Clinical trial NCT03081858
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
Keywords: NMIBC Paclitaxel Antineoplastic Agents Bladder Cancer
Sponsor: Lipac Oncology LLC
Start date: 2018-05-17; Completion date: 2021-08-05
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
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.

Part 1 of the study will enroll 6 subjects (3 per cohort) with low-grade, stage Ta transitional cell carcinoma (TCC) of the bladder who will receive escalating doses of paclitaxel formulated as TSD-001 every 2 weeks for 6 treatments until Dose Limiting Toxicity (or until the Maximum Deliverable Dose) is observed (Maximum Tolerated Dose established).

Part 2 of the study will enroll an additional 10 subjects with low-grade, stage Ta (uni-or multifocal) TCC of the bladder who will receive weekly TSD-001 for 6 weeks at the highest nontoxic dose (i.e., MTD) established in part 1 of the study. May meet definition of low grade without histological tissue diagnosis if on cystoscopic assessment they have a solitary papillary tumor.

Part 3 of the study will continue to track subjects enrolled in Parts 1 and 2 to determine rates of disease-free survival.

Detailed description:

Arms: arm 1: Part 1, Cohort 1: For the first 3 subjects enrolled, the initial dose will be 10 mg in Sterile Water for Injection (SWFI). 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). If Dose Limiting Toxicity(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. arm 2: Part 1, Cohort 1: For the next 3 subjects enrolled, the initial dose will be 90 mg in SWFI. 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). If DLT does not develop, intravesical instillation 14 days later will be titrated up according to the schedule (180, 270, 360, 450, and 540 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 6 subjects (cohorts 1 and 2) after titration up to 540 mg, then the maximum deliverable dose (MDD) will be defined and dose recommended for part 2 of the study. arm 3: In part 2, the dose will be selected as the MTD/MDD, established in part 1 and provided weekly via the intravesical route.

During part 2, up to 10 additional subjects will receive intravesical instillations of TSD-001 via urethral catheterization of the urinary bladder at the MTD/MDD established in part 1 at weekly intervals for 6 consecutive weeks. 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).
Interventions: intervention 1: TSD-001
Intervention descriptions: intervention 1: Administered via intravesical instillation.

Protocol documents:
Prot_000.pdf: 
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
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CONFIDENTIAL
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StudyProtocol
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APhase1/2aPilotStudyofIntravesicalTSD-001forTreatmentof
Low-Grade,StageTa,Non-MuscleInvasiveBladderCancer
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StudyNumber:
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TD-001
Version
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7.0
Date 
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04FEB2020
StudyPhase: 
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Phase1/2a
InvestigationalProduct:
TSD-001
InvestigationalNewDrug
(IND)/EudraCTNumber: 129419
Indication: 
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Non-MuscleInvasiveBladderCancer(NMIBC)
Sponsor:
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LIPACOncologyLLC
325SharonParkDrive,Suite739
MenloPark,CA94025-6805
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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

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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)
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______________________________
PrincipalInvestigatorSignature
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InvestigatorPrintedName:_____________________________
Date:_______________
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Institution/Location:
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Product:TSD-001
ProtocolNumber:TD-001

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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


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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


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ProtocolNumber:TD-001

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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
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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
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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
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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
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ProtocolNumber:TD-001

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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.


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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.


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• 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
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Product:TSD-001
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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
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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
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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.


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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
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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
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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
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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.


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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


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• 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.


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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.


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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.



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14.
APPENDICES


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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]).


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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.


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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:___________
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LIPACOncologyLLC

Product:TSD-001
ProtocolNumber:TD-001
Version7.0;04FEB2020
LIPACOncologyLLC
69

CONFIDENTIAL

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


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)





















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


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




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




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




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.”



SAP_001.pdf: 
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 
NCT03081858 
 
Statistical Analysis Plan FINAL Version 2.0 
27 Oct 2020 
 


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Statistical Analysis Plan
A Phase l/2a Pilot Study of Intravesical TSD-001 for Treatment of
Low-Grade, Stage Ta, Non-Muscle Invasive Bladder Cancer
Protocol Title:
Protocol Number:
TD-001
Sponsor:
LIPAC Oncology LLC
Version / Date:
FINAL Version 2.0 / 27 Oct 2020
Protocol Version:
Version 7.0, 04 Feb 2020
Confidentiality Statement
The confidential information contained in this document is the property of LIPAC Oncology
LLC. Your acceptance of this document constitutes agreement that you will not disclose the
information contained herein to others without written authorization from LIPAC Oncology
LLC.
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LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
A Phase l/2a Pilot Study of Intravesical TSD-001 for Treatment of Low-Grade, Stage Ta,
Non-Muscle Invasive Bladder Cancer
Approval Page
Sponsor Approval:
Date
/
Karl Bean
Director, Clinical Operations
Michael Oefelein, MD, FACS
Chief Medical Officer
iO-27-2olo
i>> , no
Date
Digitally signed by Margie Bell
DN:cn=Margie Bell, o, ou,
email=margie.clindata@gmail.co
m, c=US
Date: 2020.10.28 12:52:56 -06'00'
Approval: Margje Bell
Margie Bell
Statistical Consultant
Date
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ABBREVIATIONS
adverse event
Anatomical Therapeutic Chemical
body mass index
blood pressure
body temperature
degrees Celsius
Common Terminology Criteria for Adverse Events
DCL Pathology (central pathologist)
dose-limiting toxicity
electrocardiogram
electronic case report form
heart rate
International Prostate Symptom Score
kilogram
maximum
maximum deliverable dose
maximum tolerated dose
Medical Dictionary for Regulatory Activities
minimum
modified intent-to-treat
marker lesion response rate
millimeter of mercury
maximum tolerated dose
not applicable
National Cancer Institute
non-muscle invasive bladder cancer
Overactive Bladder Questionnaire
pharmacokinetic
per protocol
PRA Health Sciences (Bioanalytical Lab)
respiratory rate
serious adverse event
standard deviation
standard error of the mean
transitional cell carcinoma
transurethral resection of bladder tumor
World Health Organization drug dictionary
AE
ATC
BMI
BP
BT
°C
CTCAE
DCL
DLT
ECG
eCRF
HR
IPSS
Kg
Max
MDD
MTD
MedDRA
Min
MITT
MLRR
mm Hg
MTD
N/A
NCI
NMIBC
OAB-q
PK
PP
PRA
RR
SAE
SD
SEM
TCC
TIJRBT
WHO DRUG
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STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table of Contents
1.
STUDY OBJECTIVES
2.
OVERALL STUDY DESIGN
3.
DETERMINATION OF MTD
4.
SIZE OF TRIAL POPULATION
5.
PERSONNEL RESPONSIBLE FOR DATA ANALYSIS
6.
STATISTICAL METHODS
7.
ANALYSIS POPULATIONS
8.
DATA SOURCES
8.1. Missing or Incomplete Data
8.2. EDC Data
8.3. Central Pathologist Data
8.4. Bioanalytical Laboratory
9.
PRESENTATION OF SUBJECT DISPOSITION
10.
PRESENTATION OF SCREENING VARIABLES
11.
EXTENT OF EXPOSURE
12.
EFFICACY PARAMETERS: PART 1
12.1.Primary Endpoint
12.2.Secondary and Exploratory Endpoints
12.3.Endpoint Analysis
13.
EFFICACY PARAMETERS: PART 2
13.1.Primary Endpoint
13.2.Secondary and Exploratory Endpoints
13.3.Endpoint Analysis
13.4.Dose Proportionality and Urine Paclitaxel Concentration
14.
EFFICACY PARAMETERS: PART 3
14.1.Exploratory Endpoint
14.2.Endpoint Analysis
15.
SAFETY PARAMETERS
15.1.Adverse Events
15.2.Vital Signs Measurements
15.3.Laboratory Measurements
15.4.12-Lead ECG
15.5.Physical Examinations
15.6.Concomitant Medications
15.7.Protocol Deviations
16.
DEVIATIONS FROM STATISTICAL PLAN AND OTHER ISSUES
17.
TABLE OF CONTENTS: PLANNED TABLES
18.
TABLE OF CONTENTS: PLANNED LISTINGS
19.
TABLE OF CONTENTS: PLANNED FIGURES
20.
PLANNED TABLES
21.
APPENDIX 1
22.
APPENDIX 2
.5
.6
.8
.8
.8
.8
.8
.9
,9
.9
,9
.9
10
10
11
11
11
12
12
13
13
14
14
15
16
16
16
16
16
17
17
17
17
17
18
18
19
.23
.24
.25
.88
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1.
STUDY OBJECTIVES
This is a phase l/2a study to evaluate the safety of TSD-001, the local and systemic paclitaxel
pharmacokinetic (PK) concentrations after intravesical exposure to TSD-001, the recurrence-free
survival after TURBT and intravesical 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 reached. 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 last post-dose
time point (Week 16) in urinary HRQOL as measured by the 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 part 2, cohort 1, the assessment will occur 12
weeks (± 7 days) after Day 1 at the MTD/MDD. Subjects in part 2, cohort 2 will have the
marker lesion response rate determined 15 weeks (± 7 days) after Day 1.
Complete marker lesion response requires no evidence of transitional cell carcinoma (TCC) on
cystoscope-directed biopsy or cystoscope, if biopsy is not technically possible or safe to perform.
Partial response is at least a 30% decrease in marker lesion size (Eisenhauer et al., 2009) as
measured by longest diameter.
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; 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.
Paclitaxel PK concentration measurements of peripheral blood during part 2 will be obtained at
the following time points: A) 2 hours (± 10 minutes) after the first intravesical instillation, and
B) 15 minutes (± 15 minutes) before, and 2 hours (± 10 minutes) after the third intravesical
exposure of TSD-001 at the MTD/MDD.
Exploratory endpoints of part 2 include change from baseline to the end of the treatment 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.
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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 endpoint of part 3 (surveillance) will be disease-free survival of subjects
exposed to TSD-001 in part 1 and part 2 who have had a complete response. The endpoint will
be a time to event (recurrence) after the last instillation of TSD-001 after TURBT (Day -12 in
part 1, Day 1 in part 2), and with recurrence free survival at 12 and 24 months. 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.
Histological tissue diagnosis evidence is any diagnosis of urothelial carcinoma (i.e., TCC),
including all grades and stages. Due to pandemic circumstances in 2020, and for the safety of
study subjects, LIPAC made the decision to suspend the Phase 2a, part 3 registry. This decision
in May 2020 means part 2 subjects will not complete 12- and 24-month assessments. Available
data for the available part 2 subject visits in the long-term surveillance portion (i.e. part 3) will
be presented within the body of the final CSR.
2.
OVERALL STUDY DESIGN
This is a single-arm, phase l/2a study of intravesical proliposomal formulated paclitaxel (TSD-
001) in subjects with low-grade (WHO, 2004), stage Ta, NMIBC. These patients have low to
intermediate risk non-muscle invasive bladder cancer (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.
The study 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 transurethral resection of bladder tumor (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. Study 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 for part 2,
cohort 1 or 16 planned clinic visits for 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.
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 increased according to the schedule (25, 50, 75, 100, 150
mg) every 2 weeks for a total of 6 intravesical treatments. The 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
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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 at the following time points: A) 2 hours (± 10 minutes) after the first intravesical
instillation, and B) 15 (± 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 biopsy under general anesthesia. Complete marker lesion response
requires no evidence of TCC on cystoscope-direct biopsy or cystoscope alone, if biopsy is not
technically possible or safe to perform. Partial response is at least a 30% decrease in marker
lesion size as measured by longest diameter.
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
up to 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 the end of 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 and Week 13 of
part 2 cohort 1, and Week 16 of part 2 cohort 2. In case of withdrawal due to an adverse event,
the subject is to be followed until resolution of the AE or for 30 days.
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, and subjects will only be followed until recurrence or up to 2 years
after first exposure of TSD-001.
If there is evidence of recurrence upon cystoscopic examination in 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
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medication(s). During part 3, AEs continued from part 1 or part 2 will be followed until
resolution or stabilization, but no new AEs (other than SAEs) will be recorded.
Study assessments will be performed as noted in the schedules of events provided in Appendix 1.
3.
DETERMINATION OF MTD
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 reached. The MDD by formulation is set at 540 mg.
Or if MDD is reached. The MDD is defined as the highest dose without evidence
of precipitation.
4.
SIZE OF TRIAL POPULATION
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 I and up to 15 for part 2, for a total of up to 21, has empirically been
planned as sufficient to achieve the study goals.
PERSONNEL RESPONSIBLE FOR DATA ANALYSIS
5.
Analyses will be carried out by personnel from LIPAC Oncology LLC or designee.
6.
STATISTICAL METHODS
All tests of significance will be assessed at alpha = 0.05, 2-sided. All statistical analyses and
data presentations (tables and listings) will be conducted using SAS for Windows (version 9.4,
or higher, Cary, NC). All study data, including data not appearing in tables, will be presented in
by-subject data listings.
ANALYSIS POPULATIONS
7.
Analyses will be based on the safety, modified intent-to-treat (MITT), per protocol (PP), and PK
populations.
• Safety Population: The safety population will include all enrolled subjects who
receive at least one dose of study drug.
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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 MITT 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.
All efficacy analyses will be conducted based on the MITT population as well as the PP
population. The PK population will be analyzed for the PK analyses. All safety analyses will be
conducted on the safety population. Additional exploratory analyses of the data may be
conducted as appropriate.
8.
DATA SOURCES
8.1.
Missing or Incomplete Data
There will be no imputation of missing data.
8.2.
EDC Data
The clinical study database and data entry screens will be developed by the CRO, Linical
Accelovance, using Medrio’s electronic data capture (EDC) product. Medrio is a clinical trials
software provider and will provide software hosting for this study.
Linical will provide LIPAC with interim transfers during the study as requested. The transfers
will contain the current study data with coding and will be provided in SAS datasets. All
electronic data transfers will occur through Linical’s secured website, Egnyte. In the course of
development and sometimes due to Protocol Amendments data collection fields in Medrio EDC
were superseded. These fields were subsequently made unenterable so that they appeared on the
form (as reference) but could not be queried or updated.
These will be left in the SDTM datasets but are not shown in any tables, figures, or listings.
8.3.
Central Pathologist Data
DCL Pathology is the central pathologist. Data transfers are formatted and delivered according
to a joint Data Transfer Agreement between DCL, LIPAC, and Linical.
8.4.
Bioanalytical Laboratory
PRA Health Sciences is the bioanalytical laboratory providing method development, method
validation, and delivery of measurements of paclitaxel levels from subject urine and plasma
samples. Data transfers from PRA are formatted and delivered according to a joint Data Transfer
Agreement between PRA, LIPAC, and Linical.
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9.
PRESENTATION OF SUBJECT DISPOSITION
Frequency counts and percentages for all subjects who are enrolled, eligible for the safety
population, eligible for the MITT population, eligible for the PP population, eligible for the PK
population, completed the study, and did not complete the study will be presented for part 1
cohort 1, part 1 cohort 2, part 2 cohort 1, part 2 cohort 2 and part 3. In addition, frequency
counts and percentages of subjects’ reported reasons for discontinuation will be summarized for
each part and cohort.
10.
PRESENTATION OF SCREENING VARIABLES
Variables collected at the screening visits will be summarized and presented for part 1 cohort 1,
part 1 cohort 2, part 2 cohort 1, part 2 cohort 2 and part 3, separately. Descriptive statistics
(number of subjects, mean, standard deviation, standard error of the mean (SEM), median,
minimum, and maximum values) will be presented for the continuous variables. Frequency
counts and percentages will be presented for the categorical variables for each category. The
following variables will be presented:
> Demographic characteristics
• Sex (male, female)
• Age (years)
•
Ethnicity (Non-Hispanic/Latino, Hispanic/Latino)
•
Race (American Indian/Alaskan Native, Asian, Black/African American, Native
Hawaiian/Other Pacific Islander, White, or Other)
•
Weight (kg)
•
Height (cm)
•
BMI (kg/m2)
> Vital signs measurements (Screening)
• Systolic blood pressure (mm Hg)
•
Diastolic blood pressure (mm Hg)
•
Heart rate (bpm)
•
Respiratory rate (breaths/minute)
• Body Temperature (°C)
> Bladder Characteristics (Screening/Baseline)
•
NMIBC Recurrent (yes, no)
•
Number of Tumor Locations (solitary, multifocal)
•
Previous Intravesical Therapy (yes, no)
•
EAU Risk Stratification (low risk, intermediate risk)
Recurrence will be identified by Medical History documentation of NMIBC and TURBT within
1 year prior to study TURBT. Solitary will be identified as one tumor location identified at the
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Day -12 TURBT (Part 1) or the Day 1 TURBT (Part 2). Multifocal will be identified by more
than one tumor location at the Day -12 TURBT (Part 1) or the Day 1 TURBT (Part 2).
Risk Stratification for TD-001
Table 1:
Low Risk
Intermediate Risk
High Risk
Primary, solitary,
Low Grade/Gl
<3cm, no CIS
All tumors not
defined in the two
adjacent categories
*T1 tumor
*High Grade/G3
tumor
*CIS
*Multiple,
recurrent, and large
(>3cm) Ta G1G2
tumors (all
conditions must be
present )
EXTENT OF EXPOSURE
11.
For each subject, the following will be calculated:
•
Duration of exposure (mg*hours)
• Total dose (mg)
• Total hours exposed
•
Mean hours exposed per subject per dose.
Duration of exposure will be calculated by multiplying the dose administered by the number of
hours from treatment administration start time to treatment administration stop time.
Descriptive statistics (number of subjects, mean, standard deviation, standard error of the mean
(SEM), median, minimum and maximum values) will be presented for each exposure parameter
for all subjects and part 1 cohort 1, part 1 cohort 2, part 1 , part 2 cohort 1, part 2 cohort 2, and
part 2. The exposure table will also be presented for female subjects and male subjects.
12.
EFFICACY PARAMETERS: PART 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 reached. The severity and frequency of AEs will be
documented following TSD-001 administration, and defined according to NCI CTCAE Version
12.1.
5.0.
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Secondary and Exploratory 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. Paclitaxel
concentrations will be limited to pre-instillation (trough) and to 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 .
Exploratory endpoints of part 1 include the following:
• Change from screening to Week 10 (or last TSD-001 exposure) in IPSS total score
(men only)
• Change from screening to Week 16 (or last collection for subject) in IPSS total score
(men only)
12.2.
For the OAB-q, the following domains and total score will be calculated according to the
“Scoring Guide for the OAB-q” in Appendix 2:
•
Symptom Severity
•
HRQL-Coping
•
HRQL-Concern
•
HRQL-Sleep
•
HRQL-Social
•
HRQL- Total
For each domain and total score the following endpoints will be calculated:
• Change from screening to Week 10 (or last TSD-001 exposure) in OAB-q
• Change from screening to Week 16 (or last collection for subject) in OAB-q
12.3.
Endpoint Analysis
The dose at which DLT occurs or when a MDD is reached will be presented with the MTD.
Descriptive statistics (number of subjects, mean, standard deviation, SEM, median, minimum
and maximum) will be presented for urine and plasma concentrations collected at each visit (Day
1, Week 2, Week 4, Week 6, Week 8 and Week 10) and nominal time point (15 minutes pre-
instillation and 2 hours post-instillation) for all samples.
After the TD-001 study was begun, the urine paclitaxel concentration method development
identified that Tween should be added to the urine collection container to reduce the urine
paclitaxel negative bias. Therefore, the urine paclitaxel concentrations will also be presented by
Tween category (absent, incomplete, complete).
Comparisons between Tween addition categories may be assessed by an analysis of variance
model with urine paclitaxel concentration as the dependent variable and Tween addition as the
independent variable.
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Additionally, for the 2-hour post-instillation urine concentrations, Pearson correlation
coefficients will be generated for the following:
•
Number of AEs per subject at each instillation visit
•
Change from screening to Week 10 in IPSS total score (men only)
•
Change from screening to Week 10 in OAB-q total score
Scatter plots, including the linear regression line and equation, for each comparison will be
provided.
Urine precipitation in post-instillation void was collected for part 2. For each subject and visit
collected, a histogram will be constructed displaying the amount of precipitation (none,
observed, high amount).
For IPSS and OAB-q scores, descriptive statistics will be presented for screening, Week 10 (or
last TSD-001 exposure), Week 16 (or last collection for subject) and for the changes from
screening to Weeks 10 (or last TSD-001 exposure) and 16 (or last collection for subject). The
changes from screening will be assessed by the paired t-test or Wilcoxon signed rank test, as
appropriate.
13.
EFFICACY PARAMETERS: PART 2
Primary Endpoint
The primary endpoint of part 2 is to determine the marker lesion response rate (MLRR) using the
MTD/MDD established in part 1 at the final endoscopic assessment after weekly instillations of
TSD-001. The final endoscopic assessment will be 12 weeks (± 7 days) after Day 1 (i.e., 7 weeks
[± 7 days] after last intravesical TSD-001 instillation) for subjects in part 2 cohort 1 and 15
weeks (± 7 days) after Day 1 (i.e., 8 weeks [± 7 days] after the last intravesical instillation) for
subjects in part 2 cohort 2.
13.1.
The MLRR (part 2) will be determined by the percentage of subjects at completion cystoscopy
and biopsy to have a partial or a complete response (no evidence of TCC on cystoscope-directed
biopsy or cystoscope, if biopsy is not technically possible or safe to perform). Partial response
will be determined by comparing the pretreatment marker lesion size (i.e. longest dimension of
the marker lesion at Day 1 [or Screening if Day 1 TURBT not performed- i.e. solitary lesion]) to
the post-treatment size using the greatest (longest) dimensions. Longest dimension is the largest
measurable diameter of the lesion. Partial response is defined as at least a 30% decrease in marker
lesion size (Eisenhauer et al., 2009) as measured similarly by the longest dimension (in mm).
In addition, pathology tissue specimens of the marker lesion have parameters also measured in
millimeters (in 3 dimension). Exploratory representation of marker lesion response rate will
compare the longest dimension of the marker lesion at Day 1 (or Screening if Day 1 TURBT not
performed-i.e. solitary lesion) to the longest dimension of the pathology tissue sample.
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As an exploratory analysis, the Pearson correlation coefficient between the longest dimension
obtained at Week 12/Week 15 and the longest dimensions reported by DCL Pathology (DCL)
will be calculated. Scatter plots for Week 12/Week 15 will be presented. The partial response
rate will also be calculated using the DCL measurements. External independent validation of the
Week 12/Week 15 marker lesion longest dimension as determined by the investigator (using
cystoscopy) and the longest dimension determined by DCL pathologist (using microscopy) will
be performed, and analyzed by Pearson correlation coefficient.
Secondary and Exploratory Endpoints
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:
•
Paclitaxel levels in voided urine samples at 24, 48, and 72 hours after the third
instillation of TSD-001.
13.2.
For part 2 cohort 1:
• Change from screening to Week 5 in IPSS total score (men only)
• Change from screening to Week 13 in IPSS total score (men only)
•
Change from screening to Week 5 in OAB-q for each domain and total score
• Change from screening to Week 13 in OAB-q for each domain and total score
For part 2 cohort 2:
• Change from screening to Week 7 in IPSS total score (men only)
• Change from screening to Week 16 in IPSS total score (men only)
• Change from screening to Week 7 in OAB-q for each domain and total score
• Change from screening to Week 16 in OAB-q for each domain and total score
13.3.
Endpoint Analysis
Marker lesion response rate (part 2) will be determined by the percentage of subjects at
completion TURBT or biopsy to have 1) a reduction of the marker lesion of at least 30% in
longest dimension (partial response) and 2) and no biopsy (or cystoscope, if biopsy is not
technically possible or safe to perform) evidence of residual disease (complete response).
Additionally, marker lesion response rate in part 2 will be stratified by EAU risk category at
screening (low risk or intermediate risk).
The severity and frequency of AEs will be summarized as described in Section 15.1.
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more subjects will be summarized by system organ class and preferred term in descending
frequency by preferred term.
Additionally, adverse events will be presented by relationship to study drug, severity,
relationship to study drug and severity, adverse events meeting DLT criteria (part 1 only),
serious adverse events and serious treatment-related adverse events. If subject experiences the
same adverse event more than once, the most severe or most closely related will be presented.
Listings of adverse events meeting DLT criteria and serious adverse events will be provided.
15.2.
Vital Signs Measurements
Descriptive statistics will be presented for the vital signs measurements (systolic blood pressure,
diastolic blood pressure, pulse rate, respiratory rate, and body temperature) for each visit
collected and for the changes from baseline (Day 1) for part 1 and part 2, separately. Note that
part 2 cohort 1 and part 2 cohort 2 will be combined for all possible study days. The Week 13
visit from cohort 1 and Week 16 visit from cohort 2 will be combined as the End of Study visit.
15.3.
Laboratory Measurements
Descriptive statistics will be presented for continuous laboratory parameters for each visit
collected and for the changes from screening for part 1 and part 2, separately. Additionally,
shift tables will be constructed to display the number and percentage of values normal and
abnonnal at Screening to normal and abnormal at each subsequent visit will be presented for
each parameter.
15.4.
12-Lead ECG
Descriptive statistics will be presented for the ECG parameters (heart rate, PR interval, QRS
interval, QT interval, atrial rate and ventricular rate) for screening, study exit and for the changes
from screening to study exit for part 1 and part 2, separately. Additionally, for the overall ECG
interpretation (normal; abnormal, not clinically significant; abnormal, clinically significant), ST
segment (normal, abnormal), T-wave (normal, abnormal), interval (normal, abnormal), rhythm
(no sinus rhythm, sinus rhythm), the number and percentage of subjects will be presented as shift
tables from screening to study exit for part 1 and part 2, separately.
Physical Examinations
For each body system, a shift table will be constructed to display the number and percentage of
subjects per category (normal; abnormal, not clinically significant; abnormal, clinically
significant) at screening to study exit for part 1 and part 2, separately.
15.5.
15.6.
Concomitant Medications
Concomitant medications will be classified by site of action and therapeutic and clinical
characteristics using the World Health Organization drug dictionary (WHO DRUG Enhanced
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Sep-2017 B2 (Hierarchy and Ingredients)). Concomitant medications will be summarized by
WHO Preferred term and Level 4 Anatomical Therapeutic Chemical (ATC) for part 1 cohort 1,
part 1 cohort 2, part 1 (cohorts 1 and 2 combined), part 2 cohort 1, part 2 cohort 2, and part 2
(cohorts 1 and 2 combined). For subjects with more than one instance of WHO Preferred term
and Level 4 ATC, only the first occurrence will be tabulated.
Protocol Deviations
Protocol deviations will be summarized by deviation classification and severity for part 1 cohort
1 , part 1 cohort 2, part 2 cohort 1, part 2 cohort 2 and all subjects. The total number of
deviations per classification and severity will be presented with the number and percentage of
subjects.
15.7.
16.
DEVIATIONS FROM STATISTICAL PLAN AND OTHER ISSUES
During the analysis and reporting process, any deviations from the statistical plan designed for
this protocol will be described and justified in the clinical study report.
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Table C.2.5
Part 1: Correlation Coefficients for 2-hour Urine Concentrations: Per Protocol Population
Table C.2.6
Part 1: IPSS Total Score: Descriptive Statistics: Per Protocol Population: Men Only
Table C.2.7
Part 1: OAB-q Domains and Total Score: Descriptive Statistics: Per Protocol Population
Table C.3.1
Part 2: Marker Lesion Response Rate: Per Protocol Population
Table C.3.2
Part 2: Marker Lesion Response Rate as Stratified by EAU Risk Category: Per Protocol Population
Table C.3.3
Part 2: Cohort 1: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered and Tween
Addition: Descriptive Statistics: Per Protocol Population
Table C.3.4
Part 2: Cohort 2: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered and Tween
Addition: Descriptive Statistics: Per Protocol Population
Table C.3.5
Part 2: Cohort 1 and 2: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered and
Tween Addition: Descriptive Statistics: Per Protocol Population
Table C.3.5. 1
Part 2: Cohort 1 and 2: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered: Analysis
of Variance: Per Protocol Population
Table C.3.6
Part 2: Paclitaxel Concentration in Plasma: Descriptive Statistics: Per Protocol Population
Part 2: Correlation Coefficients for 2-hour Urine Concentrations at Week 2: Per Protocol Population
Table C.3.7
Table C.3.8
Part 2: IPSS Total Score: Descriptive Statistics: Per Protocol Population
Tabic C.3.9
Part 2: OAB-q Total Score: Descriptive Statistics: Per Protocol Population
Table C.3.10
Part 2: Post-Treatment Marker Lesion Sites Correlation of Maximum Diameter Values of DCL to
TURBT/Biopsy Measurements at Day 85/106: Per Protocol Population
Table D.1.1
Demographic Characteristics: PK Population
Table D.1.2
Vital Signs Measurements at Screening: PK Population
Bladder Characteristics at Screening: PK Population
Table D.1.3
Table D.1.4
Extent of Exposure: PK Population
Table D.2.1
Part 1: Maximum Tolerated Dose: PK Population
Table D.2.2
Part 1: Cohort 1: Paclitaxel Concentration in Urine by Dose Administered and Tween Addition: Descriptive
Statistics: PK Population
Part 1: Cohort 1: Paclitaxel Concentration in Urine by Dose Administered: Analysis of Variance: PK
Population
Table D.2.2.1
Table D.2.3
Part 1: Cohort 2: Paclitaxel Concentration in Urine by Dose Administered and Tween Addition: Descriptive
Statistics: PK Population
Part 1: Paclitaxel Concentration in Plasma by Dose Administered: Descriptive Statistics: PK Population
Table D.2.4
Part 1: Correlation Coefficients for 2-hour Urine Concentrations: PK Population
Table D.2.5
Tabic D.2.6
Part 1: IPSS Total Score: Descriptive Statistics: PK Population: Men Only
Table D.2.7
Part 1: OAB-q Domains and Total Score: Descriptive Statistics: PK Population
Table D.3.1
Part 2: Marker Lesion Response Rate: PK Population
Table D.3.2
Part 2: Marker Lesion Response Rate as Stratified by EAU Risk Category: PK Population
Table D.3.3
Part 2: Cohort 1: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered and Tween
Addition: Descriptive Statistics: PK Population
Table D.3.4
Part 2: Cohort 2: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered and Tween
Addition: Descriptive Statistics: PK Population
Table D.3.5
Part 2: Cohort 1 and 2: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered and
Tween Addition: Descriptive Statistics: PK Population
Part 2: Cohort 1 and 2: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered: Analysis
of Variance: PK Population
Table D.3.5.1
Table D.3.6
Part 2: Paclitaxel Concentration in Plasma: Descriptive Statistics: PK Population
Table D.3.7
Part 2: Correlation Coefficients for 2-hour Urine Concentrations at Week 2: PK Population
Table D.3.8
Part 2: IPSS Total Score: Descriptive Statistics: PK Population
Table D.3.9
Part 2: OAB-q Total Score: Descriptive Statistics: PK Population
Table D.3.10
Part 2: Post-Treatment Marker Lesion Sites Correlation of Maximum Diameter Values of DCL to
TURBT/Biopsy Measurements at Day 85/106: PK Population
Table E.1.1
Part 1: Overall Adverse Event Information: Safety Population
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Table E.1.2
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class and
Preferred Term: Safety Population
Table E.1.3
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class and
Preferred Term by Nearest Relationship to Study Drug: Safety Population
Table E.1.4
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class and
Preferred Term by Maximum Severity: Safety Population
Table E.1.5
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class and
Preferred Term by Nearest Relationship to Study Drug and Maximum Severity: Safety Population
Table E.1.6
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events Meeting DLT Criteria by System
Organ Class and Preferred Term: Safety Population
Table E.1.7
Part 1: Number (%) of Subjects with Serious Treatment-emergent Adverse Events by System Organ Class
and Preferred Term: Safety Population
Table E.1.8
Part 1: Number (%) of Subjects with Serious Treatment-related, Treatment-emergent Adverse Events by
System Organ Class and Preferred Term: Safety Population
Part 1: Vital Signs Measurements: Descriptive Statistics: Safety Population
Table E.2.1
Table E.2.2
Part 1: Laboratory Measurements: Descriptive Statistics: Safety Population
Table E.2.3
Part 1: Laboratory Measurements: Shift from Screening: Number (%) of Subjects: Safety Population
Part 1: ECG Measurements: Descriptive Statistics: Safety Population
Table E.2.4
Table E.2.5
Part 1: ECG ST-segment and Intervals: Shift from Screening: Number (%) of Subjects: Safety Population
Table E.2.6
Part 1: ECG Sinus Rhythm: Shift from Screening: Number (%) of Subjects: Safety Population
Table E.2.7
Part 1: ECG Overall Interpretation: Shift from Screening: Number (%) of Subjects: Safety Population
Table E.2.8
Part 1: ECG T-wave Interpretation: Shift from Screening: Number (%) of Subjects: Safety Population
Part 1: Physical Examination: Shift from Screening: Number (%) of Subjects: Safety Population
Table E.2.9
Table E.2.10
Part 1: Concomitant Medications by WHO Preferred Term and Level 4 ATC: Number (%) of Subjects:
Safety Population
Part 2: Overall Adverse Event Information: Safety Population
Table E.3.1
Table E.3.2
Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class and
Preferred Term: Safety Population
Table E.3.3
Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class and
Preferred Term by Nearest Relationship to Study Drug: Safety Population
Table E.3.4
Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class and
Preferred Term by Maximum Severity: Safety Population
Table E.3.5
Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class and
Preferred Term by Nearest Relationship to Study Drug and Maximum Severity: Safety Population
Part 2: Number (%) of Subjects with Serious Treatment-emergent Adverse Events by System Organ Class
and Preferred Term: Safety Population
Table E.3.6
Part 2: Number (%) of Subjects with Serious Treatment-related, Treatment-emergent Adverse Events by
System Organ Class and Preferred Term: Safety Population
Table E.3.7
Table E.4.1
Part 2: Vital Signs Measurements: Descriptive Statistics: Safety Population
Part 2: Laboratory Measurements: Descriptive Statistics: Safety Population
Table E.4.2
Table E.4.3
Part 2: Laboratory Measurements: Shift from Screening: Number (%) of Subjects: Safety Population
Part 2: ECG Measurements: Descriptive Statistics: Safety Population
Table E.4.4
Table E.4.5
Part 2: ECG ST-segment and Interval Measurements: Shift from Screening: Number (%) of Subjects: Safety
Population
Table E.4.6
Part 2: ECG Sinus Rhythm: Shift from Screening: Number (%) of Subjects: Safety Population
Part 2: ECG Overall Interpretation: Shift from Screening: Number (%) of Subjects: Safety Population
Table E.4.7
Table E.4.8
Part 2: ECG T-wave Interpretation: Shift from Screening: Number (%) of Subjects: Safety Population
Table E.4.9
Part 2: Physical Examination: Shift from Screening: Number (%) of Subjects: Safety Population
Table E.4.10
Part 2: Concomitant Medications by WHO Preferred Term and Level 4 ATC: Number (%) of Subjects:
Safety Population
Table E.5.1
Part 1 and Part 2: Overall Adverse Event Information: Safety Population
Part 1 and Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class
and Preferred Term: Safety Population
Table E.5.2
Part 1 and Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class
and Preferred Term by Nearest Relationship to Study Drug: Safety Population
Table E.5.3
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Table E.5.4
Part 1 and Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class
and Preferred Term by Maximum Severity: Safety Population
Table E.5.5
Part 1 and Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events by System Organ Class
and Preferred Term by Nearest Relationship to Study Drug and Maximum Severity: Safety Population
Table E.5.6
Part 1 and Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events Meeting DLT Criteria
by System Organ Class and Preferred Term: Safety Population
Table E.5.7
Part 1 and Part 2: Number (%) of Subjects with Serious Treatment-emergent Adverse Events by System
Organ Class and Preferred Term: Safety Population
Table E.5.8
Part 1 and Part 2: Number (%) of Subjects with Serious Treatment-related, Treatment-emergent Adverse
Events by System Organ Class and Preferred Term: Safety Population
Table E.5.9
Part 1 and Part 2: Treatment-emergent Adverse Events[a] by System Organ Class and Preferred Term
Reported by > 1% of Subjects: By Most Frequent Preferred Term
Table F.1.1
Part 3 (n=6): One Year Recurrence/Disease-Free Survival in Part 1 Subjects: MITT Population
Table F.1.2
Part 3 (n=6): Two Year Recurrence/Disease-Free Survival in Part 1 Subjects: MITT Population
Table G.1.1
Part 3 (n=N): One Year Recurrence/Disease-Free Survival in Part 1 Subjects: Per Protocol Population
Tabic G.1.2
Part 3 (n=N): Two Year Recurrence/Disease-Free Survival in Part 1 Subjects: Per Protocol Population
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18.
TABLE OF CONTENTS: PLANNED LISTINGS
(Note: Listing shells are not provided)
Listing 16.2.1.1
Subject Disposition
Listing 16.2.1.2
Protocol Deviations
Listing 16.2.4.1
Demographic Characteristics
Listing 16.2.4.2
Bladder Characteristics
Medical History
Listing 16.2.4.3
Listing 16.2.4.4
Pregnancy Test Results
Listing 16.2.4.5
Drug Screen Results
Listing 16.2.4.6
Prior and Concomitant Medications
Listing 16.2.4.7
Procedures/Surgeries after First Dose
Listing 16.2.5
Study Drug Administration
Listing 16.2.6.1
TURBT Procedure Results
Listing 16.2.6.2
Cytology Results
Listing 16.2.6.3
Tissue Biopsy Results
Listing 16.2.6.4
Cytology Results
Listing 16.2.6.5
Marker Lesion Response
Listing 16.2.6.6
Urine Paclitaxel Concentration (ug/L) and Urine Properties
Listing 16.2.6.7
Plasma Paclitaxel Concentration (ug/L)
Listing 16.2.7.1
Adverse Events
Listing 16.2.7.2
Serious Adverse Events
Adverse Events Leading to Dose-Limiting Toxicity
Listing 16.2.7.3
Listing 16.2.8.1
Laboratory Results: Hematology
Listing 16.2.8.2
Laboratory Results: Chemistry
Listing 16.2.8.3
Laboratory Results: Urinalysis
Listing 16.2.8.4
Abnormal Laboratory Results
Listing 16.2.9
Vital Signs Measurements
Listing 16.2.10
ECG Results
Listing 16.2.11
Physical Examination Results
Listing 16.2.12
International Prostate Symptom Score (IPSS) Questionnaire
Listing 16.2.13
Overactive Bladder Questionnaire (OAB-Q)
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STATISTICAL ANALYSIS PLAN FINAL V 2.0
19.
TABLE OF CONTENTS: PLANNED FIGURES
(Note: Figure shells are not provided)
Figure B.1.1.1
Part 1: Cohort 1: Dose Proportionality in Post Instillation Void: MITT Population
Figure B.1.1.2
Part 1: Cohort 2: Dose Proportionality in Post Instillation Void: MITT Population
Figure B.1.1.3
Part 1: Cohorts 1 and 2: Dose Proportionality in Post Instillation Void: MITT Population
Figure B.1.2.1
Part 1: Cohort I: Dose Proportionality in Post Instillation Void: Mean (±SEM) Change: MITT Population
Figure B.1.2.2
Part 1: Cohort 2: Dose Proportionality in Post Instillation Void: Mean (±SEM) Change: MITT Population
Figure B.1.3
Part 1: Cohort 2: Urine Precipitation in Post Instillation Void: MITT Population
Figure B.1.4.1
Part 1: 2-hour Urine Concentrations versus Number of AEs: MITT Population
Figure B.1.4.2
Part 1: 2-hour Urine Concentrations versus IPSS Total Score: Change from Screening to Week 10: MITT
Population
Figure B.1.4.3
Part 1: 2-hour Urine Concentrations versus OAB-q Total Score: Change from Screening to Week 10:
MITT Population
Figure B.2.1
Part 1 and Part 2: Dose Proportionality in Post Instillation Void: MITT Population
Figure B.2.2
Part 2: Post-Treatment Marker Lesion Sites: Correlation of Maximum Diameter Values of DCL to
Cystoscopy Measurements (mm): MITT Population
Figure B.2.3
Part 2: Urine Paclitaxel Concentrations Pre and Post Day 15: Dose 360 mg TSD-001: MITT Population
Figure B.2.4.1
Part 2: Cohort 1: Dose Proportionality in Post Instillation Void: Mean (±SEM) Change: MITT Population
Figure B.2.4.2
Part 2: Cohort 2: Dose Proportionality in Post Instillation Void: Mean (±SEM) Change: MITT Population
Figure B.2.5
Part 2: Urine Precipitation in Post Instillation Void at Week 2: MITT Population
Figure B.2.6.1
Part 2: 2-hour Urine Concentrations versus Number of AEs: MITT Population
Figure B.2.6.2
Part 2: 2-hour Urine Concentrations versus IPSS Total Score: Change from Screening to Week 5/7: MITT
Population
Figure B.2.6.3
Part 2: 2-hour Urine Concentrations versus OAB-q Total Score: Change from Screening to Week 5/7:
MITT Population
Figure C.1.1.1
Part 1: Cohort 1: Dose Proportionality in Post Instillation Void: Per Protocol Population
Figure C.l.1.2
Part 1: Cohort 2: Dose Proportionality in Post Instillation Void: Per Protocol Population
Figure C.1.1.3
Part 1: Cohorts 1 and 2: Dose Proportionality in Post Instillation Void: Per Protocol Population
Figure C.1.2.1
Part 1: Cohort 1: Dose Proportionality in Post Instillation Void: Mean (±SEM) Change: Per Protocol
Population
Figure C.1.2.2
Part 1: Cohort 2: Dose Proportionality in Post Instillation Void: Mean (±SEM) Change: Per Protocol
Population
Figure C.1.3
Part 1: Cohort 2: Urine Precipitation in Post Instillation Void: Per Protocol Population
Figure C.1.4.1
Part 1: 2-hour Urine Concentrations versus Number of AEs: Per Protocol Population
Figure C.1.4.2
Part 1: 2-hour Urine Concentrations versus IPSS Total Score: Change from Screening to Week 10: Per
Protocol Population
Part 1: 2-hour Urine Concentrations versus OAB-q Total Score: Change from Screening to Week 10: Per
Protocol Population
Figure C.1.4.3
Figure C.2.1
Part 1 and Part 2: Dose Proportionality in Post Instillation Void: Per Protocol Population
Figure C.2.2
Part 2: Post-Treatment Marker Lesion Sites: Correlation of Maximum Diameter Values of DCL to
Cystoscopy Measurements (mm): Per Protocol Population
Figure C.2.3
Part 2: Urine Paclitaxel Concentrations Pre and Post Day 15: Dose 360 mg TSD-001: Per Protocol
Population
Figure C.2.4.1
Part 2: Cohort 1: Dose Proportionality in Post Instillation Void: Mean (±SEM) Change: Per Protocol
Population
Figure C.2.4.2
Part 2: Cohort 2: Dose Proportionality in Post Instillation Void: Mean (±SEM) Change: Per Protocol
Population
Figure C.2.5
Part 2: Urine Precipitation in Post Instillation Void at Week 2: Per Protocol Population
Part 2: 2-hour Urine Concentrations versus Number of AEs: Per Protocol Population
Figure C.2.6.1
Figure C.2.6.2
Part 2: 2-hour Urine Concentrations versus IPSS Total Score: Change from Screening to Week 5/7: Per
Protocol Population
Figure C.2.6.3
Part 2: 2-hour Urine Concentrations versus OAB-q Total Score: Change from Screening to Week 5/7: Per
Protocol Population
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STATISTICAL ANALYSIS PLAN FINAL V 2.0
20.
PLANNED TABLES
Table A.1.1
Subject Disposition
All Enrolled Subjects
TSD-001
Part 2
Cohort 1
(N= )
Part 2
Cohort 2
(N= )
Part 1
Cohort 1
(N= )
Part 1
Cohort 2
(N= )
All Subjects
(N= )
Number of Subjects
Enrolled
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Safety Population
MITT Population
PP Population
PK Population
Completed Study
Did Not Complete Study
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Discontinued due to:
Adverse Event
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Dose Limiting Toxicity
Ineligible to Continue
Deterioration of Subject's Clinical
Condition
Significant Protocol Deviation
Subject Noncompliance
Withdrawal of Consent
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Lack of Efficacy
Lost to Follow-Up
Deceased
Other
[a] Part 3 was only available for enrollment to subjects with a Complete Response.
Part 3 was available to all Part 1 subjects because they had Complete Response after the TURBT procedure.
For Part 2 subjects, Part 3 was not available due to the Complete Response requirement and COVID-19.
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STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table A.1.2
Demographic Characteristics
Safety Population
TSD-001
Part 1
Cohort 1
(N= )
Part 1
Cohort 2
(N= )
Part 2
Cohort 1
(N= )
Part 2
Cohort 2
(N= )
All Subjects
(N= )
Characteristic
Female
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Sex
Male
Age (years)
n
xx
xx
xx
xx
xx
Mean (SEM)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Ethnicity
Flispanic Or Latino
Not Hispanic Or
Latino
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Asian
Race
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
White
Height (cm)
n
xx
xx
xx
xx
xx
Mean (SEM)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Weight (kg)
xx
xx
xx
xx
XX
n
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
Mean (SEM)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
BMI (kg/m)
n
xx
xx
xx
xx
xx
Mean (SEM)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Note: This table will be repeated for the MITT Population, the PP Population and the PK Population
CONFIDENTIAL
Page 26 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table A.1.3
Vital Signs Measurements at Screening
Safety Population
TSD-001
Part 2
Cohort 1
(N= )
Part 2
Cohort 2
(N= )
Part 1
Cohort 1
(N= )
Part 1
C ohort 2
(N= )
All Subjects
(N= )
Parameter
Systolic Blood
Pressure (mm Hg)
n
xx
xx
xx
xx
xx
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
Mean (SEM)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Diastolic Blood
Pressure (mm Hg)
n
xx
xx
xx
xx
xx
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
Mean (SEM)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Pulse Rate (bpm)
xx
xx
xx
xx
XX
n
Mean (SEM)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Respiratory Rate
(breaths/min)
n
xx
xx
xx
xx
xx
Mean (SEM)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Body Temperature (C)
n
xx
xx
xx
xx
xx
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
Mean (SEM)
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Note: This table will be repeated for the MITT Population, the PP Population and the PIC Population
CONFIDENTIAL
Page 27 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table A.1.4
Bladder Characteristics at Screening
Safety Population
TSD-001
Part 2
Cohort 1
(N= )
Part 2
Cohort 2
(N= )
Part 1
Cohort 1
(N= )
Part 1
Cohort 2
(N= )
All Subjects
(N= )
Characteristic
NM1BC Recurrent
Yes
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
No
Number of Tumor Locations
Solitary
Multifocal
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Previous Intravesical Therapy
Yes
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
No
EAU Risk Stratification[a]
Low Risk
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Intermediate Risk
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
[a] Low risk defined as: Primary, Solitary, Low Grade/Gl <3cm, no CIS
Intermediate risk defined as: All tumors not defined as Low risk or High risk
High risk defined as: *T1 tumor, *High Grade/G3 tumor, *CIS. *Multiple, recurrent, and large (>3cm) Ta G1G2 tumors (all
conditions must be present)
Note: This table will be repeated for the MITT Population, the PP Population and the PK Population
CONFIDENTIAL
Page 28 of 96


Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
LIPAC Oncology LLC
27 Oct 2020
Table A.1.5
Extent of Exposure
Safety Population
TSD-001
Part 2
Part 1
Part 1
All Subjects
Cohort 1
(N = )
Part 1
Cohort 2
(N = )
Part 2
Cohort 1
(IN = )
Part 2
Cohort 2
(N = )
Part 1
(N = )
Part 2
(N = )
Parameter
(N = )
Duration of Exposure (mg*hours)
n
xx
xx
xx
xx
xx
xx
xx
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
Mean (SEM)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Min, Max
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Total Dose (mg)
n
XX
XX
XX
XX
XX
XX
XX
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Total Hours Exposed
n
xx
xx
XX
XX
XX
XX
XX
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
Min, Max
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Mean Hours Exposed per Subject
n
xx
xx
XX
XX
XX
XX
XX
Mean (SEM)
XX.XX (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Note: This table will be repeated for the MITT Population, the PP Population and the PK Population
CONFIDENTIAL
Page 29 of 96


Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
LIPAC Oncology LLC
27 Oct 2020
Table A.1.5.1
Extent of Exposure
Safety Population: Female
TSD-001
Part 2
Part 1
Part 2
Cohort 1
(N = )
Part 2
Cohort 2
(N = )
Part 1
All Subjects
Cohort 1
(N = )
Part 1
Cohort 2
(N = )
Part 1
(N = )
Part 2
(N = )
Parameter
(N = )
Duration of Exposure (mg*hours)
n
xx
xx
xx
xx
xx
xx
xx
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Total Dose (mg)
n
XX
XX
XX
XX
XX
XX
XX
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Total Hours Exposed
n
XX
XX
XX
XX
XX
XX
XX
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Mean Hours Exposed per Subject
XX
n
xx
xx
xx
XX
XX
XX
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Note: This table will be repeated for the MITT Population, the PP Population and the PK Population
CONFIDENTIAL
Page 30 of 96


Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
LIPAC Oncology LLC
27 Oct 2020
Table A.1.5.2
Extent of Exposure
Safety Population: Male
TSD-001
Part 2
Part 1
Part 2
Cohort 1
(N = )
Part 2
Cohort 2
(N = )
Part 1
All Subjects
Cohort 1
(N = )
Part 1
Cohort 2
(N = )
Part 1
(N = )
Part 2
(N = )
Parameter
(N = )
Duration of Exposure (mg*hours)
n
xx
xx
xx
xx
xx
xx
xx
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Total Dose (mg)
n
XX
XX
XX
XX
XX
XX
XX
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Total Hours Exposed
n
XX
XX
XX
XX
XX
XX
XX
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Mean Hours Exposed per Subject
XX
n
xx
xx
xx
XX
XX
XX
Mean (SEM)
xx.xx (xx.xx) xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx (xx.xx)
xx.xx
xx.xx
xx.xx
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Min, Max
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
xx.xx, xx.xx
Note: This table will be repeated for the MITT Population, the PP Population and the PK Population
CONFIDENTIAL
Page 31 of 96


Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
LIPAC Oncology LLC
27 Oct 2020
Table A.1.6
Protocol Deviations
Safety Population
TSD-001
Part 1
Cohort 1
(N= )
Part 1
Cohort 2
(N= )
Part 2
Cohort 1
(N= )
Part 2
Cohort 2
(N= )
All Subjects
(N= )
n (%) of
Severity
Number
Subjects
Number
n (%) of
Subjects
Number
n (%) of
Subjects
Number
n (%) of
Subjects
Number
n (%) of
Subjects
Classification
Classification #1
Minor
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx
XX
XX
XX
XX
Major
Minor
xx
XX
XX
XX
XX
Classification #2
xx
xx
XX
XX
XX
Major
xx
xx
xx
xx
XX
etc.
etc.
xx
xx
xx
xx
xx
CONFIDENTIAL
Page 32 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.2.1
Part 1: Maximum Tolerated Dose
MITT Population
Dose (mg)
Maximum Tolerated Dose
N/A
Dose Limiting Toxicity Occurred at Dose
Maximum Deliverable Dose Reached
Maximum Deliverable Dose Reached due to Precipitation [a]
N/A
540 mg
360 mg
[a] Observed post void precipitation in patients with pH below 6.0
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 33 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Tabic B.2.2
Part 1: Cohort 1: Paclitaxel Concentration in Urine by Dose Administered and Tween Addition
Descriptive Statistics
MITT Population
Visit
Time Point
Tween Addition
Min
Median
Mean
SEM
SD
Max
n
Day 1: 10 mg
15 mins pre
Absent
15 mins pre
Incomplete
15 mins pre
Complete
15 mins pre
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
xx.xx
XX.XX
xx.xx
xx.xx
xx.xx
xx.xx
2 hrs post
Absent
2 hrs post
Incomplete
2 hrs post
Complete
2 hrs post
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
15 mins pre
Absent
Week 2: 25 mg
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 4: 50 mg
15 mins pre
Absent
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 6: 75 mg
15 mins pre
Absent
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 8: 100 mg
15 mins pre
Absent
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 10: 150 mg
15 mins pre
Absent
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Note: This table will be repeated for the PP Population and the PK. Population
CONFIDENTIAL
Page 34 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Tabic B.2.3
Part 1: Cohort 2: Paclitaxel Concentration in Urine by Dose Administered and Tween Addition
Descriptive Statistics
MITT Population
Visit
Time Point
Tween Addition
Min
Median
Mean
SEM
SD
Max
n
Day 1: 90 mg
15 mins pre
Absent
15 mins pre
Incomplete
15 mins pre
Complete
15 mins pre
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
xx.xx
XX.XX
xx.xx
xx.xx
xx.xx
xx.xx
2 hrs post
Absent
2 hrs post
Incomplete
2 hrs post
Complete
2 hrs post
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
15 mins pre
Absent
Week 2: 180 mg
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 4: 270 mg
15 mins pre
Absent
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 6: 360 mg
15 mins pre
Absent
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 8: 450 mg
15 mins pre
Absent
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 10: 540 mg
15 mins pre
Absent
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
etc.
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Note: This table will be repeated for the PP Population and the PK Population
CONFIDENTIAL
Page 35 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.2.4
Part 1: Cohort 1: Paclitaxel Concentration in Plasma by Dose Administered
Descriptive Statistics
MITT Population
Visit
Time Point
SD
SEM
Minimum
Median
Maximum
Mean
n
Day 1
10 mg
15 minutes pre-instillation
2 hours post-instillation
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Week 2
15 minutes pre-instillation
25 mg
2 hours post-instillation
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 4
15 minutes pre-instillation
2 hours post-instillation
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
50 mg
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 6
15 minutes pre-instillation
2 hours post-instillation
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
75 mg
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 8
15 minutes pre-instillation
100 mg
2 hours post-instillation
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 10
15 minutes pre-instillation
150 mg
2 hours post-instillation
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Note: This table will be repeated for the PP Population and the PK Population
CONFIDENTIAL
Page 36 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.2.4
Part 1: Cohort 2: Paclitaxel Concentration in Plasma by Dose Administered
Descriptive Statistics
MITT Population
Visit
Time Point
SD
SEM
Minimum
Median
Maximum
Mean
n
Day 1
10 mg
15 minutes pre-instillation
2 hours post-instillation
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Week 2
15 minutes pre-instillation
25 mg
2 hours post-instillation
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 4
15 minutes pre-instillation
2 hours post-instillation
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
50 mg
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 6
15 minutes pre-instillation
2 hours post-instillation
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
75 mg
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 8
15 minutes pre-instillation
100 mg
2 hours post-instillation
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 10
15 minutes pre-instillation
150 mg
2 hours post-instillation
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Note: This table will be repeated for the PP Population and the PK Population
CONFIDENTIAL
Page 37 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.2.5
Part 1: Correlation Coefficients for 2-hour Urine Concentrations
MITT Population
IPSS Total Score: Change from
Screening to Week 10
OAB-q Total Score: Change from
Screening to Week 10
Number of AEs
Pearson
Correlation
Coefficient
Pearson
Correlation
Coefficient
Pearson
Correlation
Coefficient
Visit
Total # of AEs
p-value
p-value
p-value
Week 2
xx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Week 4
xx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Week 6
XX
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Week 8
XX
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Week 10
XX
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 38 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.2.6
Part 1: IPSS Total Score
Descriptive Statistics
MITT Population: Men Only
Visit
SEM
Minimum
Median
Maximum
p-value*
Mean
SD
n
Screening
Value
xx
XX.XX
XX.XX
XX.XX
xx.xx
XX.XX
xx.xx
Week 10 (or last
Value
TSD-001 exposure)
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Week 16 (or last
collection for
subject)
Value
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
* P-values generated by the Paired t-test or the Wilcoxon Signed Rank test, (r) indicates Wilcoxon
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 39 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.2.7
Part 1: OAB-q Domains and Total Score
Descriptive Statistics
MITT Population
Symptom Severity
Visit
SD
SEM
Minimum
Median
Maximum
p-value*
Mean
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 10 (or last
Value
TSD-001 exposure)
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Week 16 (or last
collection for
subject)
Value
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
* P-values generated by the Paired t-test or the Wilcoxon Signed Rank test, (r) indicates Wilcoxon
Note: This table will be repeated for the domains of Coping, Concern, Sleep, Social and Total Score
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 40 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.3.1
Part 2: Marker Lesion Response Rate
MITT Population
TSD-001
Part 2
Cohort 1
(N= )
Part 2
Cohort 2
(N= )
Part 2
(N= )
Response Rate
Complete Response Rate
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
Partial Response Rate
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Marker Lesion Response Ratc[a]
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
[a] Marker Lesion Response Rate=Sum of Complete plus Partial Response Rates
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 41 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.3.2
Part 2: Marker Lesion Response Rate as Stratified by EAU Risk Category
MITT Population
TSD-001
Part 2
Cohort 1
(N= )
Part 2
Cohort 2
(N= )
Part 2
(N= )
EAU Risk Category[a|
Response Rate
Complete Response Rate
LOW RISK
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
Partial Response Rate
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Marker Lesion Response Rate
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Complete Response Rate
INTERMEDIATE RISK
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Partial Response Rate
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Marker Lesion Response Rate
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
[a] Low risk defined as: Primary, Solitary, LG/G1 <3cm, no CIS
Intermediate risk defined as: All tumors not defined in the two adjacent categories
Note: Marker Lesion Response Rate=Sum of Complete plus Partial Response Rates
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 42 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Tabic B.3.3
Part 2: Cohort 1: Paclitaxel Concentration (ug/L) in Urine by 360 mg TSD-001 Dose Administered and Tween Addition
Descriptive Statistics
MITT Population
Visit
Time Point
Tween Addition
n
SD
Min
Median
Max
Mean
SEM
Week 2
15 mins pre
Absent
15 mins pre
Incomplete
15 mins pre
Complete
15 mins pre
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
xx.xx
XX.XX
xx.xx
xx.xx
xx.xx
xx.xx
2 hrs post
Absent
2 hrs post
Incomplete
2 hrs post
Complete
2 hrs post
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
24 hrs post
Absent
24 hrs post
etc.
Day 16
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
48 hrs post
Absent
48 hrs post
etc.
Day 17
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Day 18
72 hrs post
Absent
72 hrs post
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Note: This table will be repeated for the PP Population and the PK Population
CONFIDENTIAL
Page 43 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.3.4
Part 2: Cohort 2: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered and Tween Addition
Descriptive Statistics
MITT Population
Visit
Time Point
Tween Addition
n
SD
Min
Median
Max
Mean
SEM
Week 2
15 mins pre
Absent
15 mins pre
Incomplete
15 mins pre
Complete
15 mins pre
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
xx.xx
XX.XX
xx.xx
xx.xx
xx.xx
xx.xx
2 hrs post
Absent
2 hrs post
Incomplete
2 hrs post
Complete
2 hrs post
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
24 hrs post
Absent
24 hrs post
etc.
Day 16
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
48 hrs post
Absent
48 hrs post
etc.
Day 17
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Day 18
72 hrs post
Absent
72 hrs post
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Note: This table will be repeated for the PP Population and the PK Population
CONFIDENTIAL
Page 44 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Tabic B.3.5
Part 2: Cohort 1 and Cohort 2: Paclitaxel Concentration in Urine by 360 mg TSD-001 Dose Administered and Tween Addition
Descriptive Statistics
MITT Population
Visit
Time Point
Tween Addition
n
SD
Min
Median
Max
Mean
SEM
Week 2
15 mins pre
Absent
15 mins pre
Incomplete
15 mins pre
Complete
15 mins pre
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
xx.xx
XX.XX
xx.xx
xx.xx
xx.xx
xx.xx
2 hrs post
Absent
2 hrs post
Incomplete
2 hrs post
Complete
2 hrs post
All Samples
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
24 hrs post
Absent
24 hrs post
etc.
Day 16
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
48 hrs post
Absent
48 hrs post
etc.
Day 17
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Day 18
72 hrs post
Absent
72 hrs post
etc.
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Note: This table will be repeated for the PP Population and the PK Population
CONFIDENTIAL
Page 45 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.3.6
Part 2: Cohort 1 and 2: Paclitaxel Concentration in Plasma by 360 mg TSD-001 Dose Administered
Descriptive Statistics
MITT Population
Visit
Time Point
SD
SEM
Minimum
Median
Maximum
Mean
n
Day 1
15 minutes pre-instillation
2 hours post-instillation
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Week 2
15 minutes pre-instillation
2 hours post-instillation
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Note: This table will be repeated for the PP Population and the PK. Population
CONFIDENTIAL
Page 46 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.3.7
Part 2: Correlation Coefficients for 2-hour Urine Concentrations at Week 2
MITT Population
Total Number of AEs
Complete Response
Partial Response
Total Response
Spearman
Correlation
Coefficient
Spearman
Correlation
Coefficient
Spearman
Correlation
Coefficient
Pearson
Correlation
Coefficient
p-value
p-value
p-value
p-value
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
IPSS Total Score: Change from
Screening to Week 5/7
OAB-q Total Score: Change from
Screening to Week 5/7
Pearson
Correlation
Coefficient
Pearson
Correlation
Coefficient
p-value
p-value
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Note: This table will be repeated for the Tween Addition categories of Complete, Incomplete and Absent
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 47 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.3.8
Part 2: IPSS Total Score
Descriptive Statistics
MITT Population
Cohort 1
Visit
Mean
SD
SEM
Minimum
Median
Maximum
p-value*
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 5
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Week 13
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Cohort 2
SD
SEM
Visit
Mean
Minimum
Median
Maximum
p-value*
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 7
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Week 16
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Part 2 (Cohort 1 & 2)
Visit
SD
SEM
Minimum
Median
Maximum
p-value*
Mean
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Interim Visit
Value
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Final Study Visit (or Value
last collection for
subject)
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
* P-values generated by the Paired t-test or the Wilcoxon Signed Rank test, (r) indicates Wilcoxon
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 48 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table B.3.9
Part 2: OAB-q Domains and Total Score
Descriptive Statistics
MITT Population
Symptom Severity
Cohort 1
Visit
Mean
SD
SEM
Minimum
Median
Maximum
p-value*
n
Screening
Value
xx
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
XX.XX
Week 5
Value
XX
XX.XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Week 13
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Cohort 2
Visit
SD
SEM
Minimum
Median
Maximum
p-value*
Mean
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 7
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Week 16
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Part 2 (Cohort 1 &2)
Visit
SD
SEM
Minimum
Median
Maximum
p-value*
Mean
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Interim Visit
Value
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
Final Study Visit (or
Value
last collection for
subject)
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
x.xxx
* P-values generated by the Paired t-test or the Wilcoxon Signed Rank test, (r) indicates Wilcoxon
Note: This table will be repeated for the domains of Coping, Concern, Sleep, Social and Total Score
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 49 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Tabic B.3.10
Part 2: Post-Treatment Marker Lesion Sites
Correlation of Maximum Diameter Values of DCL to TURBT/Biopsy Measurements at Day 85/106
MITT Population
Pearson Correlation
Specimen Type
Mean (SD)
Coefficient
Measurement
N
p-value
Single Specimen
CYSTOSCOPY
xx
XX.XX
X.XXX
x.xxx
DCL
XX
XX.XX
X.XXX
x.xxx
Multiple Specimens
CYSTOSCOPY
xx
xx.xx
x.xxx
x.xxx
DCL
XX
xx.xx
x.xxx
x.xxx
All Specimens
CYSTOSCOPY
XX
XX.XX
x.xxx
x.xxx
DCL
XX
xx.xx
x.xxx
x.xxx
Note: This table will be repeated for the PP Population
CONFIDENTIAL
Page 50 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.1.1
Part 1: Overall Adverse Event Information
Safety Population
TSD-001
Part 1:
Cohort 1
(N = )
Part 1:
Cohort 2
(N = )
Part 1
(N = )
Number of Subjects:
At Least One TEAE
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
At Least One Treatment-Related TEAE
At Least One TEAE meeting DLT criteria
At Least One Treatment-Related TEAE meeting DLT criteria
At Least One Serious TEAE
At Least One Serious Treatment-Related TEAE
At Least One TEAE Leading to Treatment Discontinuation
TEAE=treatment-emergent adverse event
CONFIDENTIAL
Page 51 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.1.2
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
Safety Population
TSD-001
Part 1:
Cohort 1
(N = )
Part 1:
Cohort 2
(N = )
Part 1
(N = )
System Organ Class
Preferred Term
Gastrointestinal Disorders
Diarrhea
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Dyspepsia
Nausea
etc.
Nervous System Disorders
Dizziness
Headache
Somnolence
etc.
etc.
etc.
*If a subject experiences the same event more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 52 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.1.3
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
by Nearest Relationship to Study Drug
Safety Population
TSD-001
Part 1:
Cohort I
(N = )
Part 1:
Cohort 2
(N = )
Part 1
(N = )
System Organ Class
Preferred Term
Relationship
Gastrointestinal Disorders
Diarrhea
Not Related
(%)
(%)
(%)
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%)
n
n
n
Dyspepsia
(%)
(%)
(%>
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
etc.
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%>
n
n
n
Nervous System Disorders
Dizziness
(%)
(%)
(%)
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%)
n
n
n
Headache
(%)
(%)
(%)
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
etc.
n
n
n
Unlikely
Possibly
Probably
Definitely
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%>
n
n
n
*If a subject experiences the same event more than once the most closely related to study drug is tabulated.
CONFIDENTIAL
Page 53 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.1.4
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
by Maximum Severity
Safety Population
TSD-001
Part I:
Cohort 1
(N = )
Part 1:
Cohort 2
(N = )
Preferred
Term
Part I
(N = )
System Organ Class
CCTAE Grade: Severity
Gastrointestinal Disorders
Diarrhea
Grade I: Mild
(%)
(%)
(%)
n
n
n
Grade 2: Moderate
(%)
(%>
(%>
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%)
n
n
n
Dyspepsia
Grade 1: Mild
(%)
(%)
(%)
n
n
n
Grade 2: Moderate
(%)
(%>
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
Grade 1: Mild
(%)
(%)
(%)
etc.
n
n
n
Grade 2: Moderate
(%)
(%)
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
Nervous System Disorders
Dizziness
Grade 1: Mild
(%)
(%)
(%)
n
n
n
Grade 2: Moderate
(%)
(%)
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%>
n
n
n
Headache
Grade 1: Mild
(%)
(%)
(%>
n
n
n
Grade 2: Moderate
(%)
(%)
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%>
(%)
n
n
n
(%)
(%)
(%)
n
n
n
Grade 1: Mild
(%)
(%)
(%>
etc.
n
n
n
Grade 2: Moderate
(%>
(%>
(%>
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
*If a subject experiences the same event more than once the most severe is tabulated.
CONFIDENTIAL
Page 54 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.1.5
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
by Nearest Relationship to Study Drug and Maximum Severity
Safety Population
TSD-001
Part 1:
Cohort 1
(N = )
Part 1:
Cohort 2
(N = )
Preferred
Term
Part 1
(N = )
CTCAE Grade: Severity
System Organ Class
Relationship
Gastrointestinal Disorders
Diarrhea
Not Related
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Not Related
Grade 2: Moderate
Not Related
Grade 3: Severe: Medically Significant
Not Related
Grade 4: Severe: Life-threatening
Not Related
Grade 5: Severe: Death related to AE
Unlikely
Unlikely
Unlikely
Unlikely
Unlikely
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Grade 2: Moderate
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
Possibly
Possibly
Possibly
Possibly
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Grade 2: Moderate
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
Possible
Probably
Probably
Probably
Probably
Probably
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Grade 2: Moderate
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
Definitely
Definitely
Definitely
Definitely
Definitely
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Grade 2: Moderate
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
*If a subject experiences the same event more than once the most closely related to study drug and most severe is tabulated.
CONFIDENTIAL
Page 55 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.1.6
Part 1: Number (%) of Subjects with Treatment-emergent Adverse Events* Meeting DLT Criteria by System Organ Class and
Preferred Term
Safety Population
TSD-001
Part 1:
Cohort 1
(N = )
Part 1:
Cohort 2
(N = )
Part 1
(N = )
System Organ Class
Preferred Term
Gastrointestinal Disorders
Diarrhea
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Dyspepsia
Nausea
etc.
Nervous System Disorders
Dizziness
Headache
Somnolence
etc.
*If a subject experiences the same event more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 56 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.1.7
Part 1: Number (%) of Subjects with Serious Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
Safety Population
TSD-001
Part 1:
Cohort 1
(N = )
Part 1:
Cohort 2
(N = )
Part 1
(N = )
System Organ Class
Preferred Term
Gastrointestinal Disorders
Diarrhea
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Dyspepsia
Nausea
etc.
Nervous System Disorders
Dizziness
Headache
Somnolence
etc.
*If a subject experiences the same event more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 57 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.1.8
Part 1: Number (%) of Subjects with Serious Treatment-related, Treatment-emergent Adverse Events* by System Organ Class
and Preferred Term
Safety Population
TSD-001
Part 1:
Cohort 1
(N = )
Part 1:
Cohort 2
(N = )
Part 1
(N = )
System Organ Class
Preferred Term
Gastrointestinal Disorders
Diarrhea
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Dyspepsia
Nausea
etc.
Nervous System Disorders
Dizziness
Headache
Somnolence
etc.
*If a subject experiences the same event more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 58 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.1
Part 1: Vital Signs Measurements
Descriptive Statistics
Safety Population
Systolic Blood Pressure (mm Hg)
Visit
SD
SEM
Minimum
Median
Maximum
Mean
n
Value
Day 1
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 1
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX.XX
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 2
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 3
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 4
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Value
Week 5
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 6
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Value
Week 7
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 8
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 9
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 10
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 11
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 14
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 15
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 16
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change = Visit Value minus Day 1
Note: This table will be repeated for diastolic blood pressure, pulse rate, respiratory rate and body temperature
CONFIDENTIAL
Page 59 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.2
Part 1: Laboratory Measurements
Descriptive Statistics
Safety Population
Hemoglobin (%)
Visit
SD
SEIM
Minimum
Median
Maximum
Mean
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Day 1
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX.XX
Change
xx
xx.xx
xx.xx
xx.xx
XX.XX
xx.xx
xx.xx
Week 1
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 2
Value
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 3
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 4
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 5
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 6
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Value
Week 7
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 8
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 9
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 10
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 11
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 16
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change = Visit Value minus Screening
Note: This table will be repeated for all continuous lab parameters
CONFIDENTIAL
Page 60 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.3
Part 1: Laboratory Measurements
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal at Screening to:
Visit
Parameter
Normal
Abnormal
Normal
Abnormal
Albumin (g/dL)
Week 4
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
Week 16
Albumin/Globulin (RATIO)
Week 4
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Alkaline Phosphatase (U/L)
Week 4
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Week 4
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
etc.
Week 16
Note: This table will be repeated for all lab parameters
CONFIDENTIAL
Page 61 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.4
Part 1: ECG Measurements
Descriptive Statistics
Safety Population
Heart Rate (bpm)
Visit
SD
SEM
Minimum
Median
Maximum
Mean
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 16
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change = Visit Value minus Screening
Note: This table will be repeated for all continuous ECG parameters
CONFIDENTIAL
Page 62 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.5
Part 1: ECG: ST-segment and Interval Measurements
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal, NCS at Screening to:
Visit
Abnormal, NCS
Abnormal, NCS
Parameter
Normal
Normal
PR Interval, Aggregate (msec)
Week 16
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
QRS Duration, Aggregate (msec)
Week 16
xx (xx.x%)
XX (xx.x%)
xx (xx.x%)
xx (xx.x%)
QT Interval, Aggregate (msec)
Week 16
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
CONFIDENTIAL
Page 63 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.6
Part 1: ECG: Sinus Rhythm
Shift from Screening: Number (%) of Subjects
Safety Population
Not Sinus Rhythm at Screening to:
Sinus Rhythm at Screening to:
Not Sinus
Rhythm
Not Sinus
Rhythm
Parameter
Visit
Sinus Rhythm
Sinus Rhythm
Sinus Node Rhythms
Week 16
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
CONFIDENTIAL
Page 64 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.7
Part 1: ECG: Overall Interpretation
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal, NCS at Screening to:
Visit
Abnormal, NCS
Abnormal, NCS
Parameter
Normal
Normal
Interpretation
Week 16
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
CONFIDENTIAL
Page 65 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.8
Part 1: ECG: T-wave Interpretation
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal at Screening to:
Visit
Parameter
Normal
Abnormal
Normal
Abnormal
Week 16
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
T Wave
CONFIDENTIAL
Page 66 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.9
Part 1: Physical Examination
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal,
Abnormal,
NCS
Abnormal, NCS at Screening to:
Abnormal,
NCS
Abnormal, CS
Parameter
Visit
Normal
CS
Normal
Allergies
Week 16
XX (x.xx%)
XX (x.xx%)
XX (x.xx%)
XX (x.xx%)
XX (x.xx%)
XX (x.xx%)
Cardiovascular
Week 16
XX (x.xx%)
XX (x.xx%)
XX (x.xx%)
XX (x.xx%)
XX (x.xx%)
XX (x.xx%)
Dermatological
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Endocrine/Metabolic
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Extremities
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Gastrointestinal
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
General Appear/Constitutional Symptoms
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Genitourinary/Reproductive
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
HEENT
Hematologic
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Hepatic
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Lymphatic
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Musculoskeletal
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Neurological Function
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Psychiatric
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
Respiratory
Week 16
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
xx (x.xx%)
CONFIDENTIAL
Page 67 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.2.10
Part 1: Concomitant Medications by WHO Preferred Term and Level 4 ATC: Number (%) of Subjects
Safety Population
TSD-UU1
TSD-0U1
TSD-001
Part 1
(N = )
Part 1
(N = )
Part 1
(IN = )
WHO Preferred Term
Level 4 ATC
Preferred Term #1
ATC Term #1
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
ATC Term #2
ATC Term #3
etc.
Preferred Term #2
ATC Term #1
ATC Term #2
ATC Term #3
etc.
*If a subject receives the same medication more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 68 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.3.1
Part 2: Overall Adverse Event Information
Safety Population
TSD-001
Cohort 1
(N = )
Cohort 2
(N = )
Part 2
(N = )
Number of Subjects:
At Least One TEAE
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
At Least One Treatment-Related TEAE
At Least One TEAE meeting DLT criteria
At Least One Treatment-Related TEAE meeting DLT criteria
At Least One Serious TEAE
At Least One Serious Treatment-Related TEAE
At Least One TEAE Leading to Treatment Discontinuation
TEAE=treatmcnt-emergent adverse event
CONFIDENTIAL
Page 69 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.3.2
Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
Safety Population
TSD-001
Cohort 1
(N = )
Cohort 2
(N = )
Part 2
(IN = )
System Organ Class
Preferred Term
Gastrointestinal Disorders
Diarrhea
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Dyspepsia
Nausea
etc.
Nervous System Disorders
Dizziness
Headache
Somnolence
etc.
etc.
etc.
*lf a subject experiences the same event more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 70 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.3.3
Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
by Nearest Relationship to Study Drug
Safety Population
TSD-001
Cohort 1
(N = )
Cohort 2
(N = )
Part 2
(N = )
System Organ Class
Preferred Term
Relationship
Gastrointestinal Disorders
Diarrhea
Not Related
(%)
(%)
(%)
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%>
(%)
(%>
n
n
n
(%>
(%)
(%>
n
n
n
Dyspepsia
(%)
(%)
(%>
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%>
etc.
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%>
n
n
n
Nervous System Disorders
Dizziness
(%)
(%)
(%>
n
n
n
Unlikely
Possibly
Probably
Definitely
Not Related
Unlikely
Possibly
Probably
Definitely
Not Related
Unlikely
Possibly
Probably
Definitely
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%>
(%)
(%>
n
n
n
(%)
(%)
(%>
n
n
n
Headache
(%)
(%>
(%)
n
n
n
(%>
(%)
(%>
n
n
n
(%>
(%)
(%>
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%>
(%)
(%>
etc.
n
n
n
(%>
(%)
(%>
n
n
n
(%)
(%>
(%>
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%>
(%>
n
n
n
*If a subject experiences the same event more than once the most closely related to study drug is tabulated.
CONFIDENTIAL
Page 71 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.3.4
Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
by Maximum Severity
Safety Population
TSD-001
Preferred
Term
Cohort 1
(N = )
Cohort 2
(N = )
Part 2
(N = )
System Organ Class
CCTAE Grade: Severity
Gastrointestinal Disorders
Diarrhea
Grade 1: Mild
(%)
(%)
(%)
n
n
n
Grade 2: Moderate
(%)
(%)
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
Dyspepsia
Grade 1: Mild
(%)
(%)
(%)
n
n
n
Grade 2: Moderate
(%)
(%)
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%)
n
n
n
Grade 1: Mild
(%)
(%)
(%)
etc.
n
n
n
Grade 2: Moderate
(%)
(%)
(%>
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
Nervous System Disorders
Dizziness
Grade 1: Mild
(%)
(%)
(%)
n
n
n
Grade 2: Moderate
(%)
(%)
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%>
n
n
n
(%)
(%)
(%)
n
n
n
Headache
Grade 1: Mild
(%>
(%)
(%>
n
n
n
Grade 2: Moderate
(%)
(%)
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
Grade 1: Mild
(%)
(%)
(%)
etc.
n
n
n
Grade 2: Moderate
(%)
(%)
(%)
n
n
n
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
(%)
(%)
(%)
n
n
n
*If a subject experiences the same event more than once the most severe is tabulated.
CONFIDENTIAL
Page 72 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.3.5
Part 2: Number (%) of Subjects with Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
by Nearest Relationship to Study Drug and Maximum Severity
Safety Population
TSD-001
Preferred
Term
Cohort 1
Cohort 2
(N = )
(N = )
Part 2
(N = )
System Organ Class
Relationship
CTCAE Grade: Severity
Gastrointestinal Disorders
Diarrhea
Not Related
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Not Related
Grade 2: Moderate
Not Related
Grade 3: Severe: Medically Significant
Not Related
Grade 4: Severe: Life-threatening
Not Related
Grade 5: Severe: Death related to AE
n (%)
n (%)
n (%)
Unlikely
Unlikely
Unlikely
Unlikely
Unlikely
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Grade 2: Moderate
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
Possibly
Possibly
Possibly
Possibly
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Grade 2: Moderate
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
Possible
Probably
Probably
Probably
Probably
Probably
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Grade 2: Moderate
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
Definitely
Definitely
Definitely
Definitely
Definitely
Grade 1: Mild
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Grade 2: Moderate
Grade 3: Severe: Medically Significant
Grade 4: Severe: Life-threatening
Grade 5: Severe: Death related to AE
*If a subject experiences the same event more than once the most closely related to study drug and most severe is tabulated.
CONFIDENTIAL
Page 73 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Tabic E.3.6
Part 2: Number (%) of Subjects with Serious Treatment-emergent Adverse Events* by System Organ Class and Preferred Term
Safety Population
TSD-001
Cohort 1
(N = )
Cohort 2
(N = )
Part 2
(IN = )
System Organ Class
Preferred Term
Gastrointestinal Disorders
Diarrhea
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Dyspepsia
Nausea
etc.
Nervous System Disorders
Dizziness
Headache
Somnolence
etc.
*If a subject experiences the same event more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 74 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.3.7
Part 2: Number (%) of Subjects with Serious Treatment-related, Treatment-emergent Adverse Events* by System Organ Class
and Preferred Term
Safety Population
TSD-001
Cohort 1
(N = )
Cohort 2
(N = )
Part 2
(N = )
System Organ Class
Preferred Term
Gastrointestinal Disorders
Diarrhea
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Dyspepsia
Nausea
etc.
Nervous System Disorders
Dizziness
Headache
Somnolence
etc.
*If a subject experiences the same event more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 75 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.1
Part 2: Vital Signs Measurements
Descriptive Statistics
Safety Population
Systolic Blood Pressure (mm Hg)
Visit
SD
SEM
Minimum
Median
Maximum
Mean
n
Value
Day 1
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 1
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX.XX
Change
xx
xx.xx
xx.xx
xx.xx
XX.XX
xx.xx
xx.xx
Week 2: Day 15
Value
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 2: Day 16
Value
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 2: Day 17
Value
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 2: Day 18
Value
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 3
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 4
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 5
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
Week 6
Value
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 7
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 9
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 12
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 15
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
End of Study
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change = Visit Value minus Day 1
Note: This table will be repeated for diastolic blood pressure, pulse rate, respiratory rate and body temperature
CONFIDENTIAL
Page 76 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.2
Part 2: Laboratory Measurements
Descriptive Statistics
Safety Population
Hemoglobin (%)
Visit
SD
SEIM
Minimum
Median
Maximum
Mean
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Value
Day 1
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX.XX
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 1
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 2
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 3
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Value
Week 4
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 5
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Value
Week 6
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 7
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Week 9
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
End of Study
Value
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change = Visit Value minus Screening
Note: This table will be repeated for all continuous lab parameters
CONFIDENTIAL
Page 77 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.3
Part 2: Laboratory Measurements
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal at Screening to:
Visit
Parameter
Normal
Abnormal
Normal
Abnormal
Albumin (g/dL)
Week 13
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
Week 16
Albumin/Globulin (RATIO)
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Alkaline Phosphatase (U/L)
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
etc.
Week 16
Note: This table will be repeated for all lab parameters
CONFIDENTIAL
Page 78 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.4
Part 2: ECG Measurements
Descriptive Statistics
Safety Population
Heart Rate (bpm)
Visit
SD
SEM
Minimum
Median
Maximum
Mean
n
Screening
Value
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
End of Study
Value
Change
xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
XX
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Change = Visit Value minus Screening
Note: This table will be repeated for all continuous ECG parameters
CONFIDENTIAL
Page 79 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.5
Part 2: ECG: ST-segment and Interval Measurements
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal, NCS at Screening to:
Visit
Abnormal, NCS
Abnormal, NCS
Parameter
Normal
Normal
PR Interval, Aggregate (msec)
Week 13
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
Week 16
QRS Duration, Aggregate (msec)
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
QT Interval, Aggregate (msec)
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
CONFIDENTIAL
Page 80 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.6
Part 2: ECG: Sinus Rhythm
Shift from Screening: Number (%) of Subjects
Safety Population
Not Sinus Rhythm at Screening to:
Sinus Rhythm at Screening to:
Not Sinus
Rhythm
Not Sinus
Rhythm
Parameter
Visit
Sinus Rhythm
Sinus Rhythm
Sinus Node Rhythms
Week 13
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
Week 16
CONFIDENTIAL
Page 81 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.7
Part 2: ECG: Overall Interpretation
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal at Screening to:
Visit
Parameter
Normal
Abnormal
Normal
Abnormal
Interpretation
Week 13
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
XX(xx.x%)
Week 16
CONFIDENTIAL
Page 82 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.8
Part 2: ECG: T-wave Interpretation
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal at Screening to:
Visit
Parameter
Normal
Abnormal
Normal
Abnormal
Week 13
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
XX (xx.x%)
T Wave
Week 16
CONFIDENTIAL
Page 83 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.9
Part 2: Physical Examination
Shift from Screening: Number (%) of Subjects
Safety Population
Normal at Screening to:
Abnormal, NCS at Screening to:
Abnormal,
NCS
Abnormal,
NCS
Visit
Abnormal, CS
Parameter
Normal
Normal
Allergies
Week 13
XX (xx.x%)
XX (xx.x%)
xx (xx.x%)
XX (xx.x%)
xx (xx.x%)
XX (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Cardiovascular
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Dermatological
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Endocrine/Metabolic
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Extremities
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Gastrointestinal
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
General Appear/Constitutional Symptoms
Week 13
Week 16
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Genitourinary/Reproductive
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
I1EENT
Week 16
Hematologic
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Hepatic
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Lymphatic
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Musculoskeletal
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Neurological Function
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Psychiatric
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
Respiratory
Week 13
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
Week 16
CONFIDENTIAL
Page 84 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table E.4.10
Part 2: Concomitant Medications by WHO Preferred Term and Level 4 ATC: Number (%) of Subjects
Safety Population
TSD-001
Cohort 1
(N = )
Cohort 2
(N = )
Part 2
(IN = )
WHO Preferred Term
Level 4 ATC
Preferred Term #1
ATC Term #1
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
ATC Term #2
ATC Term #3
etc.
Preferred Term #2
ATC Term #1
ATC Term #2
ATC Term #3
etc.
*If a subject receives the same medication more than once the first occurrence is tabulated.
CONFIDENTIAL
Page 85 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table F.1.1
Part 3 (n=6): One Year Recurrence/Disease-Free Survival in Part 1 Subjects
MITT Population
TSD-001
(N=)
EAU Risk Category[a|
One Year Recurrence/Disease-Free Survival
Low Risk
n (%)
n (%)
n (%)
n (%)
Intermediate Risk
All Subjects (Part 1)
n (%)
n (%)
[a] Low risk defined as: Primary, Solitary, LG/G1 <3cm, no CIS
Intermediate risk defined as: All tumors not defined as Low risk or High risk
High risk defined as: *T1 tumor, *HG/G3 tumor, *CIS. *Multiple, recurrent, and large (>3cm) Ta G1G2 tumors (all
conditions must be present)
Note: This table will be repeated for the PP population
CONFIDENTIAL
Page 86 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Table F.1.2
Part 3 (n=6): Two Year Recurrence/Disease-Free Survival in Part 1 Subjects
MITT Population
TSD-00I
(N- )
EAU Risk Category|a|
Two Year Recurrence/Disease-Free Survival
Low Risk
N
x
25th Percentile
xx.x
Median (50th percentile)
xx.x
75th Percentile
xx.x
Intermediate Risk
N
x
25,h Percentile
xx.x
Median (50th percentile)
xx.x
75lh Percentile
xx.x
All Subjects (Part 1)
N
x
25th Percentile
xx.x
Median (50,h percentile)
xx.x
75lh Percentile
xx.x
Kaplan-Meier method was used to calculate the 25th, 50th and 75th percentiles.
[a] Low risk defined as: Primary, Solitary, LG/G1 <3cm, no CIS
Intermediate risk defined as: All tumors not defined as Low risk or High risk
High risk defined as: *T1 tumor, *HG/G3 tumor, *CIS. *Multiple, recurrent, and large (>3cm) Ta G1G2 tumors (all
conditions must be present)
Note: This table will be repeated for the PP population
CONFIDENTIAL
Page 87 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
21.
APPENDIX 1
Table 2:
Part 1 Schedule of Assessments
Visit
Screening
Day 22
Week
Day 36
Week
Day 43
Week
Day 50
Week
Day 64
Week
Day 71
Week
Day 78
Week
Day 99
Week
Day
Da\
Day
Day
Day
Day 57
Week
Day
Day
-12
8
15
29
106
113
I
Week Week
3
Week
5
6
7
8
9
10
11
14
Week Week
2
4
16
1
15
Visit Window
< 28 days
before Day 1
±2
\ A ±1 day ±1 day ±1 day
±2
±2
±2
±2
±2
±2
±2 days ±2 days
±7
±7
±7 days
days
days
days
days
days
days
days
days
days
Informed consent
X
Subject demographics
X
Eligibility criteria
X
X
X
Medical/surgical history
X
Hemoglobin Ale
X
Weight and height
X
X
Drug screen
X
X
Urinalysis with pH 1
X
X
X
X
X
X
X
X
Pregnancy test (urine)2
X
X
X
12-lead ECG 1
X
X
I
Vital signs (BP, HR, RR, BT)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 1
X
X
Chemistry panel (fasted
> 2 hours)
X
X
X
Hematology panel 1
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
CONFIDENTIAL
Page 88 of 96


LIPAC Oncology LLC
27 Oct 2020
Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Treatment exit10
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 visits).
2.
For women of childbearing potential.
3.
Endoscopic assessment includes TURBT (Day -12), voided cytology (screcning/Day 78), and/or cystoscopy (scrcening/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).
CONFIDENTIAL
Page 89 of 96


Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
LIPAC Oncology LLC
27 Oct 2020
Table 3:
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
±2 days
±2 days
±2 days
±2 days
±2 days
±1 day
±7 days
±7 days ±7 days
Obtain informed consent
X
Subject demographics
X
Eligibility criteria
X
X
Medical/surgical history
X
Hemoglobin Ale
X
Weight and height
X
X
Drug screen
X
X
I
Urinalysis with pH
X
X
X
X
X
X
X
X
Pregnancy test (urine)2
X
X
X
I
12-lead ECG
X
X
Vital signs (BP, HR, RR, BT)1
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
1
X
X
Chemistry panel (fasted > 2 hours)1
X
X
I
Hematology panel
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
x9-10
X8
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 plasma''
X
X
Paclitaxel level urine6
X
X
IPSS, OAB-q
X
X
X
Treatment exit"
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.
CONFIDENTIAL
Page 90 of 96


Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
LIPAC Oncology LLC
27 Oct 2020
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).
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 Protocol Section 7.
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).
Voided cytology and cystoscopy will be performed at screening visit. Positive cytology finding will result in screen failure.
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.
TURBT performed if evidence of lesion is present.
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.
End treatment part, begin surveillance portion of study ( part 3).
4.
5.
6.
7.
8.
9.
10.
11.
CONFIDENTIAL
Page 91 of 96


Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
LIPAC Oncology LLC
27 Oct 2020
Table 4:
Part 2 Cohort 2 Schedu e 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
±2 days
±2 days ±2 days ±2 days ±2 days ±2 days
±1 day
±7 days ±7 days ±7 days ±7 days
Obtain informed consent
X
Subject demographics
X
Eligibility criteria
X
X
Medical/surgical history
X
Hemoglobin Ale
X
Weight and height
X
X
Drug screen
X
X
I
Urinalysis with pH
X
X
X
X
X
X
X
X
X
X
Pregnancy test (urine)2
X
X
X
1
12-lead ECG
X
X
Vital signs (BP, HR, RR, BT)1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
1
X
X
Chemistry panel (fasted
> 2 hours)
X
X
I
I
Hematology panel
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
Treatment exit 11
X
X
X
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).
CONFIDENTIAL
Page 92 of 96


Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
LIPAC Oncology LLC
27 Oct 2020
For women of childbearing potential.
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).
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 Protocol Section 7.
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).
Voided cytology and cystoscopy will be performed at screening visit. Positive cytology at screening will result in screen failure.
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.
TURBT performed if evidence of lesion is present.
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.
End treatment part 2, begin surveillance portion of study (part 3).
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
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LIPAC Oncology LLC
27 Oct 2020
Surveillance Schedule of Assessments (Part 3)
Table 5:
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 W indow
±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 I 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.
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LIPAC Oncology LLC
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Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
22.
APPENDIX 2
Scoring Manual for the OAB-q
To calculate a symptom severity score, create a summed score from the listed items and use the
formula below the table to transform the value. This will provide symptom scores where higher score
values are indicative of greater symptom severity or bother and lower scores indicate minimal
symptom severity.
Lowest and Highest
Possible Raw Score
Scale
Sum Item Values
Possible Raw Scores
Range
Symptom Severity
1 - 8
8,48
40
Transformation for Symptom Severity raw scores ONLY:
( Actual raw score- lowest possible raw score)
Possible raw score range
For the HRQL subscales (coping, concern, sleep, and social), create summed scores of the listed
items for each individual subscale. To calculate the HRQL total score, sum the value of each
individual subscale (do not sum all the individual items). Use the formula below the table to
transform all values. Higher scores will be indicative of better HRQL.
X 100
Transformed Score =
Scale
Sum Item Values
Lowest and Highest
Possible Raw Scores
Possible Raw Score
Range
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Protocol Number TD-001
STATISTICAL ANALYSIS PLAN FINAL V 2.0
Coping
9+11+16+21+22+26+32+33
8,48
40
12+13+14+19+23+25+29
7,42
35
Concern
Sleep
10+15+17+24+30
5,30
25
Social
18+20+27+28+31
Sum of HRQL subscales
(not individual items)
5,30
25
HRQL Total
25, 150
125
Formula for transformation of HRQL raw scores:
( Highest possible score- Actual
raw score) Possible raw
score range
x 100
Transformed Score =
Missing Items
For the subscale analyses, if < 50% of the scale items are missing, the scale should be retained
with the mean scale score of the items present used to impute a score for the missing items. If >
50% of the items are missing, no scale score should be calculated, the subscale score should be
considered missing. If a subscale score is missing, the HRQL Total score cannot be calculated.
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