurinesampling.
Forpart1andpart2,TSD-001issterilelyadministeredintravesicallyviaurethralcatheter.
Afterpassageofthecatheter,thesubject’sbladderwillbecompletelyemptiedand2separate
aliquotssavedformeasurementofpaclitaxelconcentrationbasedonthescheduleofevents
(Table1,Table2,andTable3).
Theinstillationshouldremaininthesubjectbladderfor1to2hours(60to120minutes).The
patientshouldbeencouragedtomaintaintheinstillationascloseto120minutesas
possible.Duringinstillationandwhenphysicallyable,thesubjectshouldchangepositionevery
15minuteswithatleasttwo15-minuteperiodsintheprone(facedown)position.
At2hours(±10minutes)afterspecifiedinstillations,aperipheralvenousbloodsampleshould
becollected(viavenipuncture)followingthesamplealiquottimepointinstructions(see
Section2,ScheduleofEvents).Atthecompletionofspecifiedinstillations,thesubjectshould
voidnormallyintoacollectiondevice.Proceduresoutlinedinthelabmanualincludeadditionof
anadditive(Tween)totheurinesample,andthenduplicatealiquotsshouldbecollectedforurine
PKassessmentaccordingtothePKsampletimepointinstructions(seeSection2,Scheduleof
Events).UrinepHshouldbemeasuredusingpHteststripsinthepre-andpost-instillationurine
samples.Selectsiteswillmakeobservationsonurineappearance(turbidityandprecipitation).
Thevolumeofthepost-installationvoid(s)shouldalsobemeasuredandrecorded.Any
deviationsfromtherequireddwelltimeshouldberecordedintheeCRF.
Inpart2,additionalurinesamples(24,48,and72hourspostinstillation)shouldbecollected
afterthethirdinstillationonly(seeSection2,ScheduleofEvents).
Eachsubjectwillhavemultipleinstillationsofstudydrug.Inpart1,subjectswillhave
6instillations,2weeksapartbeginningonDay1.Subjectsinpart2cohort1willhave
6instillations,1weekapartbeginningonDay1.Subjectsinpart2cohort2willhave
8instillations,1weekapartbeginningonDay1.UrinepHshouldbemeasuredinthepre-and
post-instillationurinesamplesasoutlinedintheScheduleofEvents(Section2).

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
44

CONFIDENTIAL
FormoredetailedinformationonTSD-001anditsexcipients,refertotheInvestigatorBrochure.
8.2.3.
OtherStudyProcedures
StudyproceduresshouldbeconductedasoutlinedinTable1,Table2,Table3,andTable4.All
laboratorysamplesshouldbecollectedandanalyzedperSection9.3.2.
Forpart1,oncethelastinstillationtakesplaceonWeek10visit(Day71),anadditional
follow-upvisitwilloccuratWeek11(Day78).Visitwindowsshouldbefollowedtokeepvisits
withintherequiredtimeframes.
OntheWeek11(Day78±2days)visit,thefinalcystoscopyprocedurewillbeconducted.This
scheduledeventwilloccurasusuallyperformedforbladdertumorfollow-upcystoscopy.
Forpart2,allsubjectswillhaveadditionalpost-treatmentvisits24,48,and72hoursafterthe
thirdintravesicaltreatment.Voidedurinesampleswillbecollectedatthesetimepointsafterthe
thirdtreatmentforthesesubjectstomeasuretheamountofpost-instillationpaclitaxellevelsin
thevoidedurine.Vitalsignsshouldalsobemeasuredalongwithanychangestoconcurrent
medicationsandrecordinganyAEs.
Forpart2cohort1subjects,oncethelastinstillationtakesplaceontheWeek5visit(Day36),
additionalfollow-upvisitswilloccuratWeek6(Day43)andWeek9(Day64).OntheWeek
12(Day85±7days)visit,thefinalcystoscopyprocedureandbiopsywillbeconducted(or
TURBTifabladdertumorlesionispresent).
SubjectsinPart2cohort2willhavethelastinstillationonWeek7visit(Day50).Additional
follow-upvisitswilloccuratWeek9(Day64)andWeek12(Day85).OntheWeek15(Day
106±7days)visit,thefinalcystoscopyprocedureandbiopsywillbeconducted(orTURBTifa
bladdertumorlesionispresent).
Visitwindowsshouldbefollowedtokeepvisitswithintherequiredtimeframes.Atthetimeof
finalcystoscopicassessment,aurinesampleforcytologywillalsobeobtained.Thesubject
shouldreceivegeneral/regionalanesthesiainpreparationforthecystoscopyandbladderbiopsy.
Forpart2,themarkerlesionshouldbeviewedandmeasuredfollowingnormaldiagnostic
cystoscopyprocedures.Ifnoresidualtumorisnotedatthefinalcystoscopicassessment,thesite
ofthemarkerlesionmustbebiopsied.Ifresidualtumorisnoted,TURBTofanyremaining
tumortissueshouldbeperformed.
Inaddition,anytumorbiopsysamplesshouldbecollectedandsentforpathologyexamination.
8.3.
Exit/WithdrawalfromPart1/Part2
Subjectsmaybediscontinuedfromstudytreatmentatanytime.Subjectsarealsofreeto
discontinuetheirparticipationinthestudyatanytime,withoutprejudicetofurthertreatment
outsideofthestudyprocedures.
Atthescheduledtreatmentexitvisit(endofpart1orendofpart2),allproceduresfromthe
treatmentexitvisitshouldbecompleted.
Ifthesubjectdiscontinuesstudytreatmentearly(lessthanallprotocol-requiredtreatments),they
shouldbefollowedfortheremainingscheduleofassessmentsasoutlinedintheScheduleof

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
45

CONFIDENTIAL
Events(Section2).Inthiscase,anyremainingtreatmentvisitsshouldhaveallprocedures
conductedexceptforadministrationofstudytreatmentandcollectionofsamplesforpaclitaxel
levels.Ifthesubjectisinpart1ofthestudy,afinalcystoscopyshouldbeperformed13weeks
(±7days)afterTURBT.Ifthesubjectisinpart2cohort1ofthestudy,afinalcystoscopyand
biopsyshouldbeperformed12weeks(±7days)afterDay1.Ifthesubjectisinpart2cohort2
ofthestudy,afinalcystoscopyandbiopsyshouldbeperformed15weeks(±7days)afterDay1.
Atreatmentexitvisitshouldbeperformedasindicatedinthescheduleofassessments.Ifnot
alreadydone,thesubjectshouldbepresentedwiththeinformationonthesurveillancepartofthe
study(part3).
Ifthesubjectdiscontinuesthestudyearlyandwheneverpossible,subjectsshouldbeseenand
assessedbytheinvestigatorpriortoearlywithdrawal.Atanearlywithdrawalvisitinpart1or
part2,allproceduresfromthetreatmentexitvisitshouldbecompleted.Inaddition,ifnot
alreadyperformed,afinalcystoscopy,cytology,andbiopsy(onlyforpart2)samplecollection
shouldbeperformedasdescribedinSection8.2.3.Atanearlywithdrawalvisitinpart3,no
additionalproceduresneedtobecompleted.IntheeCRF,studycompletionordiscontinuation
willbedocumentedwiththereasonforanydiscontinuation.Possiblereasonsforasubject
discontinuingparticipationinthestudyinclude:
• AE(s)thatendangerthehealthofsubjects,makingitethicallyunacceptableto
continue.ThisincludesAE(s)resultingfromthesurgicalTURBTprocedures.
• Anypatientwithgrade3or4toxicity(orprolonged[greaterthan14days]grade2
toxicity)willbeconsideredhavingexperiencedaDLT,whichwillresultin
discontinuationofstudydrug.
• Ineligibletocontinue,e.g.,TURBTproceduredoesnotresultinmarkerlesion
meetingrequirements.
• Deteriorationofthesubject’sclinicalcondition(s)thatrequiresappropriate(standard
ofcare)therapy/treatmentduringthestudyperiodasdeterminedbytheinvestigator.
• Significantprotocoldeviation
• Subjectnoncompliance
• Withdrawalofconsent
• Lackofefficacy
• Losstofollow-up
• Death
IncaseofstudywithdrawalduetoanAE,thesubjectistobefolloweduntil
resolution/stabilizationoftheAEorfor30days.Subjectswhodiscontinueprematurelyfromthe
studymaybereplacedinordertoachievestudyenrollmentgoals.
8.4.
Part3(Surveillance)Visits
ProceduresshouldbeconductedasoutlinedinTable4,perstandardofcare.Whenasubjectis
completingthescheduledtreatmentexitvisit(endofpart1orendofpart2),allprocedures

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
46

CONFIDENTIAL
fromthetreatmentexitvisitshouldbecompleted.Inaddition,ifnotalreadycompleted,the
investigatorordesignatedhealthcareprofessionalwillaskthesubjectabouthis/herwillingness
tocontinueinthesurveillancepartofthestudyandobtaininformedconsent.
Cystoscopicsurveillancewillbeperformedasstandardofcareapproximatelyevery3months
fromlastendoscopicassessmentinpart1orpart2until24months(frominitialinstillation).
Uponoraftercompletionofpart1orpart2(treatmentpart)ofthestudy,thesubjectmaybe
enteredintopart3(surveillance).Inpart3,subjectswillbefollowedfordisease-freesurvival
andreceivecystoscopicassessmentsapproximatelyevery3monthsaspartofpartofstandard
carefollowingtreatmentoflow-gradeNMIBC.Subjectswillreceivenointravesical
administrationsofTSD-001duringpart3.
Ifthereisevidenceofpossiblerecurrenceuponcystoscopicexaminationduringpart3,then
subjectswillhaveadditionalstandardcare.Ifknown,thedeterminationofgrade,stage,and
resultsofurinecytologyshouldbedetermined.Inaddition,anytreatmentsadministeredaspart
ofstandardcarefortheNMIBCrecurrencewillberecordedasconcomitantmedication(s).
Duringpart3,AEscontinuedfrompart1orpart2willbefolloweduntilresolutionor
stabilizationbutnonewAEswillberecorded.
8.5.
Unscheduled
Ifasubjectseesaninvestigatorforanunscheduledclinicvisit,thereasonfortheunscheduled
visitandanassessmentandrecordingofanyAEsshouldbenoted,ifapplicable.Additional
evaluationsshouldbeperformedasnecessary,andtheappropriateeCRFsshouldbecompleted.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
47

CONFIDENTIAL
9.
EFFICACYANDSAFETYASSESSMENTS
9.1.
MethodsofAssessment/Evaluations
9.1.1.
PrimaryEndpoint
Theprimaryendpointofpart1istheMTD,definedasthedoseimmediatelyprecedingthedose
atwhichDLToccursorwhenaMDDisdetermined.TheseverityandfrequencyofAEswillbe
documentedfollowingTSD-001administration,anddefinedaccordingtoNCICTCAEVersion
5.0.
Theprimaryendpointofpart2isthemarkerlesionresponserate.
9.1.2.
SecondaryEndpoints
Thesecondaryendpointsofpart1aretodeterminepaclitaxelPKconcentrationsintheurineand
theperipheralbloodbeforeandafterintravesicalexposuretoTSD-001.
Exploratoryendpointsofpart1includeevaluationofthefollowingparameters:
• ChangefrombaselinetoWeek16inIPSS(menonly)
• ChangefrombaselinetoWeek16inOAB-qscore
Thesecondaryendpointsofpart2areto:
1)DeterminepaclitaxelconcentrationsinbloodattheMTD/MDD.
2)DeterminetheseverityandfrequencyofAEsfollowingintravesicaladministrationof
TSD-001attheMTD/MDDestablishedinpart1,asdefinedaccordingtoCTCAE,Version5.0.
Exploratoryendpointsofpart2includeevaluationof:
• Paclitaxellevelsinvoidedurinesamplesat24,48,and72hoursafterthethird
instillationofTSD-001.
• ChangefrombaselinetotheendofthetreatmentpartinIPSS(menonly)
• ChangefrombaselinetotheendofthetreatmentpartinOAB-qscore
Theexploratoryendpointofpart3(surveillance)willbedisease-freesurvivalofsubjects
exposedtoTSD-001inpart1orpart2.
• Theendpointwillbetimetoevent(recurrence)aftertheTURBT(Day-12inpart1)
oraftercompleteresponseorWeek12TURBTinpart2.Disease-freesurvivalwill
bedefinedasnohistologicaltissuediagnosisevidenceofrecurrence.
9.2.
PharmacokineticParameters
PaclitaxelPKconcentrationswillbelimitedtopre-instillation(trough)andpost-instillation
(peak)concentrationmeasurementsofurineandplasma.Thegoalistodefinethelocaland
systemicexposureofthestudysubjectstopaclitaxel(and/oritsmetabolites).

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
48

CONFIDENTIAL
Asperthescheduleofevents,aperipheralvenousbloodandurinesampleshouldbeobtained
15±15minutesbefore,and2hours±10minutesafterpredeterminedintravesicalinstillationof
TSD-001(seeSection2,ScheduleofEvents).
TSD-001issterilelyadministeredintravesicallyviaurethralcatheter.Afterpassageofthe
catheter,andasrequiredaccordingtothescheduleofevents,2separateduplicatealiquotsof
urinewillbeobtainedforPKanalysis.
At2hours(±10minutes)post-instillationperthescheduleofevents,aperipheralvenousblood
samplewillbeobtainedatspecificvisitsforpaclitaxelconcentrationmeasurement(seeSection
2,ScheduleofEvents).
Inpart2,additionalurinesamplesforpaclitaxelconcentrationmeasurementsshouldbeobtained
at24,48,and72hourspost-instillationforthethirdinstillationonly(Section2,Scheduleof
Events).
Atcompletionofinstillation,voidedurinewillbecollectedinduplicatealiquotsforPKanalysis
accordingtothescheduleofevents.Thevolumeofthepost-installationvoid(s)shouldalsobe
measuredandrecorded.
9.3.
SafetyParameters
9.3.1.
AdverseEvents
AllAEsthatoccurduringthestudyafterthesubjecthasreceivedthefirstdoseofstudydrugare
tobecollectedandreportedontheeCRF.IncaseofstudywithdrawalduetoanAE,thesubject
istobefolloweduntilresolution/stabilizationoftheAEorforatleast30days.AEsshouldbe
recorded,regardlessofwhethertheyarereportedbythesubject,elicitedbyinvestigator
questioning,detectedthroughphysicalexamination,orbyothermeans.
Duringpart3,AEscontinuedfrompart1orpart2willbefolloweduntilresolutionor
stabilizationbutnonewAEswillberecorded.
Asfaraspossible,eachAEisdescribedby:
• duration(startandenddates)
• start/endofstudymedication
• severitygrade(mild,moderate,severe)
• forpurposesofdeterminingDLT,theNCICTCAEVersion5.0willbeutilized
• investigatordeterminationofcausality(relationshiptothestudyproduct)
• action(s)taken(concomitantmedication,changeofstudymedication,etc.)including
startandenddatesofrespectiveaction
• concomitantdiseasesandrespectivemedicationingeneral
• startdate,enddate,anddosageofrescuemedication
• outcome

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
49

CONFIDENTIAL
9.3.1.1.
AdverseEventDefinition
AnAEisanyuntowardmedicaloccurrence(changeinanatomical,physiological,ormetabolic
function)inasubject,whichdoesnotnecessarilyhaveanycausalrelationshipwiththeproduct
underinvestigation.
9.3.1.2.
SeriousAdverseEventDefinition
Aseriousadverseevent(SAE)isanyuntowardmedicaloccurrencethatatanydose:
• resultsindeath
• islife-threatening(Note:theterm“life-threatening”referstoaneventinwhichthe
subjectisatriskofdeathatthetimeoftheevent;itdoesnotrefertoaneventwhich
hypotheticallymaycausedeathifitismoresevere)
• requiressubjecthospitalizationorprolongationofexistinghospitalization(forthe
purposeofthisstudy,ahospitalizationisdefinedasahospitalstayofatleast8hours
and/oranovernightstay)
• resultsinpersistentorsignificantdisability/incapacity
• isacongenitalanomaly/birthdefect
or
• othermedicallyimportantcondition
Eventsthatrequireinterventiontopreventoneormoreoftheoutcomeslistedinthedefinition
abovearealsotobeconsideredserious.Examplesofsucheventsareintensivetreatmentinan
emergencyroomorathomeforallergicbronchospasm,blooddyscrasiasorconvulsionthatdoes
notresultinhospitalization,ordevelopmentofdrugdependencyordrugabuse.
However,medicaljudgmenthastobeexercisedindecidingwhetheraneventisseriousinany
othersituationsconsideredmedicallyrelevant.
TheevaluationoftheAEasseriousornotseriousismadeindependentlyofanyattributionof
causality.
EventsNOTconsideredtobeSAEsarethosethatrequire:
• electiveorpreplannedtreatmentforapre-existingconditionthatisunrelatedtothe
indicationunderstudyanddoesnotworsen
• treatmentonanemergency,outpatientbasisforaneventNOTfulfillinganyofthe
definitionsofseriousgivenaboveandNOTresultinginhospitaladmission(forthe
purposeofthisstudy,ahospitalizationisdefinedasahospitalstayofatleast8hours
and/oranovernightstay)
9.3.1.3.
AEIntensity
AEintensityisdeterminedbytheclinicalinvestigatoronthebasisofhis/herdirectobservations
orthesubject’sreporting.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
50

CONFIDENTIAL
• Mild:causesnolimitationofusualactivities;thesubjectmayexperienceslight
discomfort
• Moderate:causessomelimitationofusualactivities;thesubjectmayexperience
annoyingdiscomfort
• Severe:causesinabilitytocarryoutusualactivities;thesubjectmayexperience
intolerablediscomfortorpain.
9.3.1.4.
AECausality/Relationship
AnyAEhastobejudgedforcausality(relationshiptostudymedicationandrelationshiptostudy
procedure).
TherelationshipofanAEtothestudyproductistobegradedonthebasisofthefollowing:
• Probable: areactionthatfollowsareasonabletemporalsequencefrom
administrationoftheproduct;thatfollowsaknownresponsepatternto
thesuspectedproduct;thatisconfirmedbyanimprovementonstopping
theproduct;andthatcannotbereasonablyexplainedbythesubject’s
clinicalstate
• Possible:
areactionthatfollowsareasonabletemporalsequencefrom
administrationoftheproduct;thatfollowsaknownresponsepatternto
thesuspecteddrug;butthatmayhavebeenproducedbythesubject’s
clinicalstateorothertherapeuticinterventionsonhim/her
• Unlikely:
areactionthatoccurswithanimprobabletemporalsequencefrom
administrationoftheproduct;thatcanbeexplainedbytheclinicalstate
ofthesubject/participantorbyothertherapeuticinterventionsorother
drugsorunderlyingdiseaseprovidingplausibleexplanations
• Unrelated: areactionthatoccurswithoutareasonabletemporalsequencefrom
administrationoftheproduct;thatcanbeexplainedbytheclinicalstate
ofthesubjectorbyothertherapeuticinterventionsonhim/herandthat
doesnotimproveordisappearfollowinginterruptionoftheproduct
9.3.1.5.
HandlingofAEs
IfanAEoccurs,appropriatediagnosticandtherapeuticmeasuresaretobetakenandthestudy
producthastobediscontinuedifappropriate.Follow-upevaluationsofthesubjectaretobe
performeduntilthesubjectrecoversoruntiltheclinicalinvestigatorconsidersthesituationtobe
nolongerclinicallysignificant.
Ifclinicallysignificantlaboratoryabnormalitiesappearatthefinalvisit,appropriateadditional
testsmaytobeperformedtoclarifythenatureofanyclinicallysignificantlaboratory
abnormalitiesthatoccur.
AdverseeventsaremonitoredandregisteredontheAEformoftheeCRFateachvisit.Inthe
absenceofaspecificdiagnosis,anindividualAEformmustbefilledinforeachclinically
significantsignorsymptom.
PersistentAEswillbeenteredonceintheeCRFuntiltheyareresolvedoraneweventhastobe
documentedduetodeterioration.TheseAEswillbecarefullymonitored;furtherdetailsof

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
51

CONFIDENTIAL
monitoringofpersistentAEswillbeprovidedinthemonitoringplan.AnyAEthatisnot
resolvedattheendofthestudywillbedocumentedasongoing.
ForrecurrentAEs,i.e.,AEsofthesamenaturebutwithadifferentdateofonset,anindividual
AEformmustbecompletedforeachoccurrence.
Adverseeventsoccurringaftertheterminationofthestudyindividuallyand/orofthestudyin
totalaretobereportedtoLIPACevenaftertheclinicalstudyhasbeenfinishedif,inthe
judgmentoftheinvestigator,thereisanassociationbetweentheeventandtheprevioususeof
theproductunderinvestigation.
IftheAEisclassifiedasserious,theclinicalinvestigatorhasalsotocompletetheSAEreport
form.ItistheresponsibilityoftheinvestigatortosendtheSAEreportformbyfaxtotheDrug
SafetyDepartmentoftheContractResearchOrganization(CRO)withinoneworkingdayandto
retaintheoriginalcopyoftheform(keepingaphotocopyintheInvestigatorSiteFile).Atthe
earliestpossibledate,theSAEreportformhastobefollowedbyadetailedreportandany
documentationthatmaybeavailable,e.g.,hospitalcaserecords,autopsyreports,and/orother
pertinentdocuments.Noprivateand/orconfidentialdatathatallowidentificationofstudy
participantsaretobetransmitted.
AlltheabovedocumentswillbesentbyfaxtotheDrugSafetyDepartmentoftheCROwithin
oneworkingdayofreceipt.TheinvestigatorwillberesponsibleforreportingtheSAEtoIRBs
orethicscommittees;thesponsorwillberesponsibleforreportingtheSAEtotherespective
healthauthorities,accordingtothenationalregulatoryrequirements.
TheprimarypersonresponsibleforsafetyatLIPACis:

MichaelG.Oefelein,MD,FACS
ChiefMedicalOfficer
LIPACOncologyLLC
Michael@lipaconcology.com
Telephone:661-665-0505,ext.216
Mobile:714-401-3154
9.3.2.
LaboratoryMeasurementsandVariables
Alllaboratory-reportedvaluesthatareoutsideofthereferenceranges(highorlow)shouldbe
reviewedbythequalifiedinvestigator(s)andrecordedasclinicallysignificantornotclinically
significant.ClinicallysignificantvaluesshouldbereportedasAEs(seeSection9.3.1).
ClinicallaboratoryparameterstobemeasuredaresummarizedinTable5.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
52

CONFIDENTIAL

Table5:
Protocol-RequiredSafetyLaboratoryAssessments
Laboratory
Assessments
Parameters
Hematology
hemoglobin
whitebloodcell(WBC)count(with
differentialin%)
hematocrit
plateletcount
redbloodcell(RBC)count

BloodChemistry
aspartateaminotransferase
(AST)
totalprotein
alanineaminotransferase
(ALT)
albumin
gamma-
glutamyltransferase(GGT)
albumin/globulinratio
lactatedehydrogenase
(LDH)
directbilirubin
alkalinephosphatase
creatinekinase
totalbilirubin
sodium
totalcholesterol,
triglycerides
potassium
low-densitylipoprotein
cholesterol(LDL-C)
chloride
high-densitylipoprotein
cholesterol(HDL-C)
calcium
bloodureanitrogen
phosphate
creatinine
magnesium
uricacid
hemoglobinA1c
Urinalysis
pH
ketones
specificgravity
glucose
protein
nitrite
occultblood
leukocyteesterase
urobilinogen
microscopicassessmentforWBC,
RBC,andcasts
UrineCulture
Atinvestigator’sdiscretion
UrinePregnancyTest
Forwomenofchildbearingpotential
ToxicologyScreen
Urinetestforuseofcocaine,cannabinoids,opiates,barbiturates,
amphetamines,andbenzodiazepines
Urineorbreathtestforalcoholabuse
9.3.3.
OtherSafetyParameters
9.3.3.1.
VitalSigns
Vitalsigns(sittingsystolic/diastolicbloodpressure,heartrate,respiratoryrate,andbody
temperature)willbeevaluatedforscreening(eligibility)reasonsandduringthecourseofthe

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
53

CONFIDENTIAL
study.Vitalsignmeasurementsshouldbeseparatedfromblooddrawsbyaminimumof
5minutesandpreferablyupto10minutes.Specifically,bloodpressureshouldberecordedafter
5to10minutessittingwithoutintervention;repeatincontralateralarmforconfirmationifa
readingishigh(e.g.,systolic≥140mmHg,diastolic≥90mmHg).
9.3.3.2.
12-leadECG
Standard12-leadECGswillbeevaluatedforscreening(eligibility)reasonsandattheendofthe
treatmentpart.PRinterval,RRinterval,QRSinterval,QTinterval,QTcinterval,andheartrate
willberecordedontheeCRF.
TheresultsofECGsaretobeclassifiedasfollows:
1. normal
2. abnormal,butnotclinicallysignificant
3. abnormalandclinicallysignificant(shouldbereportedasanAEperSection9.3.1)
9.4.
AppropriatenessofMeasurements
Allclinicalandlaboratoryproceduresandassessmentsthatwillbeusedinthisstudyare
standardandgenerallyaccepted.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
54

CONFIDENTIAL
10.
DATAQUALITYASSURANCE
Detailedprocedureswillbeseparatelyprovidedinthedatamanagement,monitoring,andquality
plans.
10.1.
DataCollection
AllsubjectdatamustbereportedontheeCRFsinananonymousfashion.Subjectsareidentified
onlybya3-digitsubjectnumber.
Theinvestigatorwillberesponsibleforthecompleteness,accuracy,andlegibilityofthe
informationintheeCRFandotherstudydocuments.InlinewithGoodDocumentationPractice,
thesourcedatashouldbeaccurate,legible,attributable,original,andcontemporaneous.For
documentsotherthaneCRFs,onlyballpointpenistobeusedandanychangeofdataistobe
donebystrikingouttheincorrectdatawithasinglelineanddatingandinitialingthechanges
madetoprovideanaudittrail.Correctionsshouldbeexplainedinwriting,whereapplicable.
Correctionfluidorpencilsshouldnotbeused.
ThestudymonitorswillchecktheeCRFsagainstthesourcedocumentsforaccuracyandvalidity
asperthemonitoringschedule,asapplicable;anydatarecordeddirectlyontheeCRF(thatis,no
priorwrittenorelectronicrecordofdata)arealsoconsideredsourcedata.Sourcedata
verificationwillincludetheeCRFdataanddrugaccountability.
eCRFcompletionisexpectedateachsitetoensurequalityofdataandsubjectsafety.Once
eCRFsarecompleted,theywillbeavailableforreviewbythemonitorandtheCRO’sClinical
DataManagementdepartment.CompletedeCRFswillbereviewedremotelyforlogical
discrepancies.Themonitorwillensurethatalldataqueriesandsubsequentamendmentsinthe
eCRFdocumentationaremadeaccordingtoGoodClinicalPractice(GCP)guidelines.
AcopyoftheeCRFistobearchivedbytheinvestigatortogetherwiththestudydocuments,
sourcedata,andlaboratoryrecordsforthetimerequiredbythenationalregulation.
10.1.1.
Confidentiality/Property
Adequaterecordshavetobemaintainedforthestudy,including,butnotlimitedto,subject
medicalrecords,eCRFs,laboratoryreports,worksheets,nursingnotes,signedinformedconsent
forms,productforms,SAEforms,andinformationregardingsubjectdiscontinuationandreasons
fordiscontinuation.Theconfidentialityofeachrecordwithsubjectidentificationistobe
guaranteedbytheclinicalinvestigator.
Thisstudyprotocolandotherstudydocumentscontaintradesecretsandcommercialinformation
thatisprivilegedandconfidential.Suchinformationisnottobedisclosedunlessrequiredby
lawsorregulations.Theinvestigatoragreestousethisinformationonlyinconductingthisstudy
andisnotallowedtouseitforotherpurposeswithoutwrittenconsentfromLIPAC.Results
obtainedfromthisstudyarethepropertyofLIPAC.
10.1.2.
RetentionofRecords
TheinvestigatoragreestoretaincopiesoftheeCRFdatawithotherstudydocuments(e.g.,the
protocolandanyprotocolamendments,theSummaryofProductCharacteristics,IRBapproval,
signedconsentforms,andsourcedocumentsforeachsubjectinthestudy)inasecureplaceas

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
55

CONFIDENTIAL
longasneededtocomplywithnationalandinternationalregulations.Theserecordsmustbe
madeavailableforinspectionuponreasonablerequestbyarepresentativeofLIPACor
regulatoryauthorities.
Intheeventaninvestigatorretires,relocates,orforanyotherreasonwithdrawsfromthe
responsibilityformaintainingrecordsfortheperiodoftimerequired,custodyoftherecordshas
tobetransferredtoanotherpersonwhoacceptsresponsibilityfortherecords,e.g.,LIPAC,an
IRB,oranotherinvestigator.NoticeofsuchtransferhastobegiveninwritingtoLIPAC.
RecordsmaynotbedestroyedwithoutLIPAC’sapproval.
10.1.3.
RoutineMonitoring
Forprotocolmonitoringandcompliance,asitevisitwillbeheldpriortoinitiationofsubject
enrollment.Theprotocol,eCRFs,studytreatmentsupplies,andstudyprocedureswillbe
explainedindetail.
Thepurposeofmonitoringistoverifytherightsandwell-beingofhumansubjectsareprotected;
thatstudydataareaccurate,complete,andverifiablewithsourcedata;andthatthestudyis
conductedincompliancewiththeprotocol,GCP,andtheapplicableregulatoryrequirements.
AmonitorassignedbytheCROwillconductregularsitevisitsforthepurposeofstudy
monitoring.
Theinvestigatormustagreetoallowthestudymonitorandauthorizedrepresentativesofthe
CROorLIPACtoinspectalleCRFsandcorrespondingsourcedocuments(e.g.,originalmedical
records,subjectrecords,andlaboratoryrawdata);toallowaccesstotheclinicalsupplies,
dispensing,andstorageareas;andtoagreetoassistwiththeiractivities,ifrequested.The
investigatorshouldprovideadequatetimeandspaceformonitoringvisitsandvisitsofother
sponsorrepresentatives.
Themonitorwillqueryanymissingorspuriousdatawiththeinvestigator,whichshouldbe
resolvedinatimelymanner.Amonitoringlogwillbemaintainedtorecordeachvisit,the
reasonforthevisit,themonitor’ssignature,andtheinvestigator’sordesignee’sconfirmation
signature.
10.1.4.
SiteAudits
LIPACoritsdesigneemaycarryoutanauditatanytime.Investigatorswillbegivenadequate
noticebeforetheauditoccurs.Thepurposeofanauditistoconfirmthatthestudyisconducted
asperprotocol,GCP,andapplicableregulatoryrequirements;thattherightsandwell-beingof
thesubjectsenrolledhavebeenprotected;andthatthedatarelevantfortheevaluationofthe
investigationalproducthavebeencaptured,processed,andreportedincompliancewiththe
plannedarrangements.Theinvestigatorwillpermitdirectaccesstoallstudydocuments,drug
accountabilityrecords,medicalrecords,andsourcedata.
Regulatoryauthoritiesmayperformaninspectionofthestudy,evenuptoseveralyearsafterits
completion.Ifaninspectionisannounced,theinvestigatororthesitemustinformthesponsor
immediately.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
56

CONFIDENTIAL
10.2.
DatabaseManagementandQualityControl
ThedesignatedCROwillberesponsiblefortheactivitiesassociatedwiththedatamanagement
ofthisstudy,includingtheproductionofeCRFs,settinguparelevantdatabase,andappropriate
validationofdataandresolutionofqueries.AlldatawillbeenteredintoanappropriateeCRF.
AutomatedandmanualcheckswillbemadeagainstthedataenteredintotheeCRFstoensure
completenessandconsistency.Resolutionofquerieswillbeimplementedinthedatabase.
AEswillbestandardizedforterminologyandclassification,usingtheMedicalDictionaryfor
RegulatoryActivities(MedDRA).Concomitantmedicationswillbeclassifiedbysiteofaction
andtherapeuticandclinicalcharacteristicsusingtheWorldHealthOrganizationdrugdictionary
(WHODRUG).Versionsofthedictionariestobeusedwillbedocumentedinthedata
managementplanandthestatisticalanalysisplan(SAP).

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
57

CONFIDENTIAL
11.
STATISTICALMETHODSANDDETERMINATIONOF
SAMPLESIZE
11.1.
StatisticalandAnalyticalPlan
Maximumtolerateddose(part1)willbedeterminedbyarule-basedmethodasfollows:
• HighestdoseatwhichnoDLT(definedasgrade3orgrade4toxicityrelatedtostudy
drug),ORprolonged(morethan14days)grade2toxicity,occurs
− IfnoDLToccursatanydose,thedosejustbeforethedoseatwhich˃33%ofthe
studysubjectsexperiencegrade2toxicityrelatedtostudydrug.
− OriftheMDDisdetermined.
Themarkerlesionresponserate(part2)willbedeterminedbythepercentageofsubjectsat
completioncystoscopyandbiopsytohavenocystoscopicorbiopsyevidenceofresidualdisease.
Partialresponsewillbedeterminedbycomparingthepretreatmentmarkerlesionsizetothe
post-treatmentsize.Partialresponseisatleasta30%decreaseinmarkerlesionsize.
ThepaclitaxelperipheralvenousandurinePKsampleswillbecollectedformeasurementin
part1at15(±15)minutespre-instillation(trough)and2hours(±10minutes)post-exposure
(peak);inpart2,bloodsampleswillbecollectedformeasurementofpaclitaxellevels2hours(±
10minutes)afterthefirstintravesicalinstillation,and15minutes(±15minutes)prior(trough)
and2hours(±10minutes)afterthethirdintravesicalexposure(peak).Allsubjectsinpart2
willalsohaveadditionalurinesamplescollectedaftertheirthirdintravesicalinstillation(see
Section2,ScheduleofEvents).
FulldetailsofthestatisticalanalysiswillbegivenintheSAP.
11.1.1.
GeneralConsiderations
StatisticalanalysisofthisstudywillbetheresponsibilityofaCRO. 
Allefficacyanalyseswillbeconductedbasedonthemodifiedintent-to-treat(MITT)population
aswellasthePPpopulation.Allsafetyanalyseswillbeconductedonthesafetypopulation.
Additionalexploratoryanalysesofthedatamaybeconductedasappropriate.
Unlessotherwisestated,alltestsofsignificancewillbeperformedatalpha=0.05,two-sided.All
studydata,includingdatanotappearingintables,willbepresentedinby-subjectdatalistings.
Allstatisticalanalysesanddatapresentations(tablesanddatalistings)willbegeneratedusing
SASversion9orhigher.
Descriptivestatistics(numberofsubjects,mean,standarddeviation,standarderrorofthemean,
coefficientofvariation,andminimum,median,andmaximumvalues)willbepresentedfor
continuousvariablesbytreatmentgroupandtimepoint(ifapplicable).Categoricalvariableswill
besummarizedincludingnumberandpercentageofsubjectspercategoryforeachtreatment
groupandtimepoint(ifapplicable).
11.1.2.
HandlingofMissingData
Therewillbenoimputationofmissingdata.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
58

CONFIDENTIAL
11.1.3.
AnalysisPopulations
Analyseswillbebasedonthesafety,MITT,PP,andPKpopulations.
• SafetyPopulation:Thesafetypopulationwillincludeallenrolledsubjectswho
receiveatleastonedoseofstudydrug.
• MITTPopulation:TheMITTpopulationwillincludeallenrolledsubjectswho
receiveatleastonedoseofstudydrugandhaveatleastonepost-baseline
measurementofpaclitaxelconcentration.
• PPPopulation:ThePPpopulationwillincludesubjectsintheITTpopulationwho
havenomajorprotocolviolations.Allprotocolviolationswillbedefinedbeforehard
lockofthedatabase.
• PKPopulation:AllsubjectswhoreceivestudydrugandcompletepaclitaxelPK
concentrationmeasurements.
11.1.4.
DemographyandBaselineCharacteristics
Demographyandbaselinecharacteristicssummarieswillbebasedonthesafetypopulation.
11.1.5.
EfficacyParameters
Theprimaryendpointofpart1istheMTD,definedasthedoseimmediatelyprecedingthedose
atwhichDLToccursorwhenaMDDisdetermined.TheseverityandfrequencyofAEswillbe
documentedfollowingTSD-001administration,anddefinedaccordingtoNCICTCAE
Version5.0.
Thesecondaryendpointsofpart1aretodeterminePKparametersintheurineandthe
peripheralblood.
Exploratoryendpointsofpart1includethefollowing:
• ChangefrombaselinetoWeek16inIPSS(menonly)
• ChangefrombaselinetoWeek16inOAB-qscore
Theprimaryendpointofpart2istodeterminethemarkerlesionresponserateatthefinal
endoscopicassessmentafterweeklyinstillationsofTSD-001.Thefinalendoscopicassessment
willbe12weeks(±7days)afterDay1forsubjectsinpart2cohort1and15weeks(±7days)
afterDay1forsubjectsinpart2cohort2.
Thesecondaryendpointsofpart2are:1)todeterminepaclitaxelconcentrationparametersinthe
peripheralbloodafterinstillationoftheMTD/MDDofTSD-001,and2)tocharacterizethe
severityandfrequencyofAEsaftertheMTD/MDDofTSD-001isintravesicallyadministered
weeklyfor6administrations(cohort1)or8administrations(cohort2).
Exploratoryendpointsofpart2includethefollowing:
• ChangefrombaselinetotheendofthetreatmentpartinIPSS(menonly)
• ChangefrombaselinetotheendofthetreatmentpartinOAB-qscore

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
59

CONFIDENTIAL
• Paclitaxellevelsinvoidedurinesamplesat24,48,and72hoursafterthethird
instillationofTSD-001.
11.1.6.
SafetyParameters
Safetyendpointsare:
• AEs/SAEs
• vitalsigns(bloodpressure,pulserate,respiratoryrate,andbodytemperature)
• laboratorymeasurements
• 12-leadECG
• physicalexaminations
Allsafetysummarieswillbeperformedonthesafetypopulation.
11.1.7.
PharmacokineticAssessments
Paclitaxelconcentrationswillbelimitedtopre-instillation(trough)andtopost-instillation(peak)
concentrationmeasurementsofurineandplasma.Paclitaxellevelswillalsobemeasuredin
voidedurinesamplesat24,48,and72hoursafterthethirdinstillationofTSD-001.Thegoalis
todefinethelocalandsystemicexposureofthestudysubjectstopaclitaxel(and/orits
metabolites).Paclitaxelconcentrationsinplasmawillbemonitoredforevidenceofsystemic
exposure.
11.2.
InterimAnalyses
Maximumtolerateddosewillbedeterminedbasedonamodifiedacceleratedtitrationdesign
withintra-subjectescalation.Theobjectiveistofindthehighestnontoxicdose,whichwillbe
therecommendeddoseforpart2ofthestudy.Paclitaxelconcentrationsinplasmaandother
studydrugfindingsmaybeusedtoinformthedecisionregardingappropriatemaximum
deliverabledose.
11.3.
DeterminationofSampleSize
Thestudyisaproof-of-conceptstudydesignedtoestablishtheMTDinpart1,andtoassess
preliminaryefficacyviaamarkerlesionmethodinpart2.Localandsystemicpaclitaxel
exposurewillbemeasuredinstudypart1andpart2.Giventhesegoals,asamplesizeofat
least6subjectsforpart1andupto15forpart2,foratotalofupto21subjects,hasempirically
beenplannedassufficienttoachievethestudygoals.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
60

CONFIDENTIAL
12.
ETHICALANDADMINISTRATIVERESPONSIBILITIES
Theproceduressetoutinthisstudyprotocol,pertainingtotheconduct,evaluation,and
documentationofthisstudy,aredesignedtoensurethattheSponsor,itsauthorizedUS
representative,andinvestigatorabidebyGCPasdescribedintheICHguidelineE6,andinUS
regulationsdescribedin21CodeofFederalRegulations(CFR)parts50,54,56,and312.
Compliancewiththeseregulationsalsoconstitutescompliancewiththeethicalprinciplesthat
havetheiroriginsintheDeclarationofHelsinki.
DetailsofthestudyadministrationandethicalconsiderationsarepresentedinAppendix1.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
61

CONFIDENTIAL
13.
REFERENCES
AbelPD.Prognosticindicesintransitionalcellcarcinomaofthebladder.BrJUrol.
1988;62(2):103-9.
BarryMJ,FowlerFJJr,O’LearyMP,etal.TheAmericanUrologicalAssociationsymptom
indexforbenignprostatichyperplasia.TheMeasurementCommitteeoftheAmericanUrological
Association.JUrol.1992;148(5):1549-57.
CooksonMS,ChangSS,OefeleinMG,GallagherJR,SchwartzB,HeapK.Nationalpractice
patternsforimmediatepostoperativeinstillationofchemotherapyinnonmuscleinvasivebladder
cancer.JUrol.2012;187(5):1571-6.
DevesaSS,BlotWJ,StoneBJ,MillerBA,TaroneRE,FraumeniJFJr.Recentcancertrendsin
theUnitedStates.JNatlCancerInst.1995;87(3):175-82.
EisenhauerEA,TherasseP,BogaertsJ,etal.Newresponseevaluationcriteriainsolidtumours:
revisedRECISTguideline(version1.1).EurJCancer.2009;45(2):228-47.
FairWR,FuksZY,ScherHI.Cancerofthebladder.In:DeVitaVTJr,HellmanS,Rosenberg
SA,eds.Cancer:principlesandpracticeofoncology.4thed.Philadelphia,PA:Lippincott;1993.
pp.1052-72.
GofritON,ZornKC,ShikanovS,SteinbergGD.Markerlesionexperimentsinbladdercancer–
whathavewelearned?JUrol.2010;183(5):1678-84.
GorinMAandSolowayMS.Activesurveillancewithdelayedinterventionforrecurrentlowrisk
bladdercancer.UrolPract.2015;2(5):256-9.
GreenleeRT,Hill-HarmonMB,MurrayT,ThunM.Cancerstatistics,2001.CACancerJClin.
2001;51(1):15-36.
HerrHW,DonatSM,DalbagniG.Correlationofcystoscopywithhistologyofrecurrent
papillarytumorsofthebladder.JUrol.2002;168(3):978-80.
LeeCT,BarocasD,GlobeDR,etal.Economicandhumanisticconsequencesofpreventable
bladdertumorrecurrencesinnonmuscleinvasivebladdercancercases.JUrol.
2012;188(6):2114-9.
SolowayMS.Introductionandoverviewofintravesicaltherapyforsuperficialbladdercancer.
Urology.1988;31(3Suppl):5-16.
SylvesterRJ,OosterlinckW,vanderMeijdenAP.Asingleimmediatepostoperativeinstillation
ofchemotherapydecreasestheriskofrecurrenceinpatientswithstageTaT1bladdercancer:a
meta-analysisofpublishedresultsofrandomizedclinicaltrials.JUrol.2004;171(6Pt1):2186-
90.
WHO.HistologicalTypingofUrinaryBladderTumours,No.10:Geneva:WorldHealth
Organization;1973.
WHO.PathologyandGeneticsofTumoursoftheUrinarySystemandMaleGenitalOrgans.
Lyon,France:IARCPress,InternationalAgencyforResearchonCancer;2004.


LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
62

CONFIDENTIAL
14.
APPENDICES

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
63

CONFIDENTIAL
APPENDIX1. STUDYADMINISTRATIONANDETHICAL
CONSIDERATIONS
14.1.
InvestigatorsandStudyAdministrativeStructure
Theinvestigatorwhoisresponsiblefortheconductofthisstudy,incompliancewiththis
protocol,isidentifiedontheprotocolsignaturepageoftheprotocol.Theinvestigatorwillalso
signtheInvestigatorAgreementandprovideittotheSponsororSponsor’srepresentativeprior
toreceiptofinvestigationalproductandstudyinitiationatthatinvestigationalcenter.

Sponsor:




LIPACOncologyLLC
325SharonParkDrive,Suite739
MenloPark,CA94025-6805

ClinicalProjectManager:


KarlBean,LIPACOncologyLLC
3670WestTempleAve.,Suite270
Pomona,CA91768

SafetyOfficer:



MichaelG.Oefelein,M.D.,FACS
LIPACOncologyLLC
3670WestTempleAve.,Suite270
Pomona,CA91768

14.2.
InstitutionalReviewBoard(IRB)Approval
TheinvestigatorwillsubmittheprotocolandinformedconsentformforIRBreview.Thiswill
beappropriatelydocumented.Theprotocol,anyprotocolamendments,theinformedconsent
form,andallotherformsofsubjectinformationrelatedtothestudyandanyothernecessary
documentswillbereviewedbyanIRB.
ItisrequiredthatavalidIRBapproves,inwriting,theconductofthisclinicalstudy,together
withtheinformedconsentform,priortostudyinitiation.Thewrittenapprovalshouldconsistof
acompletedIRBapprovalformorwrittendocumentationfromtheIRBcontainingthesame
information.
UntilwrittenapprovalbytheIRBhasbeenreceivedbyLIPAC,nosubjectmayundergoany
procedures.
Thenamesandqualificationsofthemembersofthereviewcommitteewillberecordedand
submittedtoLIPAC,togetherwiththewrittenapprovalfortheconductofthestudy.The
membersoftheIRBmustbeindependentofLIPACandtheinvestigator.
Nodeviationsfrom,orchangesof,theprotocol,shouldbeinitiatedwithoutpriorwrittenIRB
approvaloftheappropriateamendment,exceptwhennecessarytoeliminateimmediatehazards
tothesubjectsorwhenthechange(s)involvesonlylogisticaloradministrativeaspectsofthe
study(e.g.,changeofmonitor[s],telephonenumber[s]).

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
64

CONFIDENTIAL
14.3.
EthicalConductoftheStudy
Theinvestigatoragreesthatthestudywillbeconductedaccordingtotheprotocol,the
DeclarationofHelsinkiandtheprinciplesofGoodClinicalPractice(GCP),andInternational
ConferenceonHarmonisation(ICH)guidelinesgoverningclinicalstudyconduct.
Theinvestigatorwillconductallaspectsofthisstudyinaccordancewithallnational,state,and
locallawsofthepertinentregulatoryauthorities.
Thestudywillbeconductedincompliancewith:
• theprotocol
• ethicalprinciplesoftheDeclarationofHelsinkianditsamendments
• theprinciplesofGCPprovidedintheICHHarmonisedTripartiteGuidelinesforGCP
1996
• allapplicablenationallawsandregulationsincluding,butnotlimitedto,
country-specificGCP
14.4.
SubjectInformationandConsent
Theinvestigatororhis/herrepresentativewillexplainthenatureofthestudytothesubject,and
answerallquestionsregardingthisstudy,priortoobtaininginformedconsent.Specific
instructionsrelatedtostudyconduct(e.g.,visitschedule)willbeprovidedtothesubjectwiththe
informedconsentform.
Theinvestigatorwillobtaininformedconsentfromeachsubjectenrolledinthestudy,in
accordancewiththecurrentversionoftheGCPguidelinesandthelawsandregulationsofthe
countryinwhichtheinvestigationisbeingconducted.
TheIRBmustapprovetheinformedconsentformtobeusedbytheinvestigatorpriortoitsuse.
Itistheresponsibilityoftheinvestigatortoassurethatthesubjecthassignedtheinformed
consentformbeforeanyactivityortreatmentisundertaken.Thisincludes,butisnotlimitedto,
theperformanceofdiagnosticortherapeuticproceduresandtheadministrationofthe
investigationalproduct.
14.5.
SubjectConfidentiality
Adequaterecordshavetobemaintainedforthestudy,includingbutnotlimitedtosubject
medicalrecords,electroniccasereportform(eCRFs),laboratoryreports,worksheets,nursing
notes,signedinformedconsentforms,productforms,seriousadverseevent(SAE)forms,and
informationregardingsubjectdiscontinuationandreasonsfordiscontinuation.The
confidentialityofeachrecordwithsubjectidentificationistobeguaranteedbytheclinical
investigator.
Thisprotocolandotherstudydocumentscontaintradesecretsandcommercialinformationthat
isprivilegedandconfidential.Suchinformationisnottobedisclosedunlessrequiredbylawsor
regulations.Theinvestigatoragreestousethisinformationonlyinconductingthisstudyandis
notallowedtouseitforotherpurposeswithoutwrittenconsentfromLIPAC.Resultsobtained
fromthisstudyarethepropertyofLIPAC.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
65

CONFIDENTIAL
14.6.
StudyMonitoring
Forprotocolmonitoringandcompliance,aninvestigationalcentervisitwillbeheldpriorto
initiationofsubjectenrollment.Theprotocol,eCRFs,studysupplies,andstudyprocedureswill
beexplainedindetail.
Amonitorwillconductregularinvestigationalcentervisitsforthepurposeofstudymonitoring.
TheinvestigatormustagreetoallowthestudymonitorandauthorizedrepresentativesofLIPAC
orLIPACdesigneetoinspectalleCRFsandcorrespondingsourcedocuments(e.g.,original
medicalrecords,subjectrecords,andlaboratoryrawdata);toallowaccesstotheclinical
supplies,dispensing,andstorageareas;andtoagreetoassistwiththeiractivities,ifrequested.
Theinvestigatorshouldprovideadequatetime,availability,andspaceformonitoringvisits.
Themonitorwillqueryanymissingorspuriousdatawiththeinvestigatorordesignee,which
shouldberesolvedinatimelymanner.Amonitoringlogwillbemaintainedtorecordeachvisit,
thereasonforthevisit,themonitor’ssignature,andtheinvestigator’sordesignee’sconfirmation
signature.
14.7.
CaseReportFormsandStudyRecords
Casereportformdatawillbecollectedelectronically.Subjectsourcedocumentsarethe
physician’srecordsmaintainedattheinvestigationalcenter.Theinformationcollectedonthe
eCRFmustmatchtheinformationfoundonthecharts.
InstructionsforenteringdataviainternetwillbeprovidedintheeCRFCompletionGuidelines
andtrainingwillbeprovidedtotheinvestigationalcenterstaffpriortoinitiationofthecenter.
Periodically,whereappropriate,theMonitororotherauthorizedLIPACpersonnelwillvisitthe
investigationalcenterforthepurposeofcomparingthedataontheeCRFwiththesource
documents.Theinvestigatoragreestomakesourcedocumentsavailableforthispurpose.The
eCRFshouldbecompletedassoonaspossibleafterthedataareavailable.
14.8.
DataMonitoringCommittee
Notapplicable.
14.9.
TerminationoftheStudy
LIPACreservestherighttoterminatethisstudyprematurely,eitherinitsentiretyorataspecific
site,forreasonablecauseprovidedthatwrittennoticeissubmittedareasonabletimeinadvance
oftheintendedtermination.Theinvestigatormayalsoterminatethestudyattheirsitefor
reasonablecause,afterprovidingwrittennoticetoLIPACareasonabletimeinadvanceofthe
intendedtermination.Neitherpartyrequiresadvancenoticeifthestudyisstoppedduetosafety
concerns.IfLIPACchoosestoterminatethestudyforsafetyreasons,itwillimmediatelynotify
theinvestigatorandsubsequentlyprovidewritteninstructionsforstudytermination.Subjects
whohavenotcompletedtreatmentinthestudyatthetimeofterminationwillbeadvisedand
offeredalternativetreatment,asmedicallynecessary.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
66

CONFIDENTIAL
14.10.
FinancialDisclosure
ConsistentwithTitle21CFRPart54,allinvestigatorswillcompleteaFinancialDisclosure
FormthatpermitstheSponsortodemonstratethataninvestigatorhasnopersonalorprofessional
financialincentiveregardingstudyoutcomeorthefutureapproval/disapprovalofan
investigationaldrugsuchthattheinvestigator’sresearchmightbebiasedbysuchincentive.
14.11.
PublicationandDisclosurePolicy
Anyformalpresentationorpublicationofdatafromthisstudywillbeconsideredbythe
appropriateLIPACpersonnel.Formulticenterstudies,itismandatorythatthefirstpublication
isbasedondatafromallcenters,analyzedasstipulatedintheprotocol.Investigatorsagreenot
topresentdatagatheredfromonecenterorasmallgroupofcentersbeforethefullpublication.
Inthiscase,LIPACmustreceivecopiesofanyintendedcommunicationinadvanceof
publication(atleast30workingdaysforanabstract/oralpresentationand60workingdaysfora
journalsubmission).Inanycase,LIPACwillreviewthepublications/communications/abstracts
foraccuracy(thusavoidingpotentialdiscrepancieswithsubmissionstohealthauthorities),verify
thatproprietary,confidentialinformationisnotbeinginadvertentlydivulged,andprovideany
relevantsupplementaryinformation.

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
67

CONFIDENTIAL
APPENDIX2. INTERNATIONALPROSTATESYMPTOMSCORE
(IPSS)
TheInternationalProstateSymptomScore(IPSS)isascaleoriginallydevelopedbythe
AmericanUrologicalAssociationMeasurementCommittee(Barry,etal.,1992).
TheIPSSisbasedontheanswerstosevenquestionsconcerningurinarysymptomsandone
questionconcerningrelatedqualityoflife.Eachquestionconcerningurinarysymptomsasksthe
patienttochooseoneofsixanswersindicatingincreasingseverityofthesymptom.Theanswers
aregivenpointsfrom0to5.Totalscorecanrangefromaminimumof0(asymptomatic)toa
maximumof35(verysymptomatic).
Thequestionsrefertothefollowingurinarysymptoms:
Symptom
1. Incompleteemptying
2. Frequency
3. Intermittency
4. Urgency
5. Weakstream
6. Straining
7. Nocturia

Questioneightreferstothepatient’sperceivedqualityoflife.
ThefirstsevenquestionsoftheIPSSareidenticaltothequestionsappearingontheAmerican
UrologicalAssociation(AUA)SymptomIndex,whichapproximatestotalsymptomscoresas
follows:
TotalScore

Category
≤7


Mild
8-19


Moderate
20-35 

Severe

LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
68

CONFIDENTIAL

InternationalProstateSymptomScore

Patientname:___________
DOB:__________
Subject#:_________Date:___________

/	

E
>



>








D






,










 
!

"
#
$

",




"

 
!

"
#
$

#,










 
!

"
#
$

$,



 
!

"
#
$

,


%

 
!

"
#
$

,



 
!

"
#
$


E



"

#

$





&,








!

"
#
$


LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
69

CONFIDENTIAL





 
d^

^
Y>
(

h^
(


W


D
^

D,

D
(
 h
d


./






0

1


 
!

"
#
$





LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
70

CONFIDENTIAL
APPENDIX3. OVERACTIVEBLADDERQUESTIONNAIRE(OAB-Q)






























Overactive Bladder Questionnaire (OAB-q) 
 
 
 
This questionnaire asks about how much you have been bothered by selected bladder symptoms 
during the past week. Please place a ü or û in the box that best describes the extent to which you were 
bothered by each symptom during the past week. There are no right or wrong answers. Please be sure 
to answer every question. 
 
During the past week, how 
bothered were you by. . . 
Not at 
all 
A little 
bit 
Some-
what 
Quite a 
bit 
A great 
deal 
A very 
great  
deal 
1. Frequent urination during the 
daytime hours? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
2. An uncomfortable urge to 
urinate? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
3. A sudden urge to urinate with 
little or no warning? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
4. Accidental loss of small 
amounts of urine? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
5. Nighttime urination? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
6. Waking up at night because you 
had to urinate? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
7. An uncontrollable urge to 
urinate? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
8. Urine loss associated with a 
strong desire to urinate? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 

 
 
The above questions asked about your feelings about individual bladder symptoms. For the following 
questions, please think about your overall bladder symptoms in the past week and how these 
symptoms have affected your life. Please answer each question about how often you have felt this way 
to the best of your ability. Please place a ü or û in the box that best answers each question. 


Overactive Bladder Questionnaire (OAB-q) 
 

During the past week, how often 
have your bladder symptoms . . . 
None of
the 
time 
A little
of the 
time 
Some 
of the 
time 
A good 
bit of 
the 
time 
Most of 
the 
time 
All of 
the 
time 
9.  Made you carefully plan your 
commute? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
10. Caused you to feel drowsy or 
sleepy during the day? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
11. Caused you to plan “escape 
routes” to restrooms in public 
places? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
12. Caused you distress? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
13. Frustrated you? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
14. Made you feel like there is 
something wrong with you? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
15. Interfered with your ability to get 
a good night’s rest? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
16. Caused you to decrease your 
physical activities (exercising, 
sports, etc.)? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
17. Prevented you from feeling 
rested upon waking in the 
morning? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
18. Frustrated your family and 
friends? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
19. Caused you anxiety or worry? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
20. Caused you to stay home more 
often than you would prefer? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
21. Caused you to adjust your travel 
plans so that you are always 
near a restroom? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
22. Made you avoid activities away 
from restrooms (i.e., walks, 
running, hiking)? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 



Overactive Bladder Questionnaire (OAB-q) 
 

During the past week, how often 
have your bladder symptoms . . . 
None of
the 
time 
A little
of the 
time 
Some 
of the 
time 
A good 
bit of 
the 
time 
Most of 
the 
time 
All of 
the 
time 
23. Made you frustrated or annoyed 
about the amount of time you 
spend in the restroom? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
24. Awakened you during sleep? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
25. Made you worry about odor or 
hygiene? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
26. Made you uncomfortable while 
traveling with others because of 
needing to stop for a restroom? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
27. Affected your relationships with 
family and friends? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
28. Caused you to decrease 
participating in social 
gatherings, such as parties or 
visits with family or friends? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
29. Caused you embarrassment? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
30. Interfered with getting the 
amount of sleep you needed? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
31. Caused you to have problems 
with your partner or spouse? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
32. Caused you to plan activities 
more carefully? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 
33. Caused you to locate the closest 
restroom as soon as you arrive 
at a place you have never 
been? 
o 
1 
o 
2 
o 
3 
o 
4 
o 
5 
o 
6 

 
© Copyright 2004 Pfizer. All rights reserved. 
 


LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
71
CONFIDENTIAL
APPENDIX4.
DOSEESCALATIONRULES
Part1.Ifagrade2toxicityisobserved,theintravesicalinstillationmaybedelayed(upto
14days)andtheintravesicaldosewillbereducedtohalfthedifferencebetweenthelast2doses,
andthesubjectcanbere-exposedtostudydrugatthediscretionoftheinvestigator.For
example,ifasubjectreceives180mgofTSD-001withnotoxicity,butgrade2toxicityoccurs
whenthedoseisincreasedto270mg,thenthesubjectmaybere-exposedat225mgdose.Any
patientwithgrade3or4toxicity(orprolonged[greaterthan14daydelay]grade2toxicity)will
beconsideredhavingexperiencedaDLT,whichwillresultindiscontinuationofstudydrug.
Part2.Ifanygrade2CTCAEtoxicityisobserved,theintravesicalinstillationmaybedelayed
(upto14days)andtheintravesicaldosewillbereducedby25%fromtheMTD/MDD
establishedinpart1.Forexample,ifgrade2toxicityisobservedafterexposuretothe
MTD/MDDof360mg,thenthenextdosewouldbe270mg,andmaybedelayedforupto
14days.Anypatientwithgrade3or4toxicity(orprolongedgrade2toxicity)willbe
consideredhavingexperiencedaDLT,whichwillresultindiscontinuationofstudydrug.
IfnoDLTdevelopsinpart1cohort1,thenpart1cohort2(subjects4,5,and6)willstartwith
90mgandincreaseevery2weeksupto540mgoruntilDLTisreached.
Figure3:
DiagramoftheAdaptiveAcceleratedIndividualDose-escalationSchedule
forPart1andDoseAssignmentforPart2

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
72

CONFIDENTIAL
DecelerationDoseTitrationPlanuponStudy-relatedLow-gradeToxicity:
Dose-limitingtoxicityisdefinedbyanytoxiceffectspotentiallyrelatedtodrugthatare
consideredunacceptableandlimitfurtherdoseescalation.Symptomsoflocaltoxicitywillbe
monitoredthroughoutstudytreatment.AnypatientwithevidenceofCTCAEgrade3or4
toxicity(orprolonged,greaterthan14days,grade2toxicity)willbeconsideredtohave
experiencedaDLTandwillimmediatelydiscontinuestudydrug.Ifnograde3or4CTCAE
toxicity(orprolongedgrade2toxicity)isobserved,MTDwillbedefinedasthedosejustbefore
thedoseatwhich˃33%ofthestudysubjectsexperiencegrade2CTCAEtoxicityrelatedto
studydrug,orwhentheMDDisreached.IfnoDLTisobservedinthefirst6subjectsafter
titration,then360mgwillbethedoserecommendedforpart2ofthestudy,asthispaclitaxel
concentrationissubstantiallyhigherthanthehalf-maximalinhibitoryconcentration(IC50)
observedinbladdercancercelllinesexposedtoTSD-001.
IfaCTCAEgrade2localtoxicitydevelopsineitherpart1orpart2ofthestudy,treatmentof
thesubjectwillbedelayedfornolongerthan14daysandresumedonlyifthetoxicityresolvesto
grade1orless.Subsequentdoseescalationinpatientswhoexperiencegrade2toxicitieswhich
improvetograde1orresolvewithin14dayswouldproceedathalfthemagnitudeofdose
escalationspecifiedintheprotocolforatotalofupto6intravesicalinstillations.Forexample,if
studysubject001hadgrade2toxicityinpart1cohort1afterexposuretothe50-mgdose,the
subjectwouldpostponestudydrugadministrationandbereassessedafteradelayofnolonger
than14days;ifthetoxicityimprovedtograde1orresolvedwithinaperiodof14days,the
subjectwouldbeeligibleforexposureto37.5mgTSD-001(seedoseescalationexamplefor
part1cohort1below).
Alternatively,ifthestudysubjectwhoexperiencesagrade2relatedtoxicityfollowingTSD-001
treatmentdoesnotimproveorresolveafteranupto14-daydelayfollowingthelastexposureof
studydrug,heorshewouldnotbeexposedtoadditionalTSD-001intravesicaltreatments.

Doseescalationexample–Part1Cohort1:


Asanadditionalexample(#2),ifstudysubject004(cohort2)experiencesmoderatedysuria
(grade2)at270mgTSD-001,thenextdoseforthatsubjectwouldbedelayedupto14daysif
theseverityofthetoxicityresolvesorlessenstograde1;subject004canbere-exposedto
TSD-001atthe225mgdoselevel.Iftheinitialgrade2toxicitydoesnotimprovetograde1or
resolvewithina14-daydelay,thesubjectwilldiscontinuestudyparticipation.Subsequent

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
73

CONFIDENTIAL
dosingofthesubjectwillbeatone-halfthemagnitudeoftheprotocol-specifiedincreaseindose
forupto6intravesicalinstillationsasdescribedaboveinexampleforpart1cohort1(seedose
escalationexampleforpart1cohort2below).
Doseescalationexample–Part1Cohort2:

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

PROTOCOLAMENDMENTSUMMARYOFCHANGES
APhase1/2aPilotStudyofintravesicalTSD-001forTreatmentofLow-Grade,StageTa,
Non-MuscleInvasiveBladderCancer


StudyNumber:

TD-001
Indication: 

Non-MuscleInvasiveBladderCancer(NMIBC)
Sponsor:


LIPACOncologyLLC
325SharonParkDrive,Suite739
MenloPark,CA94025

InitialVersion

26Sep2016

Revision#1(V2.0)

28Feb2017


Revision#2(V3.0)

20Mar2018

Revision#3(V4.0)

17Oct2018

Revision#4(V5.0)

05Apr2019

Revision#5(V6.0)

18Jul2019

Revision#6(V7.0)

04FEB2020










LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

SignificantChangestotheprotocolfromVersion6.0toVersion7.0
Verbiageandcontentchangesaresimilarincertainsectionsoftheprotocol.Allaffectedsectionsarelistedinthefirstcolumnfor
similarchanges.

ProtocolSection(s)
Version6.0
Version7.0
Header,TitlePage,
synopsis,



protocolthroughout,

14.1.Investigatorsand
StudyAdministrative
Structure
Sponsorlistedas“TesoRxPharma,LLC”




“TesoRx”
Sponsorupdatedto“LIPACOncologyLLC”with
accompanyingaddress:
325SharonParkDrive,Suite739
MenloPark,CA94025-6805

“LIPAC”

UpdatedLIPACOncologyLLC(Sponsor)address
asabove.
AddressforDr.MichaelOefelein(ChiefMedical
Officer)andKarlBean(ClinicalProjectManager)
remainsasPomona,CAaddress.
Synopsisandprotocol







Synopsis:Study
Duration


Synopsis:
Methodology,
5.1.OverallDesign
andPlanoftheStudy
Part2containednocohorts.











“Thestudyhasatotalof17plannedclinicvisitsfor
part1and14plannedclinicvisitsforpart2.”
Part2,Cohort1andCohort2areintroduced.
Part2Cohort1isthesamescheduleofeventsas
Protocolv6.0Part2ScheduleofEvents.

Part2Cohort2addstwotreatmentvisits,extends
totaltreatmentperiodby3weeksandaddstwo
additionalvisits.

“Part2Cohort2–upto20weeks(upto4-week
screeningperiod,7-weektreatmentperiod,and9-
weekfollow-upperiod).”

“Thestudyhasatotalof17plannedclinicvisitsfor
part1and14plannedclinicvisitsforpart2cohort
1subjectsand16plannedclinicvisitsforpart2
cohort2subjects.”

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

ProtocolSection(s)
Version6.0
Version7.0
Synopsis






4.StudyObjectives

Addeddescriptionsofhistologicaltissuediagnosis
evidence.
“Histologicaltissuediagnosisevidenceis
identificationofanyurothelialcarcinoma(i.e.,
transitionalcellcarcinoma[TCC]),includingall
gradesandstages.”

“Histologicaltissuediagnosisevidenceisany
diagnosisofurothelialcarcinoma(i.e.,TCC),
includingallgradesandstages.”
Synopsis:
Methodology:
DescriptionofPart2:
“Part2ofthestudywillenrollanadditional10
subjectswithlow-grade,stageTaTCCofthe
bladderwhowillreceiveweeklyTSD-001for6
weeksatthehighestnontoxicdoseestablishedin
part1ofthestudy.”


“Part2cohort1ofthestudywillenrollatleast5
subjectswithlow-grade,stageTaTCCofthe
bladderwhowillreceiveweeklyTSD-001for6
administrationsatthehighestnontoxicdose
establishedinpart1ofthestudy.Part2cohort2
ofthestudywillenrollupto10subjectswithlow-
grade,stageTaTCCofthebladderwhowill
receiveweeklyTSD-001for8administrationsat
thehighestnontoxicdoseestablishedinpart1of
thestudy.”
Synopsis,Scheduleof
Events(Table2and3),
4.StudyObjectives,
5.1.OverallDesign
andPlanoftheStudy,
8.3Exit/Withdrawal
fromPart1/Part2,
11.1.5.Efficacy
Parameters
SubjectsinPart2:“themarkerlesionresponserate
willbedetermined12weeks(±7days)afterDay1
(i.e.,7weeks[±7days]afterthelastintravesical
instillation),viacystoscopy,cytology,andbiopsy
undergeneral/regionalanesthesia.”






Subjectsinpart2cohort1:“themarkerlesion
responseratewillbedetermined12weeks
(±7days)afterDay1(i.e.,7weeks[±7days]after
thelastintravesicalinstillation),viacystoscopy,
cytology,andbiopsyundergeneral/regional
anesthesia.”

ForPart2cohort2subjects:“themarkerlesion
responseratewillbedetermined15weeks(±
7days)afterDay1(i.e.,8weeks[±7days]after
thelastintravesicalinstillation).”

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

ProtocolSection(s)
Version6.0
Version7.0
Synopsis:

Methodology:,
4.StudyObjectives,
5.1.OverallDesign
andPlanoftheStudy,


11.1.Statisticaland
AnalyticalPlan








“Themarkerlesionresponserate(part2)willbe
determinedbythepercentageofsubjectsat
completioncystoscopyandbiopsytohavenegative
cytologyandnocystoscopicorbiopsyevidenceof
residualdisease.”

Adddescriptionofmarkerlesionassessment,
determinationofcompleteandpartialresponse,for
allPart2subjects:
“Completemarkerlesionresponserequiresno
evidenceofTCConcystoscope-directedbiopsy.
Partialresponseisatleasta30%decreaseinmarker
lesionsize(Eisenhaueretal.,2009).”

“Themarkerlesionresponserate(part2)willbe
determinedbythepercentageofsubjectsat
completioncystoscopyandbiopsytohaveno
cystoscopicorbiopsyevidenceofresidualdisease.
Partialresponsewillbedeterminedbycomparing
thepretreatmentmarkerlesionsizetothe
post-treatmentsize.Partialresponseisatleasta
30%decreaseinmarkerlesionsize.”
Synopsis:



Methodology:,








TestProduct,Dose,
andModeof
Administration:




“Duringpart2,anadditional10subjectswill
receiveintravesicalinstillationsofTSD-001via
sterileurethralcatheterizationoftheurinarybladder
attheMTD/MDDestablishedinpart1atweekly
intervalsfor6consecutiveweeks.”
Clarificationthatsubjectsinpart2cohort1will
followpreviouspart2scheduleofeventsincluding
6treatments.Part2cohort2willhave8
treatments.
“Subjectsinpart2cohort1willreceive
intravesicalinstillationsofTSD-001viasterile
urethralcatheterizationoftheurinarybladderatthe
MTD/MDDestablishedinpart1atweekly
intervalsfor6consecutiveweeks.Subjectsinpart
2cohort2willreceiveintravesicalinstillationsof
TSD-001atweeklyintervalsfor8consecutive
weeks.”

“Forsubjectsinpart2cohort2,theMTDorMDD
willbeadministeredevery7daysfor8consecutive
administrations.”

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

ProtocolSection(s)
Version6.0
Version7.0
Synopsis,6.1.
InclusionCriteria3-5,
8.1.1.TURBT,8.1.2.
MarkerLesion(for
Part2)

Markerlesionsizecriteriawas>0.5cmand
≤2.0cmindiameter.
Markerlesionsizecriteriaupdatedto≥0.5cmand
≤2.0cmindiameter.
Synopsis,6.2.
ExclusionCriteria2,
8.1.2MarkerLesion
Excludedif“Haspositiveurinecytologyfor
urothelialmalignancyatscreening.”
Excludedif“Haspositiveurinecytologyfor
urothelialmalignancy(i.e.,high-grade)at
screening.”

Synopsis,

5.1.OverallDesign
andPlanoftheStudy,

11.3.Determinationof
SampleSize
Anenrollmentofapproximately16subjectsis
planned,with6subjectsinpart1and10subjects
inpart2


Giventhesegoals,asamplesizeofatleast6
subjectsforpart1andatleast10forpart2,fora
totalofatleast16,hasempiricallybeenplannedas
sufficienttoachievethestudygoals.
Anenrollmentofupto21subjectsisplanned,with
6subjectsinpart1andupto15additionalsubjects
inpart2(atleast5incohort1andupto10in
cohort2).

Giventhesegoals,asamplesizeofatleast6
subjectsforpart1andupto15forpart2,fora
totalofupto21subjects,hasempiricallybeen
plannedassufficienttoachievethestudygoals.

Synopsis,Appendix4.
DoseEscalationRules
Existingreferencesto‘cohort1’and‘cohort2’
refertoPart1cohort1andPart1cohort2.
Added“part1”toDoseEscalationreferencesto
distinguishfrompart2cohort1andcohort2.


LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

ProtocolSection(s)
Version6.0
Version7.0
Synopsis:Criteriafor
Evaluation




9.1.2.Secondary
Endpoints


“Theendpointwillbeatimetoevent(recurrence)
afterthelastinstillationofTSD-001.”
Clarifiedstartingpointfortimetoevent
(recurrence)endpoint.
“Theendpointwillbeatimetoevent(recurrence)
aftertheTURBT(Day-12inPart1)orafter
completeresponseorWeek12TURBTinPart2.”

“Theexploratoryendpointofpart3(surveillance)
willbedisease-freesurvivalofsubjectsexposedto
TSD-001inpart1orpart2.
· Theendpointwillbetimetoevent(recurrence)
aftertheTURBT(Day-12inpart1)orafter
completeresponseorWeek12TURBTinpart
2.Disease-freesurvivalwillbedefinedasno
histologicaltissuediagnosisevidenceof
recurrence.”
2.ScheduleofEvents

InsertedTable3:Part2Cohort2Scheduleof
Assessmentsincludingadditionaltreatmentvisits
(incomparisontocohort1)atWeek6andWeek7.
Follow-upvisitsatWeek9andWeek12.Marker
lesionassessmentatWeek15visit.Endof
treatmentpartvisitatWeek16.
2.ScheduleofEvents,
Table4:Surveillance
Scheduleof
Assessments(Part3),
5.1.OverallDesign
andPlanoftheStudy,
7.5.Prior/Concomitant
Medication&Therapy
8.4.Part3
(Surveillance)Visits,
9.3.1.AdverseEvents
1. OnlyrecordedineCRFiftheyrelatetoanAE
continuingfrompart1orpart2,atreatment
forarecurrence,orareportedSAE.
2. AEscontinuedfrompart1orpart2,butno
newAEswillberecorded.NewAEsonly
recordediftheymeetthedefinitionofaSAE.


NewAEsshouldberecordedduringthe
surveillanceportion(part3)ofthestudyonlyif
theymeetthedefinitionofaSAE.
RemovedcollectionofSAEsfromPart3.
1. OnlyrecordedineCRFiftheyrelatetoanAE
continuingfrompart1orpart2oratreatment
forarecurrence.
2. AEscontinuedfrompart1orpart2,butno
newAEswillberecorded.




LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

ProtocolSection(s)
Version6.0
Version7.0
5.1.OverallDesign
andPlanoftheStudy




8.3Exit/Withdrawal
fromPart1/Part2


8.4.Part3
(Surveillance)Visits

9.3.1.AdverseEvents


“Duringpart3,AEscontinuedfrompart1orpart
2willbefollowedbutnonewAEswillbe
recorded.”

“IncaseofstudywithdrawalduetoanAE,the
subjectistobefolloweduntilresolutionoftheAE
orfor30days.”

“Duringpart3,AEscontinuedfrompart1orpart
2willbefollowedbutnonewAEswillbe
recorded.”
“IncaseofstudywithdrawalduetoanAE,the
subjectistobefolloweduntilresolutionoftheAE
orforatleast30days.

Duringpart3,AEscontinuedfrompart1orpart
2willbefollowedbutnonewAEswillbe
recorded.”
ClarifiedcollectionofAEsinPart3.

“Duringpart3,AEscontinuedfrompart1orpart
2willbefolloweduntilresolutionorstabilization
butnonewAEswillberecorded.”

“IncaseofstudywithdrawalduetoanAE,the
subjectistobefolloweduntilresolution/
stabilizationoftheAEorfor30days.”

“Duringpart3,AEscontinuedfrompart1orpart
2willbefolloweduntilresolutionorstabilization
butnonewAEswillberecorded.”
“IncaseofstudywithdrawalduetoanAE,the
subjectistobefolloweduntil
resolution/stabilizationoftheAEorforatleast30
days.
Duringpart3,AEscontinuedfrompart1orpart
2willbefolloweduntilresolutionorstabilization
butnonewAEswillberecorded.”

5.1.OverallDesign
andPlanoftheStudy–
Figure1:Overviewof
StudyDesign

UpdatedtoincludenewfiguresforPart2Cohort1
andPart2Cohort2.
7.2.StudyDrug
DosingRules-Figure
2
Appendix4.Dose
EscalationRules

UpdatedtoshowPart2cohort1withatleast5
subject,6treatmentseach.
UpdatedtoshowPart2cohort2withupto10
additionalsubjects,8treatmentseach.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

ProtocolSection(s)
Version6.0
Version7.0
7.3.Methodof
AssigningSubjectsto
Part,Cohort,and
DosingLevels

Addedadditionaldirection:
“Additionally,subjectsthatstarttreatmentinpart2
cohort1willbere-assignedtocohort2priorto
completionoftreatmentadministrationvisits(i.e.,
Week5)afterinstitutionalreviewboard(IRB)
writtenapprovalofthepart2cohort2schedule
andtheassociatedprotocolversion.”

8.1.Screening

Addedpreviouslymissingdirectiononcystoscopic
assessment:
“Cystoscopicassessment(tobecompletedduring
screeningorwithin30dayspriortostartof
screeningaspartofstandardcare)”

8.2.2.Treatment

Addeddirection:
“Duringinstillationandwhenphysicallyable,the
subjectshouldchangepositionevery15minutes
withatleasttwo15-minuteperiodsintheprone
(facedown)position.”
8.2.3.OtherStudy
Procedures








Aurinesampleforcytologywillalsobeobtained.
…
Ifnoresidualtumorisnoted,thesiteofthemarker
lesionmustbebiopsied.
SubjectsinPart2cohort2willhavethelast
instillationonWeek7visit(Day50).Additional
followupvisitswilloccuratWeek9(Day64)and
Week12(Day85).OntheWeek15(Day106±7
days)visit,thefinalcystoscopyprocedureand
biopsywillbeconducted(orTURBTifabladder
tumorlesionispresent).

Atthetimeoffinalcystoscopicassessment,aurine
sampleforcytologywillalsobeobtained.
Ifnoresidualtumorisnotedatthefinalcystoscopic
assessment,thesiteofthemarkerlesionmustbe
biopsied.

LIPACOncologyLLC
Product:TSD-001
ProtocolNumber:TD-001

Version7.0;04FEB2020LIPACOncologyLLC
CONFIDENTIAL

ProtocolSection(s)
Version6.0
Version7.0
9.3.1.5Handlingof
AEs
MichaelG.Oefelein,MD,FACS
Michael@tesorx.com

MichaelG.Oefelein,MD,FACS
Michael@lipaconcology.com

9.3.2.Laboratory
Measurementsand
Variables-Table5

Table4:Protocol-RequiredSafetyLaboratory
Assessments
NowreferencedasTable5:Protocol-Required
SafetyLaboratoryAssessments
9.3.3.2.12-leadECG
Standard12-leadECGswillbeevaluatedfor
screening(eligibility)reasonsandattheendofthe
study.
Standard12-leadECGswillbeevaluatedfor
screening(eligibility)reasonsandattheendofthe
treatmentpart.

13.References

Added:
“EisenhauerEA,TherasseP,BogaertsJ,etal.New
responseevaluationcriteriainsolidtumours:
revisedRECISTguideline(version1.1).EurJ
Cancer.2009;45(2):228-47.”

