Clinical trial NCT02709889
Conditions: Malignant Melanoma Medullary Thyroid Cancer Glioblastoma Large-Cell Neuroendocrine Carcinoma Neuroendocrine Prostate Cancer High Grade Gastroenteropancreatic Neuroendocrine Carcinoma Other Neuroendocrine Carcinoma Other Solid Tumors
Sponsor: AbbVie
Start date: 2016-09-23; Completion date: 2019-08-27
Enrollment: 200 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to assess the safety and tolerability of rovalpituzumab tesirine in subjects with specific delta-like protein 3-expressing advanced solid tumors.

Detailed description:
This is a multicenter, open-label study involving multiple specific advanced solid tumor types, consisting of a dose escalation part A followed by an expansion part B. Cancer subtypes will be studied in separate disease-specific cohorts in both Parts. Eight separate cohorts will enroll malignant melanoma, medullary thyroid cancer (MTC), glioblastoma, large cell neuroendocrine carcinoma (LCNEC), neuroendocrine prostate cancer (NEPC), high-grade gastroenteropancreatic neuroendocrine carcinoma (GEP NEC), other NEC, and solid tumors other than the above.

Arms: arm 1: Rovalpituzumab tesirine 0.2-0.4 mg/kg administered intravenously on Day 1 of each 6-week cycle. Dexamethasone 8 mg administered orally twice daily on Day -1, Day 1 (the day of dosing), and Day 2 of each 6-week cycle.
Interventions: intervention 1: Rovalpituzumab tesirine intervention 2: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: Dexamethasone will be provided through a participant's local prescription by Investigator or other provider (i.e., dexamethasone will not be provided by the Sponsor).

Protocol documents:
Prot_SAP_000.pdf: 
NCT02709889


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Synopsis
TITLE: 
An Open-Label Study of Rovalpituzumab Tesirine in Subjects with Delta-Like Protein 3-Expressing Advanced 
Solid Tumors
PROTOCOL NUMBER: SCRX001-006
PHASE OF DEVELOPMENT: 1/2
INVESTIGATORS AND STUDY CENTERS: Multicenter
OBJECTIVES:
Primary
!
To assess the safety and tolerability of rovalpituzumab tesirine in subjects with specific delta-like protein 3 
(DLL3)-expressing advanced solid tumors.
Secondary
!
To explore the antitumor activity of rovalpituzumab tesirine in subjects with specific DLL3-expressing 
advanced solid tumors.
!
To study the pharmacokinetics (PK) of and incidence of anti-therapeutic antibodies (ATA) against 
rovalpituzumab tesirine in subjects with specific DLL3-expressing advanced solid tumors.
Exploratory
!
To explore the expression of DLL3 in specific DLL3-expressing advanced solid tumors, and its relationship to 
clinical outcome during treatment with rovalpituzumab tesirine.
!
To explore the effect of rovalpituzumab tesirine on disease biomarkers and pharmacodynamics.
!
To assess change in patient reported outcomes (PRO) within the expansion cohorts (Part B) utilizing the 
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 
30 (QLQ-C30) questionnaire and EuroQoL Five Dimension Questionnaire (EQ-5D-5L) during treatment with 
rovalpituzumab tesirine.
TEST PRODUCTS, DOSE, AND MODE OF ADMINISTRATION:
!
Rovalpituzumab tesirine 0.2–0.4 mg/kg will be administered intravenously (IV) on Day 1 of each 6-week 
cycle, or according to other dosing regimens recommended by the Safety Monitoring Committee (SMC).
!
Dexamethasone 8 mg will be administered orally (PO) twice daily on Day -1, Day 1 (the day of dosing), and 
Day 2 of each 6-week cycle. 
STUDY DESIGN AND METHODOLOGY:
This is a multicenter, open-label study involving multiple specific advanced solid tumor types. This study consists 
of a Part A dose escalation followed by a Part B expansion. Cancer subtypes will be studied in separate 
disease-specific cohorts in both study parts, A and B. Seven separate cohorts will enroll the following cancer 
types: 
1.
Malignant melanoma 
2.
Medullary thyroid cancer (MTC)
3.
Glioblastoma (GBM)
4.
Large cell neuroendocrine carcinoma (LCNEC) of any origin
5.
Neuroendocrine prostate cancer (NEPC)
6.
High-grade gastroenteropancreatic neuroendocrine carcinoma (GEP NEC)
7.
Other neuroendocrine carcinoma (NEC), and high grade neuroendocrine tumors (NET) 
8.
Solid tumors other than the above
As of protocol version 4.0, cohort 3 (GBM) is closed to enrollment.


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Part A Dose Escalation
Rovalpituzumab tesirine will be initially administered on Day 1 of each 6-week cycle, following a standard 
3+3 dose-escalation approach. For each cohort in Part A, dose escalation is planned to proceed until a single 
maximum tolerated dose (MTD) (dose level and dosing interval inclusive) is determined. 
The SMC will monitor the safety of the trial and may make dose-escalation and dosing-interval 
recommendations. The SMC may also recommend further evaluation of the safety at a given dose, investigation 
of alternative dose regimens (including a dose level that is intermediate to the planned dose levels), modification 
of the dosing interval, or limitation to the maximum number of doses. For instance, based on dose-limiting 
toxicities (DLTs) and/or adverse event (AE)-related dose delays, enrollment may change at the same dose to a 
different dosing schedule (e.g., up to 12-week cycles, in which rovalpituzumab tesirine is administered on Day 1 
of each cycle of up to 84 days). The SMC may also recommend the elimination or cancellation of a dose level(s) 
in a cohort based on the experience in other cohorts. For instance, if 3 or more initially-enrolled cohorts establish 
the same dose level as MTD, the remaining cohorts may forgo escalation to higher dose levels.
Response will be assessed by radiographic imaging at protocol-specified time points determined by the subject’s 
dosing schedule. In the 6-week cycle schedule, response assessments will be conducted between Days 36–42 of 
Cycles 1-4, and every 2 cycles thereafter. Prostate cancer-specific assessments are described in Appendix 13.6. 
Part B Expansion Cohorts
To explore the recommended dosing regimen for distinct disease subsets, subjects will be enrolled in 
disease-specific expansion cohorts in Part B. The dose regimen(s) to be examined in the disease-specific cohorts 
will be at the MTD determined in Part A or a lower dose(s) and/or regimen(s), depending on the cumulative data. 
For example, a lower dose regimen may consist of a finite number of doses and/or a mixed-dose regimen, with all 
doses at or below MTD, but varying based on the cycle. The dose(s), regimen(s), and schedule(s) for the 
expansion cohorts will be determined by the Sponsor in consultation with the SMC.
In Part B, up to approximately 174 subjects may be enrolled, including approximately 19 subjects in each of the 
5 disease-specific cohorts and up to 30 subjects each for Cohort 7 and Cohort 8. The goal of the Part B expansion 
is to provide further safety data and preliminary efficacy data for the selected dose regimens.
Response will be assessed by radiographic imaging at protocol-specified time points determined by the subject’s 
dosing schedule. In the 6-week cycle schedule, tumor response will be assessed every 6 weeks during active study 
treatment until 24 weeks, then every 12 weeks, thereafter. Prostate cancer-specific assessments are described in 
Appendix 13.6.
MAJOR ELIGIBILITY CRITERIA:
Subjects with a histologically confirmed, DLL3-expressing advanced solid tumor with measurable disease, that is 
relapsed/refractory to prior standard systemic therapy; ECOG 0–1; adequate hematologic, hepatic and renal 
function; and no prior exposure to a pyrrolobenzodiazepine (PBD)-based drug. Prostate cancer-specific criteria 
are provided in Appendix 13.6.
PLANNED SAMPLE SIZE:
Up to approximately 318 subjects are expected to participate in this two-part trial. Study accrual in Part A is 
approximately 144 subjects (depending on the number of cohorts required to reach the MTD). For Part B, 
approximately 174 subjects may be enrolled. The “Other NEC/NET” and “Other Solid Tumor” cohorts will each 
enroll 30 subjects. The rationale for the sample size is based on the assumption that an objective response rate 
(ORR) of around 15% would be indicative of efficacy worthy of further investigation, given the advanced cancers 
and extensive treatment history in this study population. Conversely, response rates less than 5% would indicate 
lack of efficacy. A sample size of 25 subjects would produce a 90% two-tailed confidence interval (CI) of 5.7% 
to 33.0% around an observed response rate of 16.0%.
STUDY TESTS AND OBSERVATIONS:
Safety assessments include physical examinations, vital signs, body weight, Eastern Cooperative Oncology Group 
(ECOG) score, monitoring of AEs, laboratory tests (hematology, serum chemistries, urinalysis, and coagulation), 
electrocardiograms (ECGs), echocardiograms (ECHOs), fluid retention questionnaire, and monitoring of 
concomitant medications.
Efficacy assessments will consist of radiographic imaging. Responses will be categorized by Response Evaluation 


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Criteria in Solid Tumors (RECIST v1.1) (Eisenhauer 2009). Prostate cancer subjects will also be categorized by 
Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria (Scher 2016), including the use of bone 
scintigraphy and prostate-specific antigen (PSA) testing, as described in Appendix 13.6.
PK assessments will include blood samples for rovalpituzumab tesirine and anti-therapeutic antibodies (ATAs).
Pharmacodynamic and biomarker assessments will include analyses of tumor tissue for DLL3 expression, and 
blood samples for tumor markers, circulating tumor cells, and soluble biomarkers, such as soluble DLL3.
Changes from baseline in PROs, utilizing the EORTC QLQ-C30 and EQ-5D-5L, will be assessed.
STATISTICAL METHODS:
As a general strategy, data will be analyzed by disease, cohort, and dose regimen. 
Safety analysis will include summaries by disease, by cohort, and/or by dose level of: AEs, laboratory measures, 
physical examinations, ECGs, and vital signs using data from subjects in the Safety Analysis set. The incidence of 
DLTs will be summarized using data from the DLT-Evaluable Set (defined as all subjects who receive any 
amount of study drug and either experienced a DLT, or were followed for the full DLT evaluation period).
The ORR will be reported with category counts, percentage, and 90% two-tailed CI. Duration of response (DOR), 
progression-free survival (PFS), and overall survival (OS) will be evaluated using Kaplan-Meier estimates, and 
curves will be generated based on these estimates.


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Table of Contents
Synopsis ............................................................................................................................2
Table of Contents...............................................................................................................5
List of Figures..................................................................................................................10
List of Tables...................................................................................................................11
Definitions of Abbreviations and Terms...........................................................................12
1.
Introduction ...................................................................................................................16
1.1
Delta-like Protein 3 ..............................................................................................16
1.2
Rovalpituzumab Tesirine......................................................................................16
1.3
DLL3-Expressing Cancers Other than Small Cell Lung Cancer............................17
1.3.1
Metastatic Melanoma................................................................................17
1.3.2
Medullary Thyroid Carcinoma..................................................................17
1.3.3
Glioblastoma ............................................................................................18
1.3.4
Neuroendocrine Carcinomas.....................................................................18
1.4
Rationale for the Study and Anticipated Risks......................................................18
2.
Objectives.......................................................................................................................20
2.1
Primary Objective ................................................................................................20
2.2
Secondary Objectives...........................................................................................20
2.3
Exploratory Objectives.........................................................................................20
2.4
Endpoints.............................................................................................................20
2.4.1
Safety Endpoints.......................................................................................20
2.4.2
Efficacy Endpoints....................................................................................21
2.4.3
Patient Reported Outcomes Endpoint........................................................21
2.4.4
Pharmacokinetics, Biomarker, and Pharmacodynamic Endpoints..............21
3.
Investigational Plan .......................................................................................................22
3.1
Summary of Study Design....................................................................................22
3.1.1
Part A Dose-Regimen Finding ..................................................................23
3.1.2
Part B Expansion Cohorts.........................................................................25
3.1.3
Definition of Dose-Limiting Toxicities .....................................................25
3.1.4
Retreatment ..............................................................................................25


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3.2
Discussion and Rationale for Study Design ..........................................................26
3.2.1
Study Design ............................................................................................26
3.2.2
Method of Assigning Subjects to Treatment Groups..................................26
3.2.3
Rationale for Selection of Doses ...............................................................26
3.2.4
Blinding....................................................................................................27
4.
Study Population............................................................................................................28
4.1
Inclusion Criteria..................................................................................................28
4.2
Exclusion Criteria.................................................................................................29
4.3
Contraception Recommendations .........................................................................30
4.3.1
Contraception for Female Subjects............................................................30
4.3.2
Contraception for Male Subjects...............................................................31
4.4
Removal of Subjects from Therapy or Assessment ...............................................31
4.4.1
Discontinuation of Study Drug..................................................................32
4.4.2
Subject Discontinuation from Study..........................................................32
5.
Treatments .....................................................................................................................33
5.1
Treatments Administered......................................................................................33
5.2
Investigational Product: Rovalpituzumab Tesirine................................................33
5.2.1
Description ...............................................................................................33
5.2.2
Packaging and Labeling............................................................................33
5.2.3
Dosing ......................................................................................................33
5.2.4
Dose Modifications...................................................................................33
5.2.4.1
Dose Holds or Delays .................................................................34
5.2.4.2
Clinical Monitoring of Grade 3 or Grade 4 Adverse Events.........34
5.2.4.3
Dose Reductions Due to Adverse Events.....................................34
5.3
Required Premedication and Postmedication ........................................................36
5.4
Concomitant Therapy...........................................................................................36
5.4.1
Required Concomitant Therapy ................................................................36
5.4.2
Allowed Concomitant Therapy .................................................................36
5.4.2.1
Treatment of Isolated Central Nervous System Progression.........37
5.4.3
Prohibited Concomitant Therapy...............................................................37
5.5
Management of Adverse Reactions.......................................................................37


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5.5.1
Serosal Effusions ......................................................................................37
5.5.2
Skin Reactions..........................................................................................38
5.5.3
Potential Drug-Induced Liver Injury .........................................................39
5.5.4
Monitoring and Management of Edema ....................................................41
5.6
Treatment Compliance .........................................................................................42
6.
Study Activities ..............................................................................................................43
6.1
Enrollment ...........................................................................................................43
6.2
Screening Visit (Days -15 to -1) ...........................................................................43
6.3
Treatment Period..................................................................................................44
6.3.1
Day -1 (Day before Dosing)......................................................................44
6.3.2
Day 1 (±2 Days) .......................................................................................44
6.3.3
Day 2........................................................................................................45
6.3.4
Day 3 (Window +1 Day) of Cycles 1, 2, and 4 Only .................................45
6.3.5
Days 8 and 15 (± 2 Days) and 29 (± 3 Days).............................................45
6.3.6
Days 22 (± 2 Days) and 36 (± 3 Days) ......................................................46
6.3.7
Disease Assessment ..................................................................................46
6.4
End-of-Treatment Visit ........................................................................................46
6.5
Long-Term Follow-up (LTFU; Every 6 to 12 Weeks ±1 Week)............................47
6.6
End of Study/End of Follow-Up ...........................................................................48
7.
Study Assessments .........................................................................................................49
7.1
Screening/Baseline Assessments ..........................................................................49
7.1.1
Central Immunohistochemistry Assessment ..............................................49
7.2
Safety Assessments ..............................................................................................49
7.2.1
Physical Examination................................................................................49
7.2.2
Vital Signs, Weight and Height.................................................................50
7.2.3
Clinical Laboratory Tests..........................................................................50
7.2.4
Electrocardiograms...................................................................................51
7.2.5
Echocardiogram........................................................................................51
7.2.6
ECOG Performance Status........................................................................51
7.2.7
Fluid Retention Questionnaire...................................................................51
7.2.8
Daily Weight Diary...................................................................................51


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7.2.9
Pregnancy Testing ....................................................................................51
7.3
Radiographic Response/Efficacy Assessments......................................................51
7.3.1
Radiographic Disease Progression ............................................................52
7.3.2
Patient Reported Outcomes.......................................................................52
7.4
Pharmacokinetic Assessments ..............................................................................52
7.5
Pharmacodynamic and Biomarker Assessments....................................................53
7.5.1
Tumor Tissue............................................................................................53
7.5.2
Inflammatory Markers ..............................................................................53
7.5.3
Blood Tumor Markers...............................................................................53
7.5.4
Soluble Biomarkers...................................................................................54
7.5.5
Circulating Tumor Cells............................................................................54
7.5.6
Serosal Fluid.............................................................................................54
7.5.7
Biospecimen Repository ...........................................................................54
8.
Complaints .....................................................................................................................55
8.1
Medical Complaints .............................................................................................55
8.1.1
Definitions................................................................................................55
8.1.1.1
Adverse Events...........................................................................55
8.1.1.2
Serious Adverse Events...............................................................56
8.1.1.3
Adverse Events Expected Due to Cancer Progression..................57
8.1.2
Adverse Event Severity.............................................................................57
8.1.3
Relationship to Study Drug.......................................................................57
8.1.4
Deaths ......................................................................................................58
8.1.5
Adverse Event Collection Period ..............................................................58
8.1.6
Adverse Event Reporting ..........................................................................59
8.1.7
Pregnancy Reporting.................................................................................60
8.2
Product Complaint................................................................................................61
8.2.1
Definition .................................................................................................61
8.2.2
Reporting..................................................................................................61
8.2.3
Events Commonly Associated in Study Population with Advanced Solid 
Tumors and/or Progression of Underlying Malignancy .............................61
8.3
Appropriateness of Measurements........................................................................62
9.
Data Quality Control and Quality Assurance...............................................................63


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9.1
Site Training and Monitoring Procedures .............................................................63
9.2
Data Management Procedures ..............................................................................63
9.3
Access to Source Data..........................................................................................64
9.4
Accuracy and Reliability of Data..........................................................................64
9.5
Quality Assurance Procedures..............................................................................64
9.6
Data Handling and Recordkeeping .......................................................................65
9.6.1
Data Handling...........................................................................................65
9.6.2
Investigator Record Retention...................................................................65
10.
Data Analysis and Statistical Methods..........................................................................66
10.1
Determination of Sample Size ..............................................................................66
10.2
Analysis Populations............................................................................................67
10.3
Planned Analyses .................................................................................................67
10.3.1 Disposition of the Study Subjects..............................................................67
10.3.2 Demographic and Baseline Characteristics................................................67
10.3.3 Exposure to Study Treatment and Compliance..........................................67
10.3.4 Analysis of Primary Efficacy Endpoints....................................................68
10.3.5 Analysis of Secondary Efficacy Endpoints................................................68
10.3.6 Futility Analysis .......................................................................................68
10.3.7 Safety Analysis.........................................................................................68
10.3.7.1 Treatment Emergent Adverse Events ..........................................69
10.3.7.2 Clinical Laboratory Evaluation ...................................................69
10.3.7.3 Vital Signs ..................................................................................69
10.3.7.4 Eastern Cooperative Oncology Group Performance Status..........69
10.3.7.5 Electrocardiogram.......................................................................69
10.3.7.6 Concomitant Medications ...........................................................69
10.3.8 Pharmacokinetic and Pharmacodynamics Analyses...................................70
10.3.9 Patient Reported Outcomes (PROs) ..........................................................70
11.
Ethical and Regulatory Considerations ........................................................................72
11.1
Informed Consent.................................................................................................72
11.2
Confidentiality of Subject Personal Information ...................................................73
11.3
Biospecimens .......................................................................................................73


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11.4
Ethics Approval....................................................................................................74
11.5
Investigator and Study Personnel Information ......................................................74
11.6
Protocol Amendments and Study Termination......................................................75
11.7
Study Documentation, Privacy and Records Retention .........................................75
11.8
Clinical Trial Agreement......................................................................................75
12.
References ......................................................................................................................77
13.
Appendices .....................................................................................................................79
13.1
Schedule of Assessments......................................................................................80
13.2
Schedule of Day 1 Peridosing Assessments ..........................................................84
13.3
Previous Protocol (version 3.0) Cohort 3 (Glioblastoma) Specific Guidance.........85
13.3.1 Efficacy Endpoint .....................................................................................85
13.3.2 Inclusion Criteria ......................................................................................85
13.3.3 Study Activities ........................................................................................85
13.3.4 Blood Tumor Markers...............................................................................85
13.3.4 Response Assessment in Neuro-Oncology Criteria....................................85
13.4
Performance Status Scales Conversion .................................................................90
13.5
New York Heart Association (NYHA) Classification ...........................................91
13.6
Response Evaluation Criteria for Solid Tumors (RECIST) v1.1............................92
13.7
Guidance for Subjects with Prostate Cancer..........................................................93
13.7.1 Additional Assessments for Subjects with Prostate Cancer........................94
13.8
CTCAE v4.03 Grading of Some Relevant AEs.....................................................95
13.9
Fluid Retention Questionnaire ..............................................................................98
13.10 Disease Related Events Associated with Solid Tumors.........................................99
13.11 Investigator Signature Page ................................................................................100
13.12 Document History..............................................................................................101
13.12.1
Protocol Amendment Version 4.0: Summary of Change............101
List of Figures
Figure 3-1
Dose-Escalation Decision Summary···················································24
Figure 8-1
Adverse Event Collection······························································· 59


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List of Tables
Table 3-1
Planned Dose Levels in Part A ·························································23
Table 5-1
Toxicities Requiring Dose Reduction ·················································35
Table 5-2
Recommended Management of Photosensitivity·····································39
Table 7-1
Disease-Specific Blood Tumor Markers ·············································· 54
Table 8-1
Criteria for a Serious Adverse Event (SAE) ··········································56
Table 10-1
Lower Exact 90% Two-Tailed Confidence Limits for Selected Objective 
Response Rate Results for 25 Subjects················································66
Table 13-1
Criteria for Determining First Progression Depending on Time from Initial 
Chemoradiotherapy······································································86
Table 13-2
Criteria for Response Assessment Incorporating MRI and Clinical Factors······89


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Definitions of Abbreviations and Terms
ADC
antibody-drug conjugate
AE
adverse event
ALT
alanine aminotransferase
ANA
antinuclear antibodies
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AR
accumulation ratios for exposure-related PK parameters
AST
aspartate aminotransferase 
AT
aminotransferase
ATA
anti-therapeutic antibody
AUC
area under the curve
AUC0–τ
AUC within a dosing interval 
∀-hCG
beta-human chorionic gonadotropin
BRAF
proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B
BSA
body surface area
BUN
blood urea nitrogen
C1D1
Cycle 1 Day 1
CBC
complete blood count
CBR
clinical benefit rate
CEA
carcinoembryonic antigen
CFR
Code of Federal Regulations
CgA
chromogranin A
CI
confidence interval
CL
plasma clearance
Cmax
maximum concentration
CNS
central nervous system
CR
complete response
CRF
case report form
CRP
C-reactive protein
CT
computerized tomography
CTC
circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
CTLA4
cytotoxic T-lymphocyte antigen 4
Ctrough
concentration at trough
D6.5
the deoxyribonucleic acid (DNA) cross-linking agent SC-DR002 
DILI
drug-induced liver injury
DLL3
delta-like protein 3
DLL3hi
delta-like protein 3 positive in ≥50% tumor cells
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid


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DOR
duration of response
EC
Ethics Committee
ECG
electrocardiogram 
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic CRF
EDC
electronic data capture
EGF
epidermal growth factor
eGFR
estimated glomerular filtration rate
EOT
end of treatment
EOS
end of study
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-5L
EuroQoL Five Dimension Questionnaire
ESR
erythrocyte sedimentation rate
FDA
Food and Drug Administration
FMTC
familial medullary thyroid carcinoma
FSH
follicle stimulating hormone
GBM
glioblastoma
GCP
Good Clinical Practice
GEP
gastroenteropancreatic
GEP NEC
gastroenteropancreatic neuroendocrine carcinoma
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IAC
intermediate atypical carcinoma 
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IHC
immunohistochemistry or immunohistochemical
IL
interleukin
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous(ly)
KIT
proto-oncogene c-Kit
LCNEC
large cell neuroendocrine carcinoma


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LDH
lactate dehydrogenase
LTFU
long-term follow-up
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MEK
mitogen-activated protein kinase 
MEN
multiple endocrine neoplasia
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
MTD
maximum tolerated dose
NASH
non-alcoholic steatohepatitis
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NEC
neuroendocrine carcinoma
NEPC
neuroendocrine prostate cancer
NET
neuroendocrine tumor
NSAIDs
non-steroidal anti-inflammatory drugs
NSE
neuron-specific enolase
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PBD
pyrrolobenzodiazepine
PCR
polymerase chain reaction
PCWG3
Prostate Cancer Clinical Trials Working Group 3
PD
progressive disease or disease progression
PD-1
programmed death receptor-1
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PO
per os (by mouth, orally)
PR
partial response
PRO
patient reported outcomes 
PSA
prostate-specific antigen
PT
prothrombin time
PTT
partial thromboplastin time
Q3wk
every 3 weeks
Q6wk
every 6 weeks
QLQ-C30
Quality of Life Questionnaire-Core 30 questionnaire
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RANO
Response Assessment in Neuro-Oncology
RECIST
Response Evaluation Criteria in Solid Tumors


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RET
rearranged during transfection receptor tyrosine kinase
rova-T
rovalpituzumab tesirine 
RP2D
recommended Phase 2 dose
RF
rheumatoid factor
S100B
S-100 calcium-binding protein B
SAE
serious adverse event
SC16
humanized DLL3-specific IgG1 monoclonal antibody
SAP
Statistical Analysis Plan
SC16
humanized DLL3-specific IgG1 monoclonal antibody
SCLC
small cell lung cancer
SD
stable disease
SMC
Safety Monitoring Committee
SPF
sun protection factor
SRS
stereotactic radiosurgery 
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
Tmax
time of maximum concentration
TPC
tumor perpetuating cells
t½
terminal half-life
ULN
upper limit of normal
USP
United States Pharmacopeia 
VAS
visual analog scale 
VEGF
vascular endothelial growth factor
Vdβ
volume of distribution
WOCBP
woman of childbearing potential
WHODRUG
World Health Organization Drug


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1.
Introduction 
1.1
Delta-like Protein 3
Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family. It is highly 
expressed in high-grade tumors of neuroendocrine origin such as small cell lung cancer (SCLC), 
including its tumor perpetuating cells (TPCs), but with no detectable expression in normal tissues 
or non-neuroendocrine tumor types (Saunders 2015; Stemcentrx data on file). While the function 
of DLL3 has not been clearly defined, it has been implicated in the regulation of cell 
development and fate decisions (Chapman 2011; Dunwoodie 1997).
1.2
Rovalpituzumab Tesirine
Rovalpituzumab tesirine (SC16LD6.5) is a DLL3-targeted antibody-drug conjugate (ADC) 
consisting of the humanized DLL3-specific IgG1 monoclonal antibody SC16; the 
deoxyribonucleic acid (DNA) cross-linking agent SC-DR002 (D6.5); and a protease-cleavable 
linker that covalently links SC-DR002 to SC16. The primary mechanism of rovalpituzumab 
tesirine is binding of the ADC to DLL3 on target-expressing cells, followed by internalization of 
the ADC-DLL3 complex and release of SC-DR002 via proteolytic cleavage in late endosomes. 
Interstrand crosslinks of cellular DNA induced by intercalated SC-DR002 leads to cellular 
cytotoxicity. ADCs like rovalpituzumab tesirine represent a potential advantage over traditional 
chemotherapy by delivering cytotoxic agents to specific target cells, resulting in an improved 
safety profile.
In a Phase 1 study (Study SCRX16-001), rovalpituzumab tesirine dosed at 0.2 – 0.4 mg/kg 
exhibited encouraging efficacy in recurrent SCLC, achieving a 31% (8/26) and 85% (22/26) 
central review-adjudicated confirmed objective response rate (ORR) and clinical benefit rate 
(CBR), respectively, in subjects whose tumors expressed DLL3 in ≥50% of cells.  Median 
overall survival was 7.7 months in DLL3 ≥ 50% subjects at all dose levels, with a 1-year survival 
rate of 30%. The most frequent grade 3 or worse treatment-related adverse events in 74 patients 
with small-cell lung cancer were thrombocytopenia (11%), pleural effusion (8%), and increased 
lipase (7%). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The 
recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks (AbbVie Stemcentrx, data 
on file).
In a Phase 2 SCRX001-002 (TRINITY) study in patients with SCLC recurrent after at least two 
systemic chemotherapy regimens, rovalpituzumab tesirine dosed at 0.3 mg/kg every 6 weeks for 
two cycles (with an option for additional two cycles upon progression occurring ≥ 12 weeks after 
the second dose) had shown confirmed objective response rate of 16%, progression-free survival 
of 3.9 months and overall survival of 5.6 months in 3rd line DLL3High patients.  Of note, 
prolonged stable disease with target lesion size reduction has been observed in a considerable 
number of patients receiving additional post-progression cycles of rovalpituzumab tesirine. Drug 
related grade 3 or above treatment emergent adverse events that occurred in at least 10 subjects 
include thrombocytopenia (11%), photosensitivity reactions (7%), anemia (4%), fatigue (4%), 


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and pleural effusion (4%). Adverse events leading to study treatment discontinuation occurred 
in7% of subjects   (AbbVie Stemcentrx, data on file).
1.3
DLL3-Expressing Cancers Other than Small Cell Lung Cancer
Several other cancers of neuroendocrine origin appear to express DLL3 in a significant 
proportion, including melanoma (~25%), medullary thyroid carcinoma (MTC; >50%), 
glioblastoma (GBM, ~70%), and neuroendocrine cancers, including large-cell neuroendocrine 
carcinoma (LCNEC, ~80%), neuroendocrine prostate cancer (NEPC, ~10%), and high-grade 
gastroenteropancreatic neuroendocrine carcinoma (GEP NEC, ~20%) (Saunders 2015;
Stemcentrx data on file). Novel therapeutic approaches continue to be needed for each of these 
cancers, as described below.
1.3.1
Metastatic Melanoma
Although most cases of cutaneous melanoma are diagnosed at an early stage when surgical 
excision can be curative, some patients have metastatic disease at presentation (2–5%), and/or 
develop metastases after initial definitive treatment. Primary treatment for metastatic melanoma 
currently involves immunotherapy, consisting of programmed death receptor-1 (PD-1) inhibitors 
(e.g., nivolumab, pembrolizumab), typically in combination with a cytotoxic T-lymphocyte 
antigen 4 (CTLA4) inhibitor (e.g., ipilimumab), and/or kinase inhibitors (e.g., BRAF inhibition 
with vemurafenib or dabrafenib, MEK inhibition with trametinib, or KIT inhibition with 
imatinib) in patients with corresponding driver mutations (e.g., in BRAF or KIT). Nonetheless, 
recurrence remains virtually inevitable despite these therapies, with median durations of response 
(DORs) of only 5–6 months and progression-free survival (PFS) generally less than 1 year 
(National Comprehensive Cancer Network, NCCN Melanoma 2016; Dummer 2015).
1.3.2
Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) accounts for approximately 1–2% of thyroid cancers. 
MTC is characterized by the production of calcitonin, and is often associated with mutations in 
the RET proto-oncogene, either sporadically or as a component of the type 2 multiple endocrine 
neoplasia (MEN) syndromes, MEN2A and MEN2B, and the related syndrome, familial MTC 
(FMTC). Most localized MTC responds to locoregional therapies, including surgery and/or 
radiation therapy, but metastatic disease is present in 10–15% of patients at the time of diagnosis, 
and may develop after failure of definitive therapy. Frontline systemic therapy in this setting 
typically involves a tyrosine kinase inhibitor (TKI) such as vandetanib or cabozantinib, where 
clinical benefit (partial response [PR] or stable disease [SD]) in 50–60% of subjects has been 
observed. However, benefit duration is generally limited to about 12–24 months, with toxicities 
often requiring drug withdrawal or dose reduction (NCCN Thyroid 2015; Wells 2015).


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1.3.3
Glioblastoma
Glioblastoma (GBM), the most common primary malignant adult brain tumor, accounts for about 
54% of all gliomas, and may arise de novo (primary GBM), usually in older patients, or evolve 
from a low-grade glioma (secondary GBM). Initial treatment typically includes a combination of 
surgery and radiation therapy, including adjunct local nitrosourea chemotherapy (carmustine). 
The alkylating agent temozolomide has emerged as the standard of care, in conjunction with 
postoperative radiation therapy for younger patients with good performance status. Nonetheless, 
the prognosis for GBM remains poor and it remains the most lethal brain tumor: nearly all GBMs 
recur, with only one-third of patients surviving for 1 year and less than 5% beyond 5 years. 
(NCCN CNS 2015; Stupp 2014).
1.3.4
Neuroendocrine Carcinomas 
The neuroendocrine tumors (NETs) comprise a rare, but broad family, often sporadic, but 
sometimes arising in the context of inherited genetic syndromes, such as MEN types 1 and 2. 
Poorly-differentiated tumors are high grade neuroendocrine carcinomas (NECs) with clinical 
behavior distinct from well-differentiated NETs, and may occur in a wide variety of organs, 
including lung, intestine and pancreas, and prostate. Early-stage cancers may sometimes be 
amenable to surgical resection and chemotherapy, with or without radiotherapy. Otherwise, 
radiotherapy in combination with chemotherapy or chemotherapy alone is generally considered 
for unresectable locoregional or metastatic disease, respectively — typically following SCLC 
guidelines. SCLC regimens, such as cisplatin or carboplatin in combination with etoposide, are 
commonly used for primary chemotherapy, although somatostatin analogues are sometimes 
considered for symptom control in hormone-secreting or scintigraphy-positive cases 
(NCCN NEC 2015; Oberg 2012; Oberg, Knigge 2012). Nonetheless, prognosis remains poor, 
with most series describing overall survival (OS) less than 18 months (e.g., Hainsworth 2006; 
Sorbye 2013; Yamaguchi 2014).
1.4
Rationale for the Study and Anticipated Risks
Rovalpituzumab tesirine may be effective in multiple cancers that express DLL3. This study will 
explore further the safety, tolerability, and potential therapeutic utility of rovalpituzumab tesirine 
in subjects with such non-SCLC DLL3+ tumors, with the intent to provide the basis for further 
development of rovalpituzumab tesirine in one or more of these evaluated indications. 
As of 30 June 2016, 104 subjects (SCLC or LCNEC) had received at least one dose of 
rovalpituzumab tesirine at doses ranging from 0.05 mg/kg to 0.8 mg/kg on an every 3 weeks 
(Q3wk) schedule (34 subjects) and 0.3 mg/kg to 0.4 mg/kg on an every 6 weeks (Q6wk) 
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The most frequently reported treatment-emergent adverse event (TEAE) terms in all treated 
subjects were fatigue (49%), pleural effusion (34%), and dyspnea (31%); the most frequently 
reported TEAE terms considered related to rovalpituzumab tesirine by the Investigator were 
fatigue (35%), pleural effusion (28%), and peripheral edema (26%). 
The most frequently reported Grade 3/4 TEAEs were dyspnea (14%), pleural effusion (12%), 
and fatigue (11%); the most frequently reported Grade 3/4 TEAEs considered related to 
rovalpituzumab tesirine were pleural effusion and thrombocytopenia (10% each), and fatigue and 
increased lipase (6% each). 
Serious adverse events (SAEs) were reported in 49 subjects (47%), 26 (25%) were considered 
related to rovalpituzumab tesirine by the Investigator. The most common SAE was pleural 
effusion, occurring in 18 subjects (17%); all occurrences were considered related to 
rovalpituzumab tesirine. The second most common related SAE was pericardial effusion, in 
8 subjects (8%). Six subjects experienced a fatal AE, 2 of which were considered related to 
rovalpituzumab tesirine (acute kidney injury and tumor hemorrhage). 
Preclinical toxicology studies conducted in the rat and the cynomolgus monkey have identified 
the bone marrow, lung, and kidney as a potential source of clinical adverse events (AEs) (refer to 
Section 4.3.1 of the current Rovalpituzumab Tesirine Investigator’s Brochure [IB]; Stemcentrx 
data on file). Accordingly, safety assessments will include regular assessments at protocol-
specified time points of routine physical examination, laboratory and imaging tests, as well as 
echocardiograms (ECHOs), a fluid retention questionnaire, daily weights, and untimed (spot) 
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2.
Objectives
2.1
Primary Objective
!
To assess the safety and tolerability of rovalpituzumab tesirine in subjects with specific 
delta-like protein 3 (DLL3)-expressing advanced solid tumors.
2.2
Secondary Objectives
!
To explore the antitumor activity of rovalpituzumab tesirine in subjects with specific 
DLL3-expressing advanced solid tumors.
!
To study the pharmacokinetics (PK) of and incidence of anti-therapeutic antibodies 
(ATA) against rovalpituzumab tesirine in subjects with specific DLL3-expressing 
advanced solid tumors.
2.3
Exploratory Objectives
!
To explore the expression of DLL3 in specific delta-like protein 3-expressing advanced 
solid tumors, and its relationship to clinical outcome during treatment with 
rovalpituzumab tesirine.
!
To explore the effect of rovalpituzumab tesirine on disease biomarkers and 
pharmacodynamics.
!
To assess change in patient reported outcomes (PRO) within the expansion cohorts 
(Part B) utilizing the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) questionnaire and EuroQoL 
Five Dimension Questionnaire (EQ-5D-5L) during treatment with rovalpituzumab 
tesirine.
2.4
Endpoints
2.4.1
Safety Endpoints
!
Adverse events (AEs)
!
Vital signs
!
Physical examination
!
Body weight
!
Laboratory abnormalities
!
Electrocardiographic parameters (e.g., QT interval corrected for heart rate [QTc], 
QT interval corrected for heart rate by Fridericia’s formula [QTcF])
!
ECHO
!
Components of a fluid retention questionnaire


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2.4.2
Efficacy Endpoints
!
Response assessments according to Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1) (Eisenhauer 2009), including ORR and CBR
!
DOR
!
PFS
!
PFS status after 6 months from the initiation of study treatment 
!
OS
!
Prostate cancer only:
#
Response assessments according to Prostate Cancer Clinical Trials Working Group 3 
(PCWG3), including prostate-specific antigen (PSA) response rate, DOR, and 
radiographic PFS
#
Circulating tumor cell (CTC) conversion rate (e.g., ≥5 CTCs/7.5 mL to <5 CTCs/ 
7.5 mL)
!
GBM only: 
GBM will be assessed using Response Assessment in Neuro-Oncology (RANO) criteria. 
(Appendix 13.3.4)
2.4.3
Patient Reported Outcomes Endpoint
!
Change in PROs (based on the EORTC QLQ-C30 and EQ-5D-5L questionnaires)
2.4.4
Pharmacokinetics, Biomarker, and Pharmacodynamic Endpoints
!
Specific PK parameters of rovalpituzumab tesirine (e.g., maximum concentration [Cmax], 
area under the curve [AUC])
!
ATA against rovalpituzumab tesirine
!
Tumor DLL3 expression
!
Inflammatory markers (locally tested) 
!
Blood tumor markers
!
Biomarkers, including soluble DLL3
!
CTCs


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3.
Investigational Plan
3.1
Summary of Study Design
This is a multicenter, open-label study of rovalpituzumab tesirine in subjects with 
DLL3-expressing advanced solid tumors. The study will include 7 cohorts of subjects with the 
following cancers:
1. Malignant melanoma
2. Medullary thyroid cancer (MTC)
3. Glioblastoma 
4. Large cell neuroendocrine carcinoma (LCNEC) of any origin
5. Neuroendocrine prostate cancer (NEPC)
6. High-grade gastroenteropancreatic neuroendocrine carcinoma (GEP NEC)
7. Other neuroendocrine carcinoma (NEC) and high grade neuroendocrine tumors (NET)
8. Solid tumors other than the above
As of protocol version 4.0, cohort 3 (Glioblastoma) is closed to enrollment. Specific guidance for 
cohort 3 (Glioblastoma) subjects (protocol version 3.0) are provided in Appendix 13.3.
Each disease-specific cohort will include two parts:
!
Part A – Dose-Regimen Finding: Will involve disease-specific dose escalation, and possible 
dose-interval modification, to define the maximum tolerated dose (MTD) and/or possible 
recommended Phase 2 dose(s) (RP2Ds).
!
Part B – Expansion Cohorts: Disease-specific expansion cohorts may be enrolled. Subjects in 
the expansion cohorts will be treated with a dose regimen(s) at or below the MTD and/or 
RP2D determined in Part A.
Dose limiting toxicities (DLTs) will be assessed during the DLT Evaluation Period 
(Section 3.1.3) for subjects in Part A, the dose regimen finding portion of the trial. 
Safety will be monitored throughout the trial by the Safety Monitoring Committee (SMC) 
consisting at least of a Medical Monitor, Investigators, and the study biostatistician. The SMC
will meet routinely to review the emerging safety, select pharmacodynamic and efficacy data, 
and may make dose-escalation and dosing-interval recommendations. The SMC may recommend 
further evaluation of safety at a given dose level, investigation of alternative dose regimens, 
including a dose level that is intermediate to the planned dose levels, modification of the dosing 
interval, limitation to the maximum number of doses, and/or elimination or cancellation of a dose 
level(s) in a cohort based on the experience in other cohorts. The SMC will also review 
cumulative safety data in order to identify safety concerns that may emerge due to cumulative 
exposure beyond the DLT window. The process for dose-escalation decisions and dose-interval 
recommendations, and the roles and responsibilities of the SMC may be detailed separately.


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Tumor response will be assessed every 6 weeks during active study treatment until 24 weeks, 
and then every 12 weeks thereafter. Treatment decisions by the Investigator will be based on
RECIST v1.1 (and/or PCWG3 for prostate cancer; Appendix 13.7).
Subjects will be eligible to continue treatment until unacceptable toxicity, disease progression 
(PD), withdrawal of consent, study termination, or completion of a planned course of treatment 
(if a regimen with a limited number of doses is selected), whichever occurs first. Subjects who 
discontinue study treatment prior to PD will be evaluated for response every 6 weeks until 
24 weeks, then every 12 weeks until PD or initiation of new anticancer treatment, whichever 
occurs first, and will afterwards be followed for survival until death or study termination, 
whichever occurs first. Appendix 13.7 includes specific additional guidance for prostate cancer 
subjects.
Blood samples for PK, immunogenicity, biomarker and pharmacodynamics assessments will be 
collected at protocol-defined time points to support the study endpoints (Sections 7.4 and 7.5).
3.1.1
Part A Dose-Regimen Finding
For Part A, the planned dose levels of rovalpituzumab tesirine are presented in Table 3-1. 
Initially, rovalpituzumab tesirine will be administered according to the Schedule Q6wk, on 
Day 1 of each 6-week cycle, continuous dosing. If the MTD is determined to be 0.3 mg/kg in the 
initial 3 dose levels, further dose escalation will be stopped.
Table 3-1
Planned Dose Levels in Part A 
Dose Level
Dose Level Schedule Q6wk (every 6 weeks)
1
0.2 mg/kg
2
0.3 mg/kg
3
0.4 mg/kg
A standard 3+3 dose-escalation approach will be utilized (Figure 3-1). Subjects will be enrolled 
in groups of 3. 


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Figure 3-1
Dose-Escalation Decision Summary
During 3+3 dose escalation, DLTs will be assessed during the DLT Evaluation Period 
(Section 3.1.3). If 0 of 3 subjects experience a DLT in a cohort, the next dose level will be 
opened for enrollment. If ≥2 of 3 subjects in a cohort experience a DLT, the MTD will have been 
exceeded and dose escalation will stop. If 1 of 3 subjects in a cohort experiences a DLT, an 
additional 3 subjects will be treated at that same dose level for a total of 6 subjects. If none of the 
3 additional subjects experiences a DLT (1 of 6 subjects with a DLT), dose escalation will 
continue to the next higher dose level. If 1 or more of the 3 additional subjects experiences a 
DLT (≥2 of 6 subjects with a DLT), the MTD will have been exceeded and dose escalation will 
not continue. Subjects who do not complete the DLT-evaluation period due to non-DLT reasons 
will not be considered DLT-evaluable and will be replaced for the DLT evaluation.
The MTD and RP2D will be determined by the Sponsor in consultation with the SMC after a 
review of all available data. At least 6 subjects must be treated at the putative MTD or RP2D, 
with no more than 1 incident of DLT.
If 3 or more disease-specific cohorts clear the 0.3 mg/kg or 0.4 mg/kg dose level and the Q6wk 
schedule, then the SMC may evaluate all the data available to determine an appropriate RP2D 
and the Part B expansion may proceed for all the cohorts in the study at these dose(s) and 
schedule.
During dose escalation, additional subjects may be enrolled at a dose level previously declared to 
be tolerated in order to explore further the safety and tolerability of the regimen. For instance, if 


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all 3 or 6 subjects necessary for DLT evaluation have been enrolled in a cohort, but have not yet 
completed the DLT evaluation period, additional subjects may be enrolled at a lower dose 
level(s), with approval of the Medical Monitor and Sponsor.
3.1.2
Part B Expansion Cohorts 
To explore the recommended dosing regimen for distinct disease subsets, subjects will be 
enrolled in disease-specific expansion cohorts in Part B. The dose regimen(s) to be examined in 
the disease-specific cohorts will be the MTD determined in Part A or a lower dose(s) and/or 
regimen(s), depending on the cumulative data. For example, a lower dose regimen may consist 
of a finite number of doses and/or a mixed-dose regimen, with all doses at or below MTD, but 
varying based on the cycle. The dose(s), regimen(s) and schedule(s) for each expansion cohort 
will be determined by the Sponsor in consultation with the SMC. For Part B, approximately 
174 subjects may be enrolled. The “Other NEC/NET” and “Other Solid Tumor” cohorts will 
each enroll 30 subjects. Additional information regarding sample size is provided in 
Section 10.1, Determination of Sample Size.
3.1.3
Definition of Dose-Limiting Toxicities 
The DLT evaluation period is the first 3 weeks of the first cycle of treatment for all subjects in 
Part A. DLTs are defined as any of the following in the DLT evaluation period, graded according 
to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 4.03:
!
Grade 4 thrombocytopenia (or Grade 3 thrombocytopenia with bleeding) lasting more than 
7 days and/or requiring platelet transfusion
!
Grade 4 neutropenia lasting more than 7 days, and/or requiring hematopoietic growth factor 
rescue, or any febrile neutropenia (Grade 3 or 4 neutropenia with concurrent fever ≥38.3°C) 
!
Grade 4 anemia unrelated to underlying disease
!
Clinically-significant Grade 3 or 4 non-hematologic laboratory abnormality that does not 
resolve to Grade 0/1 or baseline within 7 days
!
Grade 3 or 4 non-laboratory AE with the exception of fatigue, asthenia, nausea, or other 
manageable constitutional symptom
The following events will not be considered DLTs:
!
Any AE ≥ Grade 3 clearly determined to be unrelated to study drug (e.g., PD)
!
≥Grade 3 isolated alkaline phosphatase, amylase or lipase laboratory abnormality of any 
duration
3.1.4
Retreatment
Retreatment with rovalpituzumab tesirine may be permitted, with Medical Monitor and Sponsor 
approval, for subjects who tolerate all doses of rovalpituzumab tesirine, achieve clinical benefit 


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as defined by stable disease or better, receive no other systemic anti-cancer therapy after 
rovalpituzumab tesirine as administered in accordance with this protocol, and then experience 
PD at least 12 weeks after the most recent dose of rovalpituzumab tesirine. The retreatment dose 
level and regimen for each subject will be determined by the Medical Monitor, Sponsor or 
designee and the site Investigator, not to exceed the MTD.
3.2
Discussion and Rationale for Study Design
3.2.1
Study Design
This is the first clinical study with rovalpituzumab tesirine that will have cohorts dedicated to 
specific tumor types other than SCLC. Since the safety and tolerability of rovalpituzumab 
tesirine in tumor types other than SCLC has not been well-studied, separate dose escalations are 
planned for each cohort. In addition, some NEC cancer types warrant specific considerations in 
trial design, such as the utility of bone scintigraphy and PSA in prostate cancer (Kulke 2011; 
Scher 2016), and the safety and tolerability of rovalpituzumab tesirine may differ in cancers of 
different primary organs (Stemcentrx data on file). Therefore, some specific NECs will be 
enrolled and analyzed in distinct cohorts in this study, including LCNEC, NEPC, and high-grade 
GEP NEC (Section 3.1; Appendix 13.7).
Each Part A dose escalation will utilize a traditional rule-based design, including 3+3 cohorts at 
anticipated active doses to evaluate the safety and tolerability of multiple dose levels in a 
disease-specific fashion (Le Tourneau 2009), and will allow definition of the MTD, if one can be 
identified. In Part B, potential therapeutic doses (i.e., the MTD and/or lower doses as guided by 
the cumulative clinical experience in Part A) may be studied in expansion cohorts of subjects 
with specific solid tumor types. 
Evaluation of the study endpoints will inform the safety profile of rovalpituzumab tesirine in 
advanced solid tumors and may provide evidence of antitumor activity that could influence the 
trial design of subsequent studies.
3.2.2
Method of Assigning Subjects to Treatment Groups
Upon approval of subject registration, the Sponsor or designee will assign each subject to a 
disease-specific cohort. The cohort assignment decisions will be documented in the clinical trial 
master file.
3.2.3
Rationale for Selection of Doses
In a Phase 1 study with rovalpituzumab tesirine, the MTD was established at 0.4 mg/kg Q3wk 
based on the incidence of Cycle 1 toxicities, while the RP2D in SCLC was chosen as 0.3 mg/kg 
Q6wk based on the toxicity and efficacy profile during multiple cycle dosing (Stemcentrx data 
on file). For this study, dosing will begin with 0.2 mg/kg Q6wk, a dose level -1 relative to the 


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RP2D (that was determined for SCLC), and dose escalation is planned to continue through
0.4 mg/kg Q6wk, the MTD in SCLC. 
3.2.4
Blinding
This is not a blinded trial.


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4.
Study Population
Subjects must meet all of the enrollment criteria to be eligible for this study. Eligibility criteria 
may not be waived by the Investigator and are subject to review in the event of Good Clinical 
Practice (GCP) audit and/or appropriate health regulatory authority inspection.
To be eligible for retreatment as described in Section 3.1.4, subjects must meet all inclusion and 
exclusion criteria outlined in this section.
4.1
Inclusion Criteria
1. Ability to provide written informed consent.
2. Histologically confirmed, unresectable advanced solid malignancy other than SCLC.
Note:
Subjects with prostate cancer must also meet the additional prostate-specific criteria 
in Appendix 13.7.
3. Measurable disease, defined as at least one tumor lesion ≥10 mm in the longest diameter, or a 
lymph node ≥15 mm in short-axis measurement, assessed by computerized tomography (CT) 
scan (by RECIST v1.1). 
4. Disease refractory to standard therapy or for which standard or curative therapy does not 
exist or is not considered appropriate by the Investigator.
5. DLL3-expressing malignancy based on central immunohistochemical (IHC) testing of 
representative baseline tumor tissue (archived tissue or on-study biopsy). Positive is defined 
as staining in ≥1% of tumor cells.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Refer to 
Appendix 13.3 for conversion of performance status using Karnofsky scales, if applicable.
7. Minimum life expectancy of at least 12 weeks.
8. Subjects with a history of central nervous system (CNS) metastases must have 
documentation of stable or improved brain imaging for at least 2 weeks after completion of 
definitive treatment and within 2 weeks prior to first dose of Study Drug, off or on a stable 
dose of corticosteroids. Definitive treatment may include surgical resection, whole brain 
irradiation, and/or stereotactic radiation therapy. (Applicable to tumor types of non-CNS 
primary origin only).
9. Recovery to Grade 1 of any clinically significant toxicity (excluding alopecia) prior to 
initiation of study drug administration.
10. Satisfactory laboratory parameters:
a.
Absolute neutrophil count (ANC) ≥1,500/∃L.
b. Platelet count ≥75,000/∃L.
c.
Hemoglobin ≥8.0 g/dL.
d. Total bilirubin ≤1.5× upper limit of normal (ULN) or ≤3× ULN for subjects with 
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e.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5× ULN 
(≤5× ULN if evidence of hepatic involvement by malignant disease).
f.
Creatinine ≤1.5× ULN or estimated glomerular filtration rate (eGFR) 
≥30 mL/min/1.73m2.
g.  Serum albumin ≥3.0 g/dL
11. Last dose of any prior therapy administered by the following time intervals before the first 
dose of study drug:
a.
Chemotherapy, small molecule inhibitors, radiation, and/or other investigational 
anticancer agents (excluding investigational monoclonal antibodies): 2 weeks.
b. Immune-checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, or anti-CTLA-4), 
monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or 
other cell-based therapies: 4 weeks (2 weeks with documented disease progression).
12. If female, subject must be either postmenopausal defined as:
!
Age >55 years with no menses for 12 or more months without an alternative medical 
cause.
!
Age ≤55 years with no menses for 12 or more months without an alternative medical 
cause AND follicle stimulating hormone (FSH) level >40 IU/L.
OR
!
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy)
OR
!
A Woman of Childbearing Potential (WOCBP) practicing at least one protocol specified 
method of birth control (Section 4.3.1) starting at Study Day 1 through at least 6 months 
after the last dose of study drug.
13. If the male subject is sexually active, he must agree, from Study Day 1 through at least 
6 months after the last dose of study drug, to practice the protocol specified contraception 
(Section 4.3.2).
14. Females of childbearing potential must have a negative serum pregnancy test result at 
screening and a pre-dose negative urine pregnancy test on Cycle 1 Day 1 (C1D1). Females of 
non-childbearing potential (either postmenopausal or permanently surgically sterile as 
defined in Section 4.3) at screening do not require pregnancy testing.
4.2
Exclusion Criteria
1. Any significant medical condition, including any suggested by screening laboratory findings 
that, in the opinion of the Investigator or Sponsor, may place the subject at undue risk from 
the study, including but not necessarily limited to uncontrolled hypertension and/or diabetes, 
clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease 


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requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder 
active within 3 months).
2. Documented history of a cerebral vascular event (stroke or transient ischemic attack), 
unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart 
Association (NYHA) Class III–IV (refer to Appendix 13.5) within 6 months prior to their 
first dose of study drug.
3. Recent or ongoing serious infection, including:
a.
Any active Grade 3 or higher (according to NCI CTCAE version 4.03) viral, bacterial, 
or fungal infection within 2 weeks of the first dose of the study drug. Routine 
antimicrobial prophylaxis is permitted.
b. Known seropositivity for or active infection by human immunodeficiency virus (HIV).
c.
Active Hepatitis B (by surface antigen expression or polymerase chain reaction) or 
Hepatitis C (by polymerase chain reaction) infection or on hepatitis-related antiviral 
therapy within 6 months of first dose of study drug.
4. Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during 
the study or for approximately 6 months after the last dose of study drugs.
5. Male subject who is considering fathering a child or donating sperm during the study for 
approximately 6 months after the last dose of study drugs.
6. Systemic therapy with corticosteroids at >20 mg/day prednisone or equivalent within 1 week 
prior to the first dose of study drug.
7. History of another invasive malignancy that has not been in remission for at least 3 years. 
Exceptions to the 3year limit include non-melanoma skin cancer, curatively treated localized 
prostate cancer, ductal carcinoma in situ, and cervical cancer in situ on biopsy or squamous 
intraepithelial lesion on PAP smear.
8. Prior exposure to a pyrrolobenzodiazepine (PBD)-based drug, prior participation in a 
rovalpituzumab tesirine clinical trial, or known hypersensitivity to rovalpituzumab tesirine or 
excipient contained in the drug formulation, unless undergoing retreatment with 
rovalpituzumab tesirine in the context of this protocol.
4.3
Contraception Recommendations 
In WOCBP, pregnancy testing will be conducted at scheduled time points during screening and 
the course of the study (refer to Appendix 13.1). Pregnancy testing guidelines are outlined in 
Section 7.2.9.
4.3.1
Contraception for Female Subjects
If female, subject must be either postmenopausal or permanently surgically sterile (refer to 
Inclusion Criteria 12) OR a WOCBP, practicing at least one of the following methods of birth 
control, on Study Day 1 (or earlier) through at least 6 months after the last dose of study drug.


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!
Combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal) associated with the inhibition of ovulation, initiated at least 
1 month prior to Study Day 1.
!
Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 1 month prior to Study Day 1.
!
Bilateral tubal occlusion/ligation.
!
!
Vasectomized partner(s), provided the vasectomized partner verbally confirms receipt of 
medical assessment of the surgical success, and is the sole sexual partner of the WOCBP 
trial participant.
!
Intrauterine device (IUD).
!
Intrauterine hormone-releasing system (IUS).
!
True abstinence: Refraining from heterosexual intercourse when this is in line with the 
preferred and usual lifestyle of the subject [periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable].
4.3.2
Contraception for Male Subjects
Male subjects who are sexually active with a WOCBP, even if the male subject has undergone a 
successful vasectomy, must agree from Study Day 1 through at least 6 months after the last dose 
of study drug to use condoms and his female partner(s) must use at least one of the contraceptive 
measures (as defined in the protocol for female study subjects of childbearing potential).
Male subject agrees not to donate sperm from Study Day 1 through at least 6 months after the 
last dose of study drug.
4.4
Removal of Subjects from Therapy or Assessment
The Sponsor or its designee must be notified if a subject is withdrawn from study treatment or 
from the study. The reason(s) for withdrawal must be documented in the subject’s medical 
records and case report form (CRF). When a subject withdraws from treatment, all safety data 
normally required at the end of the study (i.e., the end-of-treatment visit and long-term 
follow-up) will be obtained if possible.


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4.4.1
Discontinuation of Study Drug
Treatment with study drug may be discontinued for any of the following reasons:
!
Progressive disease (PD) per RECIST 1.1 
!
Adverse event 
!
Physician decision
!
Study terminated by sponsor
!
Withdrawal by subject
!
Other
4.4.2
Subject Discontinuation from Study
Any subject may be discontinued from the study for any of the following reasons:
!
Withdrawal by subject
!
Death
!
Physician decision
!
Lost to follow-up
!
Study terminated by Sponsor
!
Other


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5.
Treatments
5.1
Treatments Administered
Rovalpituzumab tesirine, the investigational agent under study in this protocol, is an ADC. 
Detailed information describing the preparation, administration, and storage of rovalpituzumab 
tesirine is located in the Pharmacy Binder.
5.2
Investigational Product: Rovalpituzumab Tesirine
5.2.1
Description
Rovalpituzumab tesirine drug product is provided in a sterile clear USP Type I 10 mL glass vial 
and includes histidine hydrochloride, sucrose and polysorbate 20. A complete description of the 
chemistry and formulation are provided in the Investigator’s Brochure.
5.2.2
Packaging and Labeling
Rovalpituzumab tesirine is provided in sterile clear USP Type I, 10 mL glass vials. The vials 
and/or primary vial carton will have labels bearing the appropriate label text as required by 
governing regulatory agencies.
5.2.3
Dosing
The actual dose is based on the subject’s actual body weight on C1D1 to the nearest kilogram, 
and administered according to the assigned dose. If the subject’s actual weight at subsequent 
cycles is within 10% of the C1D1 weight, the dose will not be adjusted due to weight changes. 
Otherwise, the dose will be adjusted based on the actual body weight to the nearest kilogram at 
that cycle. Rovalpituzumab tesirine will be administered intravenously (IV) over 30 minutes 
(treatment window: 20 to 40 minutes) on Day 1 of each 6-week cycle.
Subjects must meet all of the following on each dosing day before receiving study drug:
!
ANC ≥1,000/∃L
!
Platelet count ≥75,000/∃L
!
Resolution to Grade 0 or 1, or to baseline grade if pre-existing, of any clinically-
significant AEs or laboratory abnormalities occurring during the previous cycle
5.2.4
Dose Modifications
Information and guidelines regarding Part A dose-regimen finding, including information 
regarding DLTs and the methods for determination of the MTD, are provided in Section 3.1.1. 
Information regarding Part B expansion cohorts is provided in Section 3.1.2.
Instructions for dose modifications for individual subjects in the Part A dose-regimen finding 
and Part B expansion groups are the same. No intrasubject dose escalation will be permitted. 
Adjustments to Dose Modification Guidelines may occur based on the clinical judgment of the 
Investigator with approval from the Medical Monitor.


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5.2.4.1
Dose Holds or Delays
Subjects who experience DLT in Cycle 1 should not receive further treatment with study drug 
unless clinical benefit is demonstrated with adequately managed toxicity and there is approval 
from the Medical Monitor and/or Sponsor. The subsequent dose level will be defined by the 
Medical Monitor and/or Sponsor in discussion with the site Investigator in the context of the type 
of AE observed.
If a subject has a clinically significant, unresolved AE on Day 1 of Cycle 2 or beyond, the start 
of the cycle may be delayed for up to 12 weeks. Longer dose delays may be permitted with the 
approval of the Medical Monitor if there was no documented PD. The AE must resolve to 
baseline or ≤Grade 1 prior to proceeding with treatment, unless the AE is determined to be 
clearly unrelated to study drug, or toxicity has been adequately managed.
Serosal effusions (e.g., pleural, pericardial, or ascites) that have been drained should remain 
stable or improved for at least 2 weeks prior to resumption of dosing (refer to Table 5-1, below).
5.2.4.2
Clinical Monitoring of Grade 3 or Grade 4 Adverse Events 
Subjects who experience Grade 3 or 4 non-laboratory AEs will require weekly or more frequent 
clinical assessments, as appropriate. The assessments should include review of AEs, concomitant 
medications, vital signs, weight, physical examination, ECOG performance status, laboratory 
and other testing, as clinically appropriate.
Subjects who experience Grade 3 or 4 hematologic AEs should have repeat complete blood 
count (CBC) assessment at least every 3 days or more frequently, as clinically appropriate, until 
resolution of hematologic toxicity to Grade 2 or lower.
Subjects who experience Grade 3 or 4 non-hematologic laboratory AEs will require more 
frequent laboratory assessments, as clinically appropriate, until resolution of the AEs.
Subjects who experience Grade 3 or 4 laboratory abnormalities may require more frequent 
laboratory assessments, as clinically appropriate.
5.2.4.3
Dose Reductions Due to Adverse Events
Subjects who experience a Grade 3 or 4 AE (unless the AE is determined to be clearly unrelated 
to study drug) should have a dose reduction in subsequent treatment cycles to dose level -1 or -2, 
or as suggested following discussion with the Medical Monitor and/or Sponsor. If the Grade 3 or 
4 AE recurs after dose reduction, study treatment must be permanently discontinued. Table 5-1
displays specific toxicities requiring dose reduction and/or discontinuation. Adjustments to these 
guidelines may occur based on the clinical judgment of the Investigator and with approval of the 
Medical Monitor.


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Table 5-1
Toxicities Requiring Dose Reduction
Toxicities Requiring 1 Dose Level Reduction at First Occurrence
#
2nd occurrence = 2nd dose level reduction
#
Discontinue after 2 dose level reductions 
Serosal Effusions and Edema
!
Grade 2 or higher pericardial effusion
!
Grade 2 or higher pleural effusion 
!
Grade 2 or higher ascites
!
Grade 2 or higher peripheral edema
Hematology
!
Grade 3 thrombocytopenia (platelets <50.0–25.0 × 109 /L)
!
Grade 4 neutropenia (ANC <0.5 × 109 /L) lasting more than 7 days
!
Grade 3 or higher febrile neutropenia (with ANC <1.0 × 109 /L) 
(concurrent fever ≥38.3° C)
Laboratory Abnormalities
!
Clinically significant Grade 3 or higher non-hematologic laboratory 
abnormality that does not resolve to Grade 0/1 or baseline within 
7 days
!
Any other Grade 3 or 4 laboratory abnormality considered clinically 
significant and treatment-related; adjustments to these guidelines 
may occur based on the clinical judgment of the Investigator and 
with approval of the Medical Monitor and Sponsor
!
Grade 2 hypoalbuminemia
Other Adverse Events
!
Grade 3 photosensitivity reaction (Section 5.5.2)
!
Grade 3 or Grade 4 nonlaboratory treatment-related toxicity, with 
the exception of fatigue, asthenia, nausea, or other manageable 
constitutional symptom
Toxicities Requiring 2 Dose Level Reductions at First Occurrence
#
Discontinue at second occurrence 
!
Grade 3 serosal effusions (pleural effusions, pericardial effusions, and ascites) and edema
!
Grade 2 capillary syndrome
!
Grade 4 thrombocytopenia/ Grade 3 thrombocytopenia with bleeding/ Need for platelet transfusion
!
Grade 4 febrile neutropenia
!
Grade 4 (>20.0 × ULN) ALT or AST or Grade 3 (>5.0–20.0 × ULN) ALT or AST elevation with 
concomitant total bilirubin Grade 2 or higher (>1.5 ULN)
!
Grade 3 or higher hypoalbuminemia (<2 g/dL)
!
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Toxicities Requiring Discontinuation of Investigational Product at First Occurrence
!
Grade 4 photosensitivity or skin reaction (Section 5.5.2)
!
Drug induced liver injury is confirmed (refer to Section 5.5.3 for definition)
!
Life threatening Infusion related reaction or hypersensitivity
!
Grade ≥3 pneumonitis
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; DILI = drug induced liver injury; INR = International normalized ratio; ULN = upper limit of 
normal.
5.3
Required Premedication and Postmedication
All subjects enrolled will receive premedication consisting of dexamethasone orally (PO) at 
8 mg twice daily given on Day –1, Day 1 (the day of dosing), and Day 2 of each cycle. 
Dexamethasone will be provided through a subject’s local prescription by Investigator or other 
provider (i.e., dexamethasone will not be provided by the Sponsor). When dexamethasone is not 
available, the glucocorticoid-equivalent dose of an alternate corticosteroid may be administered. 
Parenteral (e.g., IV) administration may be substituted for PO at the discretion of the 
Investigator.
5.4
Concomitant Therapy
All concomitant medications, blood products, procedures and radiotherapy administered will 
be recorded from Day 1 (predose) through the safety reporting period (Section 7.2 and 
Appendix 13.1). Any concomitant therapy given for a study protocol-related AE should be 
recorded from the time of informed consent.
5.4.1
Required Concomitant Therapy
Other than dexamethasone (Section 5.3), there are no required concomitant therapies. However, 
due to the potential for rovalpituzumab tesirine-related skin photosensitivity, subjects should be 
advised to avoid unprotected sun exposure and use a broad spectrum sunscreen (sun protection 
factor [SPF] of at least 30), protective clothing, a broad-brimmed hat, and sunglasses when 
outdoors or when driving or riding in the car for more than 1 hour, with re-application of 
sunscreen as activity-appropriate.
5.4.2
Allowed Concomitant Therapy
Standard supportive care for drug-related toxicity is permitted, including growth factors and 
blood product transfusions in accordance with local institutional standards. Other standard 
supportive care for symptom control or drug-related toxicity is allowed, such as analgesics, 
anti-emetics, electrolyte replacement, and hydration. Bone modifying agents for bone metastases 
are also permitted in accordance with local institutional standards. Other prescribed medications 
for non-neoplastic conditions are allowed, as well as vitamins and nutritional supplements. 


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Further ongoing treatments may be permitted for prostate cancer subjects according to 
Appendix 13.7.
Concomitant prednisone (or equivalent) may be used at a dose of ≤20 mg/day. The use of 
intermittent high-dose corticosteroid treatment to prevent or manage hypersensitivity reactions, 
serosal effusions (refer to Section 5.5.1), or other non-cancer-related symptoms, including 
premedication for known hypersensitivity reactions to contrast for scans is allowed.
Routine prophylaxis with vaccines is permitted; however, vaccines used should not contain live 
micro-organisms.
If the subject is taking chronic suppressive anti-infectives (antiviral, antifungal, or antibacterial), 
appropriate investigation must be completed prior to registration and documentation must 
exclude active infection. The subject should continue suppressive anti-infectives for the duration 
of study participation.
Palliative radiation therapy is permitted. Study drug must be held during therapy. If more than 
6 weeks have elapsed since the previous dose of study drug, the subject should undergo a 
radiographic tumor assessment before restarting study drug. If PD is detected in new sites, the 
subject will be required to discontinue study treatment (but may be eligible for re-treatment 
according to Section 3.1.4).
5.4.2.1
Treatment of Isolated Central Nervous System Progression
In the event of isolated CNS progression during study treatment, study drug may be withheld 
while palliative treatment is administered, e.g., a standard course of whole brain radiotherapy or 
stereotactic radiosurgery (SRS) in accordance with institutional practice, and restarted within 
1 week after completion of radiotherapy. During this time the subject should be fully evaluated 
for other sites of progression. If more than 6 weeks have elapsed since the previous dose of study 
drug, the subject should undergo a radiographic tumor assessment before restarting study drug. If 
additional sites of PD are present, the subject will be required to discontinue study treatment (but 
may be eligible for re-treatment according to Section 3.1.4).
5.4.3
Prohibited Concomitant Therapy
Subjects may not receive other investigational drugs, immunosuppressive medications, or 
systemic anti-neoplastic therapy during the study, other than as allowed in Sections 4, 5.2.4, 
and 5.4.2, and Appendix 13.7.
5.5
Management of Adverse Reactions
5.5.1
Serosal Effusions
Serosal effusions (pleural or pericardial, or ascites) have been observed with rovalpituzumab 
tesirine, and have the potential to be life-threatening (e.g., pericardial tamponade). Therefore, 


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development of any of these events, or worsening from baseline, warrants prompt evaluation by 
the Investigator or designee. Cytology analysis should be done for pleural and pericardial 
effusion as appropriate. Alternative causes, such as infection, congestive heart failure, or PD, 
should be ruled out. When appropriate, a unifying diagnosis or reached diagnosis should be 
reported (e.g., “heart failure,” not simply “pleural effusion” and “edema limbs”). When 
considered clinically significant (e.g., Grade 2 or higher and considered related to study drug):
!
Systemic corticosteroids, when initiated promptly, have been reported to be beneficial in 
some prior cases. The Investigator should consider a tapering regimen, such as 
dexamethasone up to 8 mg orally twice a day for 5 days, followed by 4 mg orally twice 
a day for 5 days, then 2 mg orally twice a day for 5 days. Alternatively, nonsteroidal 
therapies for serositis may be considered, such as non-steroidal anti-inflammatory drugs 
(NSAIDs, e.g., ibuprofen 400–600 mg orally 3 to 4 times daily) or colchicine (e.g., 
0.6 mg orally 2 to 3 times daily) given for 1–2 weeks.
!
Until clinical experience suggests otherwise, guidance for dose delay and/or reduction, 
as well as criteria for ongoing dosing, should follow Section 5.2.4.
5.5.2
Skin Reactions
Recommendations for management of photosensitivity reactions are outlined below in Table 5-2.
Photosensitivity was reported in patients treated with Rova-T including severe events.  
Photosensitivity reactions may occur hours to days after sun exposure. The median time to onset 
was 30 days (range 1 to 247 days). Patients should be advised to avoid direct and indirect sun 
exposure as much as possible during Rova-T treatment and for 30 days after the last dose. If 
unavoidable, patients should wear protective clothing and sunglasses, and use a broad-spectrum 
sunscreen and lip balm (SPF 30 or greater). 31 – 90 days after last dose, the patient may resume 
outdoor activities with appropriate sun protection including broad brimmed hat, protective 
clothing and sunscreen SPF 30 or higher. Skin reactions should be evaluated promptly and 
treated with topical or systemic steroids as indicated (refer to Table 5-2). Rova-T dose should be 
delayed, reduced or discontinued as necessary (refer to Table 5-1)
All cutaneous reactions which develop during treatment warrant prompt evaluation. Skin toxicity 
with rovalpituzumab tesirine may consist of photosensitivity but possibly other reactions such as 
palmar-plantar erythrodysesthesia or erythema multiforme. As such, development of a cutaneous 
reaction during treatment warrants prompt evaluation by the Investigator or designee:
!
If clinically consistent with photosensitivity, the AE should be reported as such (using 
medically accurate and descriptive AE terminology), and managed as described below in 
Table 5-2.


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!
For clinically more severe cases of photosensitivity or if clinically not consistent with 
photosensitivity, photodocumentation to facilitate later review by the Sponsor or designee 
may occur.
o
Formal evaluation by a dermatologist, including possible skin biopsy to rule out 
alternative etiologies, such as erythema multiforme which may warrant 
discontinuation of study drug, and to facilitate the most appropriate terminology for 
AE reporting, is recommended.
o
Photodocumentation of skin toxicity, if available, may be requested by the TAMD. 
The investigative site will take measures to protect the identity of the patient. These 
measures include taking the photograph very close to the affected skin region to 
exclude facial features, or if facial features cannot be excluded due to the location of 
the skin reaction, covering identifying features (such as the eyes) with a black 
rectangle.
All events of cutaneous toxicity should be monitored until resolution or return to baseline.
Table 5-2
Recommended Management of Photosensitivity
CTCAE v4.03
Treatment Recommendations
Dose Modifications
Grade 1
Painless erythema and erythema 
covering <10% BSA
Low-potency topical steroid (face)
High-potency topical steroid (body)
–
Grade 2
Tender erythema covering 10–30% 
BSA
Low-potency topical steroid (face)
High-potency topical steroid (body)
Nonsteroidal anti-inflammatory agents 
orally as needed
–
Grade 3
Erythema covering >30% BSA and 
erythema with blistering; 
photosensitivity; oral corticosteroid 
therapy indicated; pain control 
indicated (e.g., narcotics or NSAIDs)
Low-potency topical steroid (face)
High-potency topical steroid (body)
Prednisone 0.5 mg/kg × 7 days
Reduce dose 
Grade 4
Life-threatening consequences; 
urgent intervention indicated
Low-potency topical steroid (face)
High-potency topical steroid (body)
Prednisone 0.5 mg/kg × 7 days
Hospitalization
Reduce dose 
BSA = body surface area; CTCAE = Common Terminology Criteria for Adverse Events; NSAIDs = non-steroidal 
anti-inflammatory drug.
5.5.3
Potential Drug-Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug-induced liver injury (DILI) event. All occurrences 
of potential DILIs, meeting the defined criteria, must be reported as SAEs.


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Potential drug-induced liver injury is defined as:
!
ALT or AST elevation >3× ULN; and
!
Concurrent total bilirubin >2× ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase), and
!
No other immediately apparent possible causes of aminotransferase (AT) elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease or tumor(s), or the administration of other drug(s) known to be 
hepatotoxic
In general, an increase of AT to >3× ULN should be followed by repeat testing within 48–
72 hours of all four of the usual measures (ALT, AST, alkaline phosphatase, total bilirubin) to 
confirm the abnormalities and to determine if they are increasing or decreasing. Inquiry 
regarding symptoms should also be made (e.g., fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash). Subjects may be retested locally, but normal laboratory ranges 
should be recorded and results made to the Investigator immediately. All data must be recorded 
in the CRF. If symptoms persist or repeat testing shows AT >3× ULN for subjects with normal 
baseline measures or 2-fold increases above baseline values for subjects with elevated values 
before drug exposure, close observation should be initiated. If close monitoring is not possible, 
study drug should be discontinued.
Close observation includes:
!
Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the trial drug 
has been discontinued and the subject is asymptomatic.
!
Obtaining a more detailed history of symptoms and prior or concurrent diseases
!
Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets
!
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; non-alcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and 
biliary tract disease
!
Obtaining a history of exposure to environmental chemical agents
!
Obtaining additional tests to evaluate liver function, as appropriate (e.g., international 
normalized ratio [INR], direct bilirubin)
!
Considering gastroenterology or hepatology consultations
Discontinuation of study drug should be considered if potential DILI is suspected and:
!
ALT or AST >8× ULN
!
ALT or AST >5× ULN for more than 2 weeks


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ALT or AST >3× ULN and (TBL >2× ULN or INR >1.5)
!
ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia
All subjects showing possible DILI should be followed until all abnormalities return to normal or 
to the baseline state.
5.5.4
Monitoring and Management of Edema
!
The majority of the edema events with rovalpituzumab tesirine have been reported as low 
grade 1 or 2 (mild or moderate); however, a small number of fatal events of generalized 
edema have been reported with rovalpituzumab tesirine.  Physical exams and monitoring 
of weight gain and signs or symptoms of fluid retention should be conducted during 
treatment.
!
Consistent with institutional guidelines or standard practice, the use of diuretics with or 
without albumin may be considered in subjects with clinically significant edema and 
hypoalbuminemia.  The selection and use of diuretics in subjects should be based on 
individual clinical characteristics and include monitoring of electrolyte status and signs or 
symptoms of intravascular volume depletion such as hypotension and impaired renal 
function.
!
Systemic corticosteroids, when initiated promptly, have been reported to be beneficial in 
some prior cases.
5.5.5
Monitoring and Management of Pneumonitis:
!
Pneumonitis has been infrequently reported with rovalpituzumab tesirine but has resulted 
in fatal outcomes. Although the causal role of rovalpituzumab tesirine could not be ruled 
out, the reports of pneumonitis had one or more confounders including underlying 
pulmonary disease/cancer, prior thoracic radiation, prior cytotoxic chemotherapy or 
clinical evidence suggestive of an alternative diagnosis including pneumonia.
!
Heavily pretreated SCLC patients and patients with a history of pneumonitis may be at 
increased risk, and careful monitoring for signs and symptoms of pneumonitis is 
important. The risk of pneumonitis is increased with prior radiation to lung.
!
In general signs and symptoms coinciding with or preceding pneumonitis may include 
new or worsening cough, chest pain and/or shortness of breath, fever, and radiographic 
changes (reticular markings, ground glass opacities). Protocol defined disease 
assessments provide for the opportunity for on study pulmonary monitoring for detection 
of pneumonitis. The protocol allows for additional imaging per physician discretion for 
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The diagnosis of drug induced pneumonitis is one of exclusion. Other etiologies 
including infection, which is a common cause of pulmonary infiltrates with clinical and 
radiographic appearance similar to drug-induced pneumonitis, need to be carefully 
considered and excluded before the diagnosis of drug induced pneumonitis can be 
established.
!
If pneumonitis is suspected, close monitoring including additional laboratory and 
imaging investigation per institutional guidelines may be necessary. Systemic 
corticosteroids may be beneficial for rapidly progressive or more severe pneumonitis.
For Grade 1 pneumonitis, monitor closely. For dose modification, please see Table 5-1 of the 
protocol.
5.6
Treatment Compliance
Study drug administration must be performed by study site staff and documented in source 
documents and the CRF.


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6.
Study Activities
6.1
Enrollment
Once screening procedures have been completed for the subject, the Registration and Enrollment 
Form will be completed and submitted to the Sponsor or designee to confirm eligibility. Refer to 
the study manual for the enrollment form, contact numbers, and other details of enrollment.
AEs and concomitant therapies will be recorded from Day 1 (predose) through the safety 
reporting period (Section 7.2 and Appendix 13.1). At the same time, subjects will maintain a 
diary of daily weights, which will be recorded in the CRF. Any study protocol-related AE should 
be recorded from the time of informed consent as well as any concomitant therapies given for 
treatment of the AE. Schedules of events are provided in Appendices 13.1 and 13.2. Study 
activities are listed by visit in this section and descriptions of all study assessments are presented 
in Section 7.
Subjects undergoing retreatment as described in Section 3.1.4 will follow the same study 
schedule from screening through end of treatment (EOT) and long-term follow-up (LTFU).
6.2
Screening Visit (Days -15 to -1)
!
Informed consent – omitted for retreatment subjects
!
Demographics (Section 7.1) – omitted for retreatment subjects
!
Study eligibility – according to Inclusion/Exclusion Criteria (Section 4)
!
Medical and surgical history (Section 7.1) – omitted for retreatment subjects
!
Malignancy history (Section 7.1) – omitted for retreatment subjects
!
Prior anticancer treatments (Section 7.1) – omitted for retreatment subjects
!
Physical examination (Section 7.2.1)
!
Vital signs (Section 7.2.2)
!
Height (Section 7.2.2)
!
PRO questionnaires EORTC QLQ-C30 and EQ-5D-5L – for subjects in Part B of the 
study only (Section 7.3.2)
!
Complete blood count (Section 7.2.3)
!
Serum chemistries (Section 7.2.3)
!
Coagulation tests (Section 7.2.3)
!
Urinalysis (Section 7.2.3)
!
Hepatitis B and C tests (Section 7.2.3) – omitted for retreatment subjects
!
Pregnancy test (Section 7.2.9) – for women of childbearing potential
!
Electrocardiogram (ECG) in triplicate (Section 7.2.4)
!
ECHO – the screening ECHO should be done any time before the first dose of study 
drug.


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ECOG performance status (Appendix 13.3)
!
Disease assessment consisting of CT scans of the chest, abdomen, and pelvis (and neck if 
indicated; Section 7.3) – may be omitted for retreatment subjects if recent scans 
demonstrating PD are within 2 weeks of study drug dosing (Day 1 of the first cycle of 
retreatment).
!
MRI of the brain – may be omitted for retreatment subjects if recent scans demonstrating 
PD are within 2 weeks of study drug dosing (Day 1 of the first cycle of retreatment). 
CT of the brain with intravenous contrast may be substituted at the discretion of the 
Investigator.
!
Tumor tissue – Collected upon an archived or fresh specimen (Section 7.5.1). Previously 
obtained DLL3 tumor expression results may be substituted if assessed previously via 
central immunohistochemistry assessment – omitted for retreatment subjects.
!
Prostate cancer subjects only:
#
Serum total testosterone – omitted for retreatment subjects
#
99mTc Bone Scintigraphy (Section 7.3) – may be omitted at initial screening if scans 
have been performed within 2 weeks. May be omitted for retreatment subjects if 
recent scans demonstrating PD are within 2 weeks of study drug dosing (Day 1 of the 
first cycle of retreatment).
6.3
Treatment Period
The treatment period for subjects in Schedule Q6wk is Day 1 to 42 of each 6-week cycle.
6.3.1
Day -1 (Day before Dosing)
!
Subjects will take dexamethasone 8 mg PO twice a day
6.3.2
Day 1 (±2 Days)
If screening visit activities occur within 1 day prior to Cycle 1, Day 1, the following pre-dose 
assessments do not need to be repeated at the Cycle 1, Day 1 visit: physical examination, ECOG 
performance status, and local safety labs (CBC, chemistries, coagulation tests, urinalysis, 
pregnancy test; if obtained within 1 calendar day).
Day 1 procedures may be performed within 1 calendar day prior to dosing of study drug. Results 
from local clinical laboratory tests (at least CBC with differential and serum chemistry panel) 
must be available prior to dose.
!
Physical examination (Section 7.2.1)
!
Vital signs – within 30 minutes prior to the infusion, then post-infusion at 30 minutes 
after start of infusion (±10 minutes), 2 hour (±15 minutes) and 4 hour (±30 minutes; 
Section 7.2.2)


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!
PRO questionnaires EORTC QLQ-C30 and EQ-5D-5L – for subjects in Part B of the 
study only; to occur at screening, Cycle 2 (Days 1 and 29), and EOT (Section 7.3.2)
!
CBC (Section 7.2.3)
!
Serum chemistries (Section 7.2.3)
!
Coagulation tests (Section 7.2.3)
!
Urinalysis (Section 7.2.3)
!
Pregnancy test (Section 7.2.9) – for women of childbearing potential
!
ECG in triplicate – within 180 minutes prior to infusion, and then post-infusion at 30 
minutes (±10 minutes; Section 7.2.4)
!
ECHO (Section 7.2.5) – The screening ECHO should be done any time before the first 
dose of study drug; all ECHOs after C1D1 should be conducted within 4 days before the 
next dosing.
!
ECOG performance status (Section 7.2.6)
!
Fluid retention questionnaire (Section 7.2.7)
!
Blood sample for PK – Should be drawn within 30 minutes prior to the infusion, and then 
post-infusion at 30 minutes after start of infusion (±10 minutes). In Cycles 1 and 2, an 
additional sample will be taken at 6 hour (±30 minutes). The 6 hour PK sample is 
required for Cycles 1 and 2 only - omitted for retreatment subjects.
!
Blood sample for ATA
!
Blood inflammatory markers (Section 7.5.2)
!
Blood tumor markers (Section 7.5.3)
!
Soluble biomarkers (Section 7.5.4)
!
Circulating tumor cells (CTCs), collected at Cycle 1 Day 1. (Section 7.5.5)
!
Subjects will take dexamethasone 8 mg PO twice a day (the first dose of the day should 
be at least 30 minutes, but no more than 4 hours, prior to the rovalpituzumab tesirine 
dose)
!
Administration of rovalpituzumab tesirine (Section 5.1)
6.3.3
Day 2 
!
Subjects will take dexamethasone 8 mg PO twice a day
6.3.4
Day 3 (Window +1 Day) of Cycles 1, 2, and 4 Only
!
ECG in triplicate (Section 7.2.4)
!
Blood sample for PK for Cycles 1 and 2 only – omitted for retreatment subjects
6.3.5
Days 8 and 15 (± 2 Days) and 29 (± 3 Days)
!
Physical examination (Section 7.2.1)
!
Vital signs (Section 7.2.2)


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!
PRO questionnaires EORTC QLQ-C30 and EQ-5D-5L – for subjects in Part B of the 
study only; to occur at screening, Cycle 2 (Days 1 and 29), and EOT (Section 7.3.2)
!
CBC (Section 7.2.3)
!
Serum chemistries (Section 7.2.3)
!
Urinalysis (Section 7.2.3)
!
Fluid retention questionnaire (Section 7.2.7)
!
Blood sample for PK for Cycles 1 and 2 only – omitted for retreatment subjects
In Cycles 5 and higher, the Day 8 visit may be reduced to a virtual visit consisting only of the 
Fluid retention questionnaire (similar to visits on Days 22 and 36, Section 6.3.6), but only if the 
previous 4 consecutive cycles lacked any clinically significant AEs. Visits on Days 15 and 29 
must consist of all above procedures in all cycles.
6.3.6
Days 22 (± 2 Days) and 36 (± 3 Days)
!
Fluid retention questionnaire (Section 7.2.7) – may be conducted virtually
6.3.7
Disease Assessment 
!
Disease assessment consists of CT scans of the chest, abdomen, and pelvis (and neck if 
indicated; Section 7.3). Tumor response will be assessed every 6 weeks counting from 
Cycle 1 Day 1, preferably before each dosing if possible, until 24 weeks, then every 
12 weeks, thereafter.
!
MRI of the brain – if clinically indicated (e.g., if CNS progression has been documented 
previously). CT of the brain with intravenous contrast may be substituted at the discretion 
of the Investigator. CNS lesion will be assessed every 6 weeks counting from Cycle 1 
Day 1, preferably before each dosing if possible, until 24 weeks, then every 12 weeks, 
thereafter.
!
Prostate cancer subjects only: 99 mTc Bone Scintigraphy, will be assessed every 6 weeks 
counting from Cycle 1 Day 1, preferably before each dosing if possible, until 24 weeks, 
then every 12 weeks, thereafter (Section 7.3).).
6.4
End-of-Treatment Visit
The EOT visit occurs 42 ±3 days after the last dose of study drug or within 7 days of 
documentation of the decision to discontinue treatment, whichever is later.
!
Physical examination (Section 7.2.1)
!
Vital signs (Section 7.2.2)
!
PRO questionnaires EORTC QLQ-C30 and EQ-5D-5L – for subjects in Part B of the 
study only; to occur at screening, Cycle 2 (Days 1 and 29), and EOT (Section 7.3.2)
!
CBC (Section 7.2.3)
!
Serum chemistries (Section 7.2.3)


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!
Coagulation tests (Section 7.2.3)
!
Urinalysis (Section 7.2.3)
!
Pregnancy test (Section 7.2.9) for women of child-bearing potential
!
ECG in triplicate (Section 7.2.4)
!
ECHO (Section 7.2.5) – The EOT ECHO should be conducted on EOT (±3 days) 
(Appendix 13.1).
!
ECOG performance status (Appendix 13.3)
!
Fluid retention questionnaire (Section 7.2.7)
!
Disease assessment consisting of CT scans of the chest, abdomen, and pelvis (and neck if 
indicated) – may be omitted if a Disease/Response Assessment was performed within the 
last 6 weeks (Section 7.3)
!
MRI of the brain – if clinically indicated (e.g., if CNS progression has been documented 
previously); may be omitted if a Disease/Response Assessment was performed within the 
last 6 weeks. CT of the brain with intravenous contrast may be substituted at the 
discretion of the Investigator.
!
Blood sample for PK
!
Blood sample for ATA
!
(Optional) fresh tumor tissue, collected at PD (Section 7.3)
!
Blood inflammatory markers (Section 7.5.2)
!
Blood tumor markers (Section 7.5.3)
!
Soluble biomarkers (Section 7.5.4)
!
CTCs (Section 7.5.5)
!
Prostate cancer subjects only: 99mTc Bone Scintigraphy – may be omitted if performed 
within the last 6 weeks (Section 7.3)
6.5
Long-Term Follow-up (LTFU; Every 6 to 12 Weeks ±1 Week)
For all subjects without PD (including those who discontinue study treatment for reasons other 
than PD), the first follow-up visit will occur at 6 weeks (±1 week) after the last dose of study 
drug, then every 6 weeks (±1 week) until 6 months, then every 12 weeks (±1 week), consisting 
of:
!
Disease assessment consisting of CT scans of the chest, abdomen, and pelvis (and neck if 
indicated; Section 7.3)
!
MRI of the brain – if clinically indicated (e.g., if CNS progression has been documented 
previously). CT of the brain with intravenous contrast may be substituted at the discretion 
of the Investigator.
!
Blood tumor markers (Section 7.5.3)
!
Circulating tumor cells (Section 7.5.5)


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!
Prostate cancer subjects only: 99mTc Bone Scintigraphy (Section 7.3)
!
Survival status
At progression, an optional collection of fresh tumor tissue may be conducted (Section 7.3).
After PD, subjects who are not retreated will be followed for subsequent anticancer therapies and 
dates, as well as survival status, similarly every 6 weeks (±1 week) until 6 months, then every 
12 weeks (±1 week). 
6.6
End of Study/End of Follow-Up
The date the subject met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. Where available, subsequent anticancer therapies and dates, 
date of progression (if not already captured on study), and survival status will be recorded.


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7.
Study Assessments
7.1
Screening/Baseline Assessments
Only subjects who meet all inclusion and exclusion criteria specified in Section 4 (and 
Appendix 13.7, for prostate cancer subjects) will be enrolled in this study.
Absence of active CNS tumor or metastases will be confirmed by MRI of the brain. CT of the 
brain with intravenous contrast may be substituted at the discretion of the Investigator.
Demographics include age, gender, and race.
Subject medical history includes a thorough review of significant past medical history, current 
conditions, smoking history, any diagnosis and treatment for prior malignancies, including 
response to treatment, and any concomitant therapies.
Malignancy history should include tumor type, stage, grade and grading system, sites of 
metastases, and mutational status. The latter should include, at least, status of BRAF for 
melanoma subjects, and RET for MTC subjects.
Standard of Care procedures completed prior to the subject signing ICF, but within the study 
screening window, may be used as screening procedures.
7.1.1
Central Immunohistochemistry Assessment 
For all subjects, tumor tissue representative of the qualifying malignancy must be submitted to a 
central laboratory for determination of DLL3 expression. An archived tumor specimen, or a fresh 
specimen, obtained via on-study biopsy, may be used. DLL3 positivity, for purposes of 
eligibility, will be defined as staining in ≥1% tumor cells. The central assessment will be 
definitive regarding DLL3 expression, which will be relayed to the Investigator. All decisions 
regarding study eligibility will be based upon DLL3 expression adjudicated by this central 
assessment.
7.2
Safety Assessments
In addition to the surveillance and recording of AEs, the assessment of safety during the course 
of this study will consist of the recording of concomitant therapies, protocol-specified physical 
examination findings including vital signs, daily weight diary, ECOG performance status, 
disease assessments, and diagnostic testing (including laboratory testing, radiographic imaging, 
ECGs and ECHOs).
Safety will be monitored over the course of the study by an SMC.
7.2.1
Physical Examination
Physical examinations will include assessments of the head and neck, heart, lungs, abdomen, 
extremities, neurological and skin.


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7.2.2
Vital Signs, Weight and Height
Vital signs will include heart rate, respirations, blood pressure, temperature, and weight. All vital 
signs should be measured after the subject has been sitting/resting for at least 5 minutes. For 
adult subjects (>18 years), measurements of height obtained within the prior 6 months may be 
utilized. In the event of an infusion reaction or hypersensitivity reaction, vital signs should be 
monitored more frequently than originally scheduled and as clinically indicated.
Weight will be measured at the times indicated, preferably without outer garments such as hats, 
coats or shoes. Measurements while in light indoor clothing only, or undergarments only, are 
acceptable; but every effort should be made to measure subjects in the same or similar clothing, 
including any accessories or jewelry, at each assessment.
7.2.3
Clinical Laboratory Tests
Laboratory assessments will be performed to evaluate safety at scheduled time points (refer to 
Appendix 13.1) during the course of the study. The following assessments will be performed at 
the local laboratory:
!
CBC, including white blood cell (WBC) count with five-part differential (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils), red blood cell (RBC) count, 
platelet count, hemoglobin, and hematocrit.
!
Chemistry panel, including electrolytes (sodium, potassium, chloride, and carbon 
dioxide), creatinine, blood urea nitrogen (BUN), calcium, phosphorus, magnesium, 
estimated glomerular filtration rate, glucose, albumin, total protein, amylase, lipase, and 
liver function tests (total and direct bilirubin, ALT, AST, alkaline phosphatase, lactate 
dehydrogenase [LDH]).
!
Coagulation tests, including prothrombin time (PT), activated partial thromboplastin time 
(aPTT)/partial thromboplastin time (PTT), and INR.
!
Urinalysis, including dipstick results for color, appearance, specific gravity, pH, glucose, 
bilirubin, ketones, occult blood, and protein; as well as untimed (spot) analysis of protein 
and creatinine for ratio.
!
Hepatitis B and C tests include Hep B surface antigen (HBsAg), Hep B surface antibody 
(HBsAb), Hep B core antibody (HBcAb) and hepatitis C virus (HCV) antibody. Results 
that may be consistent with chronic or active infection, and/or subjects with known prior 
active hepatitis B or C infection, should undergo polymerase chain reaction (PCR) tests 
for Hep B and/or C, respectively.
!
Pregnancy test, consisting of blood or urine testing for beta-human chorionic 
gonadotropin (∀-hCG). Repeat testing may be performed as requested by the Investigator.


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7.2.4
Electrocardiograms
Throughout the study, subjects will be monitored for changes in cardiac conduction through 
ECGs. ECGs will be done in triplicate at the times indicated in Appendices 13.1 and 13.2.
7.2.5
Echocardiogram
ECHOs will be performed at the indicated times (Appendix 13.1) to assess any pericardial 
effusions, if present, as well as cardiac function (left ventricular ejection fraction, LVEF).
7.2.6
ECOG Performance Status
ECOG performance Status (Appendix 13.3) will be evaluated at protocol-specific time points 
(Appendix 13.1).
7.2.7
Fluid Retention Questionnaire
Throughout the treatment period, subjects will be asked about the development of any new or 
worsening peripheral edema or dyspnea (Appendix 13.9). This assessment may take place 
virtually (e.g., by phone).
7.2.8
Daily Weight Diary
Throughout the treatment period, subjects will maintain a diary of daily weights.
7.2.9
Pregnancy Testing
In WOCBP, pregnancy testing will be conducted at scheduled time points during screening and 
the course of the study (refer to Appendix 13.1). Contraception recommendations are outlined in 
Section 4.3.
7.3
Radiographic Response/Efficacy Assessments
Radiographic evaluations at protocol-specified time points include:
!
CT scans of the chest, abdomen and pelvis (scans of the neck must also be obtained 
for MTC and/or if there is documented or suspected involvement in this region)
!
MRI of the brain, if indicated. CT of the brain with intravenous contrast may be 
substituted at the discretion of the Investigator.
!
Whole-body technetium-99m (99mTc) bone scintigraphy (prostate cancer subjects only)
Diagnostic quality, spiral CT scans are recommended; other methods may be used if performed 
consistently throughout the study for each individual subject. Positron emission tomography 
(PET) and/or octreotide/somatostatin scans may be used in an ancillary manner; however, no 
decisions relating to PD may be made based on PET or octreotide/somatostatin scans alone. 
Clinical response will be determined by the Investigator at each assessment according to 
RECIST v1.1 (Appendix 13.6; Eisenhauer 2009), and/or for prostate cancer subjects, PCWG3 
criteria (Appendix 13.7). 


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For tumors to be assigned a status of responder (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments performed no less than 4 weeks, but preferably not 
more than 6 weeks, after the criteria for response are first met; i.e., two consecutive assessments 
of PR or CR are required. In instances where a follow-up visit is not otherwise scheduled to 
occur for more than 6 weeks, repeat radiographic disease assessments should be conducted at 
least 4 but not more than 6 weeks after the criteria for response are first met, in order to confirm 
response, whether or not a formal follow-up visit is conducted at the same time.
7.3.1
Radiographic Disease Progression
Radiographic PD will be defined as either of the following:
!
PD by RECIST v1.1 (refer to Appendix 13.6)
!
Confirmed PD by Bone Scan (for prostate cancer subjects using PCWG3 criteria; 
Appendix 13.7)
Treatment beyond what would be considered PD using RECIST v1.1 or PCWG3 is permitted if 
the following criteria, as assessed by the Investigator, are met:
!
Ongoing clinical benefit, without rapid PD
!
Subject continues to meet all other study protocol eligibility criteria
!
Tolerance of study drug
!
Stable ECOG performance status
Treatment beyond progression must not delay an imminent intervention to prevent serious 
complications of PD (e.g., CNS metastases).
Subjects’ clinical data must be available for CRF source verification. Copies of tumor images 
must be made available for review by the Sponsor or its designee upon request.
7.3.2
Patient Reported Outcomes
PROs will be evaluated for subjects in Part B of the study (only) by assessment of health-related 
quality of life and symptoms using the EORTC QLQ-C30 and EQ-5D-5L questionnaires. The 
questionnaires will be completed during screening, Cycle 2 (Days 1 and 29), and EOT (as 
outlined in the Schedule of Assessments Appendix 13.1). Additional details regarding the 
questionnaires are provided in Section 10.3.9.
7.4
Pharmacokinetic Assessments
Blood samples for PK and ATA testing will be collected throughout the study as indicated in 
Appendices 13.1 and 13.2.
Sensitive, qualified assays will be used to measure plasma concentrations of rovalpituzumab 
tesirine ADC (SC16LD6.5).  Plasma concentrations of rovalpituzumab total antibody and blood 
concentrations of SC-DR002, the small molecule component of rovalpituzumab tesirine, may 


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also be measured if deemed necessary and appropriate. A qualified immunoassay will be used to 
assess ATA against rovalpituzumab tesirine.
7.5
Pharmacodynamic and Biomarker Assessments
Blood and/or tissue samples for pharmacodynamics and biomarker testing will be collected at the 
time points throughout the study as indicated in Appendices 13.1 and 13.2. Refer to the 
laboratory manual for additional details.
AbbVie (or people or companies working with AbbVie) will store the samples in a secure 
storage space with adequate measures to protect confidentiality. The samples may be retained 
while research on rovalpituzumab tesirine (or drugs of this class) or this disease and related 
conditions continues, but for no longer than 20 years after study completion, or per local 
requirement.
7.5.1
Tumor Tissue
Tumor tissue, consisting of a representative archived specimen, or a fresh tumor biopsy, will be 
assessed at baseline for expression of DLL3 by methods such as but not necessarily limited to 
immunohistochemistry (Section 7.1.1). Additional studies, such as routine hematoxylin and eosin 
for morphology and histological classification, IHC for confirmation of diagnosis (e.g., for 
synaptophysin, chromogranin-A, or CD56 for neuroendocrine tumors, or HMB45, S100, or 
MART-1 for melanoma), or scoring of immune infiltrates (e.g., IHC for CD3+, CD4+, CD8+, 
and Foxp3+ cells) may be performed. Tumor material may also be utilized for exploratory 
research that includes assessments of nucleic acid or protein based biomarkers of drug 
sensitivity, resistance, or disease biology and development of a companion diagnostic assay. 
At PD, an optional tumor biopsy may be performed for the assessment of expression of DLL3 
and/or execution of additional studies, such as but not necessarily limited to scoring of immune 
infiltrates or assessment of molecular pathways related to the response to rovalpituzumab 
tesirine. Tumor material may also be utilized for exploratory research that includes assessments 
of nucleic acid or protein based biomarkers of drug sensitivity, resistance, or disease biology and 
development of a companion diagnostic assay. Additional instructions will be provided in the 
laboratory manual.
7.5.2
Inflammatory Markers
At the indicated times, blood will be collected for local testing of inflammatory markers, 
including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies 
(ANA), and rheumatoid factor (RF).
7.5.3
Blood Tumor Markers
At the indicated times, blood will be collected for testing of tumor-specific biomarkers, including 
but not necessarily limited to, the disease-specific biomarkers in Table 7-1.


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Table 7-1
Disease-Specific Blood Tumor Markers
Note: Blood tumor markers are NOT collected for Cohort 8, Other Solid Tumors.
Tumor
Calcitonin
CEA
CgA
LDH
NSE
PSA
S100B
Melanoma
X
X
MTC
X
X
All NECs(Cohorts 4, 5, 6, and 7)
X
X
X
Xa
Abbreviations: CEA = carcinoembryonic antigen; CgA = chromogranin A; LDH = lactate dehydrogenase; 
MTC = medullary thyroid carcinoma; NEC = neuroendocrine carcinoma; NSE = neuron-specific enolase; 
PSA = prostate-specific antigen; S100B = S-100 calcium-binding protein B.
a Required for prostate cancer subjects only.
7.5.4
Soluble Biomarkers
At the indicated times, blood samples will be collected for possible testing of biomarkers that 
may be related to the pharmacodynamics effects of rovalpituzumab tesirine, such as but not 
necessarily limited to, soluble DLL3, or circulating chemokines or cytokines such as vascular 
endothelial growth factor (VEGF), epidermal growth factor (EGF), interleukin (IL)-6 or IL-8.
7.5.5
Circulating Tumor Cells
At the indicated times, blood samples from subjects with neuroendocrine prostate cancer will be 
collected for assessment and characterization of CTC as a possible reflection of disease burden 
for central processing at all sites. A sample for exploratory analyses of CTC-associated 
biomarkers, such as DLL3, will be collected from subjects with large cell neuroendocrine 
carcinoma (cohort 4), neuroendocrine prostate cancer (cohort 5), and high-grade 
gastroenteropancreatic neuroendocrine carcinoma (cohort 6).
7.5.6
Serosal Fluid
Any pericardial, pleural and/or ascitic fluid collected as part of routine care (e.g., as part of a 
therapeutic thoracentesis, pericardiocentesis, or paracentesis) will be procured, where feasible, 
for possible PK, pharmacodynamic and/or biomarker testing. Refer to the laboratory manual for 
additional details. For clinical serosal effusions, refer to Section 7.2.3.
7.5.7
Biospecimen Repository
For subjects who provide additional written consent, remaining de-identified unused clinical 
samples (blood and/or tissue) will be retained by the Sponsor and used for the Sponsor’s future 
research, including, but not limited to, the evaluation of DLL3 and of additional targets for novel 
therapeutic agents, the biology of DLL3, and to identify biomarkers. Blood and tissue samples 
donated for future research may be retained by the Sponsor or its designee indefinitely or as 
permitted by the applicable laws and regulations in the relevant country in which the study is 
conducted. If additional written consent is not provided, any remaining biological samples will 
be destroyed by Sponsor or its designee following study completion.


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8.
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to 
the physical characteristics, identity, quality, purity, potency, durability, reliability, safety, 
effectiveness, or performance of a product/device after it is released for distribution.
The investigational product in this study is defined as rovalpituzumab tesirine. Complaints
associated with any component of this investigational regimen must be reported to the Sponsor 
(Section 8). For AEs, please refer to Section 8.1. For product complaints, please refer to 
Section 8.2.
8.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of AEs on a 
routine basis throughout the study. The Investigator will assess and record any AE in detail, 
including the date of onset, event diagnosis (if known) or sign/symptom, severity, time course 
(end date, ongoing, intermittent), relationship of the AE to study drugs, and any action(s) taken. 
For SAEs considered as having "no reasonable possibility" of being associated with study drugs, 
the Investigator will provide another cause of the event. For AEs to be considered intermittent, 
the events must be of similar nature and severity. AEs, whether in response to a query, observed 
by site personnel, or reported spontaneously by the subject will be recorded.
All AEs will be followed to a satisfactory conclusion.
8.1.1
Definitions
8.1.1.1
Adverse Events
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not the event is considered causally 
related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as 
from accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening of a 
pre-existing condition or illness is considered an AE.
Worsening in severity of a reported AE should be reported as a new AE. Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention (including 
interruption/dose reduction of study drug, starting or discontinuing medication, etc.), meets 
protocol specific criteria (refer to Sections 5.5 and 8.1 regarding toxicity management) and/or if 
the Investigator considers them to be AEs.


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An elective surgery/procedure scheduled to occur during a study will not be considered an AE if 
the surgery/procedure is being performed for a pre-existing condition and the surgery/procedure 
has been pre-planned prior to study entry. However, if the pre-existing condition deteriorates 
unexpectedly during the study (e.g., surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done will be 
considered an AE.
All protocol-related AEs must be collected from the signing of the study specific informed 
consent until study drug administration.
In addition, AEs with onset or worsening reported by a subject from the time that the first dose 
of study drug is administered until 70 days have elapsed following discontinuation of study drug 
administration will be considered as TEAEs.
8.1.1.2
Serious Adverse Events
If an AE meets any of the criteria outlined in Table 8-1, the AE is to be reported to AbbVie as an 
SAE within 24 hours of the site being made aware of the SAE.
Table 8-1
Criteria for a Serious Adverse Event (SAE)
Death of Subject
An event that results in the death of a subject.
Life Threatening
An event that, in the opinion of the Investigator, would have resulted in immediate 
fatality if medical intervention had not been taken. This does not include an event 
that would have been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length of time or 
prolongs the subject's hospital stay. This does not include an emergency room visit 
or admission to an outpatient facility, or hospitalization for respite care.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with the activities 
of daily living of a study subject. Disability is not intended to include experiences 
of relatively minor medical significance such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome
An important medical event that may not be immediately life threatening or result 
in death or hospitalization, but based on medical judgment may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
Note: For SAEs with the outcome of death, the date and cause of death will be recorded on the appropriate CRF.


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8.1.1.3
Adverse Events Expected Due to Cancer Progression
The term "disease progression" alone should not be used when reporting AEs or SAEs, due to its 
lack of specificity. Rather, symptoms of disease progression (PD) should be collected under the 
unifying diagnosis of "malignant neoplasm progression;" symptoms of progression may be 
subsumed under this diagnosis.
8.1.2
Adverse Event Severity
The Investigator will rate the severity of each AE according to the NCI CTCAE v4.03. If a 
reported AE increases in severity, the initial AE should be given an outcome date and a new AE 
reported on a different date from the end date of the previous AE to reflect the change in 
severity. For all reported SAEs that increase in severity, the supplemental eCRFs also need to be 
updated to reflect the change in severity.
When CTCAE criteria cannot be used, the event should be graded as defined below:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the subject's 
usual activities (moderate).
Grade 3/4
The adverse event causes considerable interference with the subject's usual 
activities and may be incapacitating or life threatening (severe). 
Grade 5
The adverse event resulted in death of the subject (severe).
8.1.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the AE to the use 
of study drug:
Reasonable Possibility
After consideration of factors, including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable Possibility
After consideration of factors, including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship
For causality assessments, events assessed as having a reasonable possibility of being related to 
the study drug will be considered "associated." Events assessed as having no reasonable 
possibility of being related to study drug will be considered "not associated." In addition, when 
the Investigator has not reported a causality or deemed it not assessable, AbbVie will consider 
the event associated.


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If an Investigator's opinion of no reasonable possibility of being related to study drug is given, an 
“Other” cause of event must be provided by the Investigator for the SAE.
8.1.4
Deaths
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
Deaths that occur during the protocol specified AE reporting period (Section 8.1.5) that are more 
likely related to PD will therefore be considered as an expected AE and will not be subject to 
expedited reporting to regulatory agencies. These SAEs should be reported as “malignant 
neoplasm progression” and also recorded on the AE eCRF. After the AE reporting period, deaths 
attributed to PD under study should be recorded only on the end of study (EOS) eCRF.
Death should be considered an outcome and not a distinct event. The event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept on 
the AE eCRF. Generally, only one such event should be reported. The term "sudden death" 
should only be used for the occurrence of an abrupt and unexpected death due to presumed 
cardiac causes in a patient with or without pre-existing heart disease, within 1 hour of the onset 
of acute symptoms or, in the case of an unwitnessed death, within 24 hours after the patient was 
last seen alive and stable. If the cause of death is unknown and cannot be ascertained at the time 
of reporting, "unexplained death" should be recorded on the AE eCRF. If the cause of death later 
becomes available (e.g., after autopsy), "unexplained death" should be replaced by the 
established cause of death.
8.1.5
Adverse Event Collection Period
All AEs reported from the time of study drug administration until 70 days following 
discontinuation of study drug administration will be collected, whether solicited or 
spontaneously reported by the subject. In addition, protocol-related serious and non-serious AEs 
will be collected from the time the subject signed the study-specific informed consent.
Serious and non-serious AEs occurring after the study-specific informed consent is signed but 
prior to the initial dose of study drug will be collected only if they are considered by the 
Investigator to be causally related to the study-required procedures.
AE information will be collected as shown in Figure 8-1.




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For any subject safety concerns, please contact the study Medical Monitor listed below:
, MD, PhD
Novella Clinical
1700 Perimeter Park Drive
Morrisville, NC 27560 USA
Telephone Contact Information:
Phone: 
 
In emergency situations involving study subjects when the Medical Monitor is not available by 
phone, please contact the 24-hour AbbVie Medical Escalation Hotline where your call will be 
re-directed to a designated backup AbbVie TA MD:
Phone: 
8.1.7
Pregnancy Reporting
Pregnancy in a study subject must be reported to the Sponsor within 24 hours of the site 
becoming aware of the pregnancy. Subjects who become pregnant during the study must be 
discontinued.
All subjects should be informed that contraceptive measures (refer to Section 4.3 Contraception 
Recommendations) should be taken throughout the study and for at least 6 months after the last 
dose of study drug. Male subjects should be informed that contraceptive measures should be 
taken by their female partner. 
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected. In the event of a pregnancy occurring in the partner of an enrolled 
subject, written informed consent for release of medical information from the partner must be 
obtained prior to the collection of any pregnancy-specific information, and the pregnancy will be 
followed to outcome. In the event a study subject or the partner of an enrolled subject delivers a 
baby, they will be asked to provide information including the following will be requested: date of 
delivery, birth weight and length, boy or girl, problems during pregnancy or delivery, and if the 
baby has any birth defects.
Pregnancy in a study subject is not considered an AE. However, the medical outcome of an 
elective or spontaneous abortion, stillbirth or congenital anomaly is considered an SAE and must 
be reported to AbbVie within 24 hours of the site becoming aware of the event.


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8.2
Product Complaint
8.2.1
Definition
A Product Complaint is any Complaint (refer to Section 8 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, 
product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example: printing illegible), missing 
components/product, device not working properly, or packaging issues.
Any information available to help in the determination of causality to the events outlined directly 
above should be captured.
8.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the Sponsor 
within 24 hours of the study site's knowledge of the event via the Product Complaint form. 
Product Complaints occurring during the study will be followed-up to a satisfactory conclusion. 
All follow-up information is to be reported to the Sponsor (or an authorized representative) and 
documented in source as required by the Sponsor. Product Complaints associated with AEs will 
be reported in the study summary. All other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint condition. In 
instances where a return is requested, every effort should be made by the Investigator to return 
the product within 30 days. If returns cannot be accommodated within 30 days, the site will need 
to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
8.2.3
Events Commonly Associated in Study Population with Advanced Solid Tumors 
and/or Progression of Underlying Malignancy
Certain AEs are anticipated to occur in the study population at some frequency independent of 
drug exposure. Such events include known consequences of the underlying disease or condition 
under investigation (e.g., symptoms, PD).
A list of AEs associated with advanced solid tumors is provided in Appendix 13.10. These AEs 
are preferred terms coded according to the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary; the AEs may occur alone or in various 
combinations and are considered expected for reporting purposes for this protocol. Although 
exempted from expedited reporting to Health Authorities and IRBs as individual cases, if these 
AEs meet serious criteria these SAEs must be reported to AbbVie within 24 hours of the site 


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being made aware of the SAE (as required in Section 8.1.6). For deaths related to disease 
progression (coded to malignant neoplasm progression), the date and cause of death will be 
recorded on the appropriate case report form (CRF), but the event will not be expedited as an 
Individual Case Safety Report (ICSR) to regulatory authorities (Section 8.1.4).
8.3
Appropriateness of Measurements
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. AEs and, when applicable, clinical 
laboratory data will be graded using NCI CTCAE, version 4.03.
Response will be assessed according to RECIST v1.1 (Eisenhauer 2009), which includes 
standard criteria for evaluating response in solid tumors. Prostate cancer is assessed by PCWG3 
criteria. The intervals of evaluation in this protocol are appropriate for disease management.
Standard tests will be performed to detect the possible presence of specific antibodies to study 
drug. PK assessments for drug activity are also common in clinical studies.


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9.
Data Quality Control and Quality Assurance
9.1
Site Training and Monitoring Procedures
A study manual that includes instructions for study compliance and CRF completion will be 
provided. Prior to the enrollment of subjects at the site, the Sponsor or its designated clinical and 
medical personnel will review the following items with the Investigator and clinic staff:
!
The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes
!
Current Investigator’s brochure
!
Recording and reporting AEs and SAEs
!
Enrollment goals and study timelines
!
The CRF completion process and source documentation requirements
!
Monitoring requirements
!
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and 
approval process
!
Informed consent process
!
Good Clinical Practice guidelines and related regulatory documentation requirements
!
Key study team roles and responsibilities
!
Investigational product storage, accountability, labelling, dispensing and recordkeeping
!
Subject coding
!
Study samples/specimen collection, handling and shipping
!
Protocol compliance
!
Clinical study recordkeeping, document retention, and administrative requirements
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment and 
workload at each site. During monitoring visits, the Sponsor representative will review 
regulatory documentation, CRFs, source documentation, investigational product storage, 
preparation, and accountability. The CRFs will be reviewed for completeness, adherence to the 
provided guidelines, and accuracy compared to the source documents. The Investigators must 
ensure that the monitor is allowed to inspect all source documents pertinent to study subjects, 
and must cooperate with the monitor to ensure that any problems noted in the course of the trial 
are resolved. The Investigator must maintain a comprehensive and centralized filing system of all 
study-related documentation that is suitable for inspection by the Sponsor or its designated 
monitors and by quality assurance auditors, or representatives of regulatory authorities.
9.2
Data Management Procedures
The Sponsor or its designee will provide CRF Completion Guidelines for eCRF data entry. Study 
specific data management procedures will be maintained in the data management plan. Queries 


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resulting from edit checks and/or data verification procedures will be posted electronically in the 
eCRF.
9.3
Access to Source Data
The Investigator will permit the Sponsor’s representatives to monitor the study as frequently as 
the Sponsor deems necessary during or after the completion of the study to determine that 
protocol adherence and data recording are satisfactory. Appropriate measures to protect subject 
confidentiality are to be employed during monitoring. The CRFs and related source documents 
will be reviewed in detail by the monitor at each site visit. Original source documents or certified 
copies must be provided to the Sponsor for review. This review includes inspection of data 
acquired as a requirement for participation in this study and other medical records as required to 
confirm that the information contained in the CRFs, such as disease assessments, AEs, and 
concomitant therapies, is complete and correct. Other study records, such as correspondence with 
the Sponsor and the IRB/IEC and screening and drug accountability logs will also be inspected. 
All source data and study records must also be made available during or after completion of the 
study for inspection by representatives of regulatory authorities. In the event of an inspection by 
regulatory authorities, the Sponsor may be available to assist in any preparations. All pertinent 
study data must be made available as requested to the regulatory authority for verification, audit, 
or inspection purposes.
9.4
Accuracy and Reliability of Data
The Sponsor or its designee shall take steps to assure the accuracy and reliability of data, 
including:
!
The selection of qualified Investigators and appropriate study centers.
!
Review of protocol procedures with the Investigators and associated personnel prior to 
the study.
!
Periodic monitoring visits by the designated monitor(s).
!
Review of CRFs for accuracy and completeness by the designated monitor(s) during 
monitoring visits to the study centers. Any discrepancies will be resolved with the 
Investigator or designees as appropriate.
9.5
Quality Assurance Procedures
The Quality Assurance group or its designee may conduct audits at the clinical site or other 
study-related facilities and organizations during or at any time after the study. Audit reports will 
be retained by the Sponsor’s Quality Assurance group or its designee as part of the written record.


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9.6
Data Handling and Recordkeeping
9.6.1
Data Handling
It is the Investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the Sponsor in the CRFs and in all required reports. The CRFs 
should be captured in the Sponsor EDC system within ten (10) business days of the subject’s 
visit to the site. Data reported on the CRF that is derived from source documents should be 
consistent with the source documents or the discrepancies must be explained.
Any change or correction to a CRF must be maintained in an audit trail within the electronic data 
capture system. Data changes may only be made by those individuals so authorized. The 
Investigator must retain records of the changes and corrections, written and/or electronic. Prior to 
database lock the Investigator must review and approve the completed electronic CRFs to verify 
their accuracy.
9.6.2
Investigator Record Retention
The Investigator shall retain study drug disposition records and all source documentation (such 
as original ECG tracings, laboratory reports, and in-patient or office patient records) for the 
maximum period required by the country and institution in which the study will be conducted, or 
for the following periods, whichever is longer: for at least 2 years after the last approval of a 
marketing application in an International Conference on Harmonisation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or for at least 
2 years after the relevant authority has been informed of the discontinuation of clinical 
development of the study drug. The Investigator may not destroy any records associated with the 
study without obtaining the prior, written consent of the Sponsor. If the Investigator withdraws 
from the study (due to relocation, retirement, etc.), the records will be transferred to a mutually 
agreed upon designee, such as another Investigator or IRB/IEC. No records shall be transferred 
without prior, written authorization from the Sponsor or its designee.


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10.
Data Analysis and Statistical Methods
This section provides the key details of the statistical analyses to be performed using data 
captured according to this protocol. Further details on planned analyses for the data captured in 
this protocol will be provided in the Statistical Analysis Plan (SAP).
10.1
Determination of Sample Size
Up to approximately 318 subjects are expected to participate in this two-part trial.
In Part A, up to approximately 144 subjects may be enrolled, assuming 3 dose-escalation cohorts 
of 6 subjects each (18 subjects) across 8 disease cohorts. The exact number will depend on the 
number of cohorts required to reach the MTD in each disease, and the number of subjects 
enrolled in each disease-specific cohort. 
In Part B, up to approximately 174 subjects may be enrolled, including approximately 
19 subjects in each of the 5 disease-specific cohorts. The rationale for the sample size is based on 
the assumption that an ORR of around 15% would be indicative of efficacy worthy of further 
investigation given the advanced cancers and extensive treatment history in this study 
population. Additionally, an ORR below 5% would provide evidence of an ineffective treatment. 
The goal of the efficacy analyses is to provide a preliminary signal that the response rate may 
potentially be within that target range.
When Part B is enrolled, each disease-specific cohort will have approximately 25 subjects treated 
at the RP2D, including the Part A and Part B subjects. Table 10-1 presents the 90% two-tailed 
lower exact confidence limits for selected response rates.
Table 10-1
Lower Exact 90% Two-Tailed Confidence Limits for Selected Objective 
Response Rate Results for 25 Subjects
Number of Responses
Response Rate
Lower Confidence Limit 
1
4.0%
0.2%
2
8.0%
1.4%
3
12.0%
3.4%
4
16.0%
5.7%
The final decision to pursue the clinical development of any disease-specific cohort will be based 
on safety evaluations, the complete results of the study, and other factors; fewer than 3 responses 
could be considered a discouraging result. When 3 or more responses are observed, there is 
approximately a 75% probability this occurs when the true rate is 15%, but less than 13% when 
the true rate is 5%. When 4 responses are observed, a 5% rate is excluded by the 90% confidence 
interval (CI) lower bound.


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An interim futility analysis is planned for each cohort, which may have an impact on the number 
of subjects ultimately enrolled in Part B. The futility analysis is described in Section 10.3.6.
!
The Other NEC/NET and Other Solid Tumor cohorts will enroll subjects until all other 
disease cohorts complete enrollment, and are expected to enroll approximately 30 subjects 
each by the time of study completion.
!
Details will be provided in the SAP.
10.2
Analysis Populations
The following populations will be considered:
!
Full Analysis Set: All enrolled subjects who receive any amount of study drug.
!
Safety Set: All subjects who receive any amount of study drug and have at least one 
post-baseline safety evaluation.
!
DLT-Evaluable Set: All subjects who receive any amount of study drug and either 
experienced a DLT or were followed for the full DLT evaluation period.
!
Pharmacokinetic-Evaluable Set: All subjects who receive at least 1 dose of study drug 
and for whom a baseline measurement and at least one blood sample following a dose of 
study treatment are available.
Based on the actual deviations, the criteria for exclusion of subjects from the different data sets 
will be specified and updated, if necessary, prior to database lock.
10.3
Planned Analyses
As a general strategy, continuous efficacy and safety endpoints will be summarized using the 
five-number summary (mean, standard deviation, median, minimum, and maximum). Frequency 
distributions (counts and percentages) will be used to summarize categorical endpoints.
10.3.1 Disposition of the Study Subjects
The disposition of subjects will be described with summaries by disease and cohort of the 
number of subjects enrolled, the number of subjects treated, the number of subjects for whom 
study drug was permanently discontinued (including the reasons for discontinuation), and the 
number of subjects who discontinued early from the study.
10.3.2 Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized and compared by disease and 
cohort. Results will be reported using subjects in the full analysis set.
10.3.3 Exposure to Study Treatment and Compliance
Frequency distributions of the number of received doses will be presented by disease and cohort. 
Treatment duration and treatment compliance for all randomized subjects will be described by 


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disease and cohort.
10.3.4 Analysis of Primary Efficacy Endpoints
The first primary efficacy endpoints are the best objective response rate based on RECIST v1.1 
and/or, for prostate cancer subjects, PCWG3 criteria. It is defined as the proportion of subjects 
whose best overall response is either CR or PR according to RECIST v1.1 or PCWG3. The best 
overall response is the highest recorded response through End of Treatment. The number and 
percentage of responders along with the corresponding 90% two-tailed CI will be provided for 
each disease and cohort.
10.3.5 Analysis of Secondary Efficacy Endpoints
The analysis of the secondary efficacy endpoints will be conducted using data from the Full 
Analysis set.
Burden of disease will be analyzed in a way similar to the analysis of the best ORR (described in 
the previous section).
DOR will be summarized for responders (i.e., subjects with CR or PR only) by disease and 
cohort. PFS and OS will be summarized by disease and cohort. The PFS rate at additional time 
points may also be evaluated (e.g., 26, 39 and 52 weeks). DOR, and PFS, will be obtained by 
using the Kaplan-Meier approach similar to OS described in the previous section. 
Details of the analysis of secondary efficacy endpoints will be described in the Statistical 
Analysis Plans.
10.3.6 Futility Analysis
A non-binding futility analysis is planned for each cohort when 12 subjects have at least 
2 evaluable tumor response evaluations after starting therapy. This analysis is designed to give a 
timely preliminary signal of response to consider along with cohort safety data to assess the 
advisability of continuing to enroll the cohort. Reported probabilities are based on exact 
calculations. There is a 54% chance that a result of 0 responses is observed when the true 
response rate is 5%. When the response rate in the population is the target rate of interest (15%); 
the chance of 0 responses is 14%, 1 response 30%, and 1 or more responses 96%. Therefore, 
observing 1 or more responses at the interim analysis would be supportive of further enrollment.
10.3.7 Safety Analysis
Safety endpoints will be summarized using data from the Safety Set. Safety analyses will involve 
examination of the incidence, severity, and type of TEAEs reported, changes in vital signs and 
laboratory test results from baseline (the assessment prior to first dose) to specified time points 
throughout the study, and concomitant medications use.


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10.3.7.1 Treatment Emergent Adverse Events
TEAEs reported during the study will be coded using a Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary. Incidence of TEAEs will be summarized by disease and cohort 
and the following:
!
System organ class and preferred term
!
System organ class, preferred term and severity
These summaries will be presented for the following subsets:
!
Serious adverse events
!
All adverse events
!
Drug-related adverse events
!
Adverse events leading to treatment discontinuation
For tables reporting AEs by severity, if a subject has multiple occurrences of an AE with the 
same organ class and preferred term, the most severe event will be presented.
10.3.7.2 Clinical Laboratory Evaluation
Laboratory parameters will be summarized by disease and cohort at each visit. Each summary 
will include the values of the laboratory parameters and their change from baseline. Shift tables 
from baseline will be presented for laboratory values in the chemistry and hematology panels. 
Parameters will be classified according to the laboratory reference normal ranges. A listing will 
be provided for out of normal range as well as clinically significant abnormal lab values.
10.3.7.3 Vital Signs
Vital signs, including pulse, blood pressure, temperature, height, and body weight will be 
summarized by disease and cohort and time point. For each assessment of vital signs, change and 
percent change in vital signs from baseline will be summarized by disease and cohort.
10.3.7.4 Eastern Cooperative Oncology Group Performance Status
ECOG performance status will be summarized for each visit by disease and cohort. Shifts from 
baseline to the best and worst post-baseline score may be tabulated.
10.3.7.5 Electrocardiogram
Electrocardiogram status will be summarized for each scheduled visit by disease and cohort. 
Shifts from baseline may be tabulated. Additionally, ECG parameters will be described using the 
five-number summary.
10.3.7.6 Concomitant Medications
Concomitant medications will be classified according to the anatomical therapeutic chemical 
codes in the World Health Organization Drug (WHODRUG) dictionary. The incidence rate of 


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each coded concomitant medication will be tabulated by disease and cohort. The table will be 
sorted by the incidence use of the entire sample.
10.3.8 Pharmacokinetic and Pharmacodynamics Analyses
Data from the Pharmacokinetic-Evaluable Set will be used in the analysis of PK and 
Pharmacodynamics endpoints. The PK of rovalpituzumab tesirine will be estimated from 
concentration-time data using non-compartmental methods. The reporting of PK parameters will 
be determined based on the final parameter analysis on the available data. The PK parameters 
that may be assessed include, as appropriate:
!
Cmax
Maximum plasma concentration 
!
AUC
Area under the plasma concentration-time curve 
!
Tmax
Time of Cmax
!
Ctrough
Plasma concentrations at trough
!
t1/2
(Apparent) terminal half-life 
!
CL
Plasma clearance 
!
Vdβ
Volume of distribution 
The above parameters will be summarized by descriptive statistics.
The incidence and timing of ATA to study drug will be summarized by descriptive statistics. The 
possible effects of ATA on PK, efficacy and safety may be explored. Details will be provided in 
the SAP.
The five-number summary will be used to describe absolute and percent change from baseline in 
IHC, blood tumor markers (like NSE), soluble biomarkers (such as soluble DLL3) and 
circulating tumor cells. Regressions may be performed as appropriate. Exploratory analyses may 
be performed to evaluate a possible correlation between each of these endpoints and disease 
response and/or toxicities. Additional analyses may also be performed. Details will be provided 
in the SAP.
10.3.9 Patient Reported Outcomes (PROs)
PROs will be evaluated for subjects in Part B of the study (only) by assessment of health-related 
quality of life and symptoms using the EORTC QLQ-C30 and EQ-5D-5L questionnaires. The 
questionnaires will be completed according to Section 7.3.2 (and as outlined in the Schedule of 
Assessments, Appendix 13.1). The EORTC QLQ-C30 is a cancer-specific instrument that has 
30 items and 5 functional domain scales: Physical, Role, Emotional, Social, and Cognitive; 
2 items evaluate global quality of life. The EQ-5D-5L is a generic preference instrument that has 
been validated in numerous populations. The EQ-5D-5L is composed of 5 questions and a visual 
analog scale (VAS) assessing overall health that can be converted into a single health status or 


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"utility" score for use in an economic evaluation to adjust life-years gained by the subject's 
health-related quality of life.
Details of the analysis of PROs will be described in the SAP.


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11.
Ethical and Regulatory Considerations
This study will be conducted in accordance with ICH Guidance E6 (R1) (ICH 1996); FDA CFR 
[21 CFR Parts 50, 56, and 312]); Declaration of Helsinki World Medical Association 
Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, as it 
may be amended; applicable data protection laws and regulations; and all laws, rules, and 
regulations applicable to the study or the study drug in jurisdictions in which the Investigator 
conducts the study. 
11.1
Informed Consent
The Investigator is responsible for presenting the risks and benefits of study participation, along 
with the aims and methods of the study, to the subject in terms understandable to the subject 
using the IRB/IEC approved Informed Consent Form (ICF). The Investigator will also instruct 
the subjects that they are free to withdraw their consent and discontinue their participation in the 
study at any time without prejudice. The Investigator or his/her designee shall re-consent 
subjects when the ICF is updated during the study, if required. The Investigator will ensure that 
written informed consent is obtained from each subject or their legally authorized representative, 
if applicable to this study, by obtaining the signature and date on the ICF prior to the 
performance of protocol evaluations or procedures.
The ICF will document the study-specific information the Investigator or his/her designee 
provides to the subject and the subject’s agreement to participate in the study and to comply with 
the instructions of the Investigator and study staff. Informed consent will be verified and 
countersigned by the Investigator or their designee. If informed consent is obtained from a 
legally authorized representative for a subject who is unable to provide informed consent at study 
entry but the subject is later able to provide informed consent, the Investigator must obtain 
written informed consent from the subject using the IRB/IEC approved ICF.
Prior to the start of the study, the Investigator will provide the Sponsor with an ICF approved by 
the IRB/IEC for use during the study that is based on Sponsor’s model template ICF. The model 
ICF template prepared by the Sponsor will be provided in the study manual. The proposed ICF 
and the informed consent process must comply with US regulations 21 CFR Part 50.25 as well as 
other applicable national and international laws, rules and regulations. The proposed ICF should 
contain the 20 elements of the informed consent described in ICH E6 4.8 and adhere to the 
ethical principles of the Declaration of Helsinki. The ICF must have been reviewed and approved 
by the Sponsor and the study IRB prior to initiation of the study. In addition, any amendments to 
the ICF will need to be approved by the Sponsor and the IRB/IEC. The ICF must contain, or 
subjects must separately be provided with, an authorization for use and disclosure of protected 
health information and include the elements required by 45 CFR Part 164.508(b) for valid 
authorizations.


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Each subject will be given a copy of the signed ICF. The source documents for each subject shall 
document that the informed consent was obtained prior to participation.
11.2
Confidentiality of Subject Personal Information
During the informed consent process, subjects shall be provided with information in the ICF 
regarding the confidential treatment of their personal information collected in the study. In 
addition, an authorization for the collection, use, storage, disclosure, and transfer of subject 
personal information (an “Authorization”) in compliance with applicable laws, rules, and 
regulations of the jurisdiction where the study is conducted, must be obtained from each subject, 
either as part of the ICF or as a separate signed document, for example, in the United States a 
Health Insurance Portability and Accountability Act (HIPAA) Authorization, approved by the 
IRB and the Sponsor, will be used. Such Authorization shall include the use of personal 
information by the Sponsor, its representatives, collaborators, licensees and assigns for purposes 
of conducting and monitoring the study, regulatory submissions and conducting future research 
related to the diseases or study drug covered by this protocol.
A unique identifier or code will be assigned to each subject to be used in lieu of the subject’s 
name in study documentation and in reporting of AEs for the purpose of ensuring the 
confidential treatment of the study participant’s personal and health information. The 
Investigator will maintain a master key to the subject identifier list in a secure location at the 
study site consisting of the unique subject identifiers, subject names, and dates of birth to allow 
unambiguous identification of each subject included in the study.
Subject personal information that is collected for the study may be transferred to countries 
outside the country where the study is conducted for purposes relating to the study, including 
regulatory submissions by the Sponsor. The Authorization will include information on any 
potential transfer of subject personal information, including, if applicable, a statement that the 
laws governing the treatment of personal data in countries to which subject personal data is 
transferred may not be as stringent as those of the country where the study is being conducted.
Researchers, monitors, and auditors shall be required to adhere strictly to professional standards 
and applicable law concerning the confidential treatment of the subject information.
11.3
Biospecimens
Clinical samples donated by subjects in the study (blood, urine, tissue, etc.) comprise study 
results of the Sponsor and will be collected and processed in accordance with this protocol and 
delivered to the Sponsor or Sponsor’s designee, as instructed by Sponsor. Clinical samples shall 
not be retained or used by the Investigator or institution except as expressly permitted by 
Sponsor in writing. The ICF will contain information on the handling of subject personal 


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information relating to clinical samples, including, if applicable, the labeling of clinical samples 
with the subject’s unique code.
11.4
Ethics Approval
The Investigator will provide the Sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the ICF before the study may begin at the investigative site(s). The 
name and address of the reviewing ethics committee will be included in the Investigator file.
The Investigator will supply the following to the investigative site’s IRB/IEC:
!
Protocol and amendments
!
ICF and updates
!
Clinical Investigator’s Brochure and updates
!
Relevant curricula vitae, if required
!
Required safety and SAE reports
!
Any additional submissions required by the site’s IRB/IEC
The Investigator must provide the following documentation to the Sponsor or its designee:
!
The IRB/IEC periodic (e.g., quarterly, annual) re-approval of the protocol.
!
The IRB/IEC approvals of any amendments to the protocol or revisions to the ICF.
!
The IRB/IEC receipt of safety and SAE reports, as appropriate.
11.5
Investigator and Study Personnel Information
The contact information and qualifications of the Principal Investigator, Subinvestigators and 
name and address of the research facilities shall be included in the Investigator file. The 
Investigator is responsible for the supervision of study conduct in accordance with this protocol, 
including collection of and maintenance of adequate and appropriate study documentation. The 
Investigator may delegate some of the work involved in the conduct of the study to study staff 
under his/her supervision. The Investigator shall ensure that all study staff are qualified by 
education, experience, and training to perform their specific responsibilities in relation to the 
study. The Investigator has final responsibility for the accuracy and authenticity of all study data.
Each Investigator and Subinvestigator (as designated on the Form FDA 1572) will provide a 
signed Financial Disclosure Form in accordance with 21 CFR Part 54. Each Investigator will 
notify the Sponsor or its authorized representative of any relevant changes to the information 
included on such Financial Disclosure Form during the conduct of the study and for 1 year after 
the study has been completed.
If the study site is located in the European Union, the Principal Investigator and any 
Subinvestigators must provide their express authorization for the Sponsor’s collection, use, 
transfer (including to countries outside of the country where the study is conducted and the EU) 
and storage of their personal data, including their name, address, phone number for: review by 


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governmental authorities with regard to Sponsor’s regulatory submissions related to the study; 
fulfilling regulatory or legal requirements; and publication of the study on the 
www.clinicaltrials.gov website.
11.6
Protocol Amendments and Study Termination
Any Investigator-initiated changes to the protocol (with the exception of changes to eliminate an 
immediate hazard to a study subject) must be approved by the Sponsor prior to seeking approval 
from the IRB/IEC, and prior to implementing. The Investigator is responsible for enrolling 
subjects who have met protocol eligibility criteria. Protocol deviations must be reported to the 
Sponsor and the local IRB/IEC in accordance with IRB/IEC policies.
The Sponsor may close a cohort at their discretion, or terminate the study at any time. The 
IRB/IEC must be advised in writing of study completion or early termination.
11.7
Study Documentation, Privacy and Records Retention
To protect the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the Investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study. If requested, the 
Investigator will provide the Sponsor, its licensees and collaborators, applicable regulatory 
agencies, and applicable IRB/IEC with direct access to original source documents and certified 
copies within no more than ten (10) days of request by Sponsor (or sooner if required by a 
regulatory authority).
Records containing subject medical information and other personal data must be handled in 
accordance with local and national laws, rules, and regulations and consistent with the terms of 
the subject Authorization contained in the ICF for the study. Care should be taken to ensure that 
such records are not shared with any person or for any purpose not contemplated by the 
Authorization. Furthermore, CRFs and other documents to be transferred to the Sponsor should 
be completed in strict accordance with the instructions provided by the Sponsor, including the 
instructions regarding the coding of subject identities.
In compliance with local and/or regional regulations, this trial may be registered and trial results 
may be posted on public registries, such as ClinicalTrials.gov.
11.8
Clinical Trial Agreement
A separate written clinical trial agreement covering the obligations of the Sponsor and of the 
institution and Investigator in relation to the study is required before the study site is initiated. 
The clinical trial agreement will include terms for payments by the Sponsor to Investigators and 
institutions conducting the trial, requirements for Investigators’ and institutions’ insurance, 
provisions for reimbursement of the treatment of subject injuries attributable to the study or the 
study drug, the publication of clinical trial data, and other relevant provisions.


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The Investigator and the institution shall collect and record all data and results of the study, 
including all information, CRFs, laboratory work sheets, slides, biospecimens, findings and 
reports (“Results”) as required by this protocol, the Sponsor’s instructions and the clinical trial 
agreement. Results are the exclusive property of Sponsor and are deemed its confidential 
information. Subject medical records and other source documentation are not included in Results. 
The written permission of the Sponsor is required prior to disclosure by the Investigator or the 
study sites of Results or any other information related to the study or the study drug. After 
conclusion of the study at all study sites, the Investigator may publish or present the Results that 
have been generated at the institution, provided that, the Results of the overall study have already 
been published or disclosed with Sponsor’s permission in an abstract, manuscript or 
presentation; or the overall study has been completed at all sites for at least 2 years; or as 
otherwise approved by Sponsor in writing. The Investigator will submit to Sponsor for review 
any proposed publication or presentation along with the name of the applicable scientific journal 
or presentation forum prior to its submission for publication or presentation. The Investigator 
will comply with the Sponsor’s request to delete references to its confidential information in any 
proposed publication or presentation and the Investigator or institution will withhold publication 
or presentation for an additional time period in order to allow the Sponsor to obtain patent 
protection. Investigators will conduct all interactions with third parties, including journal editors 
and reviewers, in a manner consistent with the confidentiality provisions of the clinical trial 
agreement in place with Sponsor. The foregoing shall not operate to restrict publication but is
intended solely to ensure the accuracy and completeness of data intended for publication, to 
provide an opportunity to share with the Investigator any new and/or unpublished information of 
which he/she may be unaware and to ensure that Sponsor’s confidential information is not 
disclosed.


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12.
References
Chapman G, Sparrow D, Kremmer E, Dunwoodie S. Notch inhibition by the ligand DELTA-
LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. 
Hum Mol Genet, 2011;20(5):905–16.
Dummer R, Hauschild A, Lindenblatt N, Pentheroudakis G, Keilholz U. Cutaneous melanoma: 
ESMO clinical practice guidelines. Ann Oncol, 2015;26(s5):v126–v132.
Dunwoodie S, Henrique D, Harrison S, Beddington R. Mouse Dll3: a novel divergent Delta gene 
which may complement the function of other Delta homologues during early pattern formation in 
the mouse embryo. Development, 1997;124(16):3065–76.
Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer, 
2009;45:228–47. 
Food and Drug Administration. Guidance for industry and investigators, safety reporting 
requirements for INDs and BA/BE studies – small entity compliance guide. Dec 2012.
Hainsworth J, Spigel D, Litchy S, Greco F. Phase II trial of paclitaxel, carboplatin, and etoposide 
in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research 
Network Study. J Clin Oncol, 2006;24:3548–54.
International Conference on Harmonisation. Guideline for Industry, Clinical safety data 
management: definitions and standards for expedited reporting, E2A, Mar 1995. 
International Conference on Harmonisation. Guidance for Industry, E6 Good Clinical Practice: 
Consolidated Guidance. Apr 1996.
Kulke M, Siu L, Tepper J, Fisher G, Jaffe D, Haller D, et al. Future Directions in the treatment of 
neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor 
Clinical Trials Planning Meeting. J Clin Oncol, 2011;29:934-943.
Le Tourneau C, Lee J and Siu L. Dose escalation methods in phase I cancer clinical trials. J Natl 
Cancer Inst, 2009;101:708–20.
Lin Y, Shih, W. Adaptive two-stage designs for single arm phase IIA cancer trials. Biometrics, 
2004;60:482–90.
National Comprehensive Cancer Network. Central Nervous System Cancers (Version 1.2015). 
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National Comprehensive Cancer Network. Melanoma (Version 2.2016). Accessed 
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January 22, 2016.
National Comprehensive Cancer Network. Thyroid Carcinoma (Version 2.2015). Accessed 
January 22, 2016.
Öberg K, Hellman P, Ferolla, Papotti M. Neuroendocrine bronchial and thymic tumors: ESMO 
clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol, 
2012;23(s7):vii120–vii123.
Öberg K, Knigge U, Kwekkeboom D, Perren A. Neuroendocrine gastro-entero-pancreatic 
tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol, 
2012;23(s7):vii124–vii130.
Saunders L, Bankovich A, Anderson W, Aujay M, Bheddah S, Black K, et al. A DLL3-targeted 
antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells 
in vivo. Science Trans Med, 2015;7(302ra136):1–14.
Scher H, Morris M, Stadler W, Higano C, Basch E, Fizazi K, et al. Trial design and objectives 
for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer 
Clinical Trials Working Group 3. J Clin Oncol, 2016;34:1402–18.
Sorbye H, Welin S, Langer S, Vestermark L, Holt N, Osterlund P, et al. Predictive and 
prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal 
neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol, 2013;24:152–60.
Stupp R, Brada M, van den Bent M, Tonn J, Pentheroudakis G. High-grade glioma: ESMO 
clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol, 
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Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 
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Appendices


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13.1
Schedule of Assessments
Screening24
Treatment (Each Cycle)
EOT1
LTFU
Day
–15 to –1
Day
–1
Day 12
Day 2
Day 33
Day 84
Day 15
Day 22
Day 29
Day 36
42 days
(6 weeks) 
after last 
dose
Every 
6–12 
weeks 
thru 
4 years6
Window
–
–
±2 d
–
+1 d
±2 d
±2 d
±2 d
±3 d
±3 d
±3 d
Location
Clinic Visit
X
X
X
X
X
X
X
Virtual Visit
X
X
X
Investigator (MD) present7
X
X
X
X
X
X
Screening, 
Baseline, 
and Safety 
Assessments
Informed Consent
X
Demographics
X
Inclusion/Exclusion Criteria
X
Medical and Surgical History8
X
Malignancy History9
X
Prior Anticancer Treatments10
X
Physical examination
X
X
X
X
X
X
Vital Signs11
X
See 13.2
X
X
X
X
Height
X
Complete Blood Count12
X
X
X
X
X
X
Chemistries13
X
X
X
X
X
X
Coagulation Tests14
X
X
X
Urinalysis15
X
X
X
X
X
X
Hepatitis B and C tests16
X
Pregnancy Test17
X
X
X
Electrocardiogram (ECG)18
X
See 13.2
X
X
Echocardiogram19
X
X
X
Performance Status (ECOG)
X
X
X


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Screening24
Treatment (Each Cycle)
EOT1
LTFU
Day
–15 to –1
Day
–1
Day 12
Day 2
Day 33
Day 84
Day 15
Day 22
Day 29
Day 36
42 days
(6 weeks) 
after last 
dose
Every 
6–12 
weeks 
thru 
4 years6
Window
–
–
±2 d
–
+1 d
±2 d
±2 d
±2 d
±3 d
±3 d
±3 d
Fluid Retention Questionnaire20
X
X
X
X
X
X
X
Daily Weight Diary21
Day 1 predose thru EOT or 30 days after last study treatment, whichever is later
Adverse Events
Procedure-related 
only
Concomitant Medications22
Treatment
Rovalpituzumab tesirine
X
Dexamethasone
X
X
X
Response 
Assessment
Disease/Response Assessment23
X
Subjects will be assessed for response every 6 weeks (± 1 week) counting from C1D1 until week 24, 
and then every 12 weeks thereafter (± 1 week) 
MRI of the Brain25
X
CNS lesions will be assessed every 6 weeks (± 1 week) counting from Cycle 1 Day 1 until week 24, 
then every 12 weeks, thereafter (± 1 week).26
Survival Status
X
PRO27
X
X
X
X
PK and PD
Pharmacokinetics
See 13.2
X5
X5
X5
X5
X
Anti-therapeutic antibody
X
X
Tumor Tissue28
X
X29
X29
Blood Inflammatory Markers30
X
X
Blood Tumor Markers31
X
X
X
Soluble Biomarkers32
X
X
Circulating Tumor Cells33
X
X
X
Serosal Fluid34
Day 1 thru EOT or 30 days after last study treatment, whichever is later
Prostate 
Cancer Only
Serum Total Testosterone
X
99mTc Bone Scintigraphy
X
Bone lesions will be assessed every 6 weeks (± 1 week) counting from Cycle 1 Day 1 until week 24, 
then every 12 weeks, thereafter (± 1 week). 


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Abbreviations for Schedules of Assessments (Table and Footnotes): AE = adverse event; ALT = alanine aminotransferase; ANA = antinuclear antibodies; aPPT = activated 
partial thromboplastin time; AST = aspartate aminotransferase; ∀-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; C = Cycle; CBC = complete blood 
count; CNS = central nervous system; CRP = C-reactive protein; CT = computerized tomography; CTC = circulating tumor cells; d = Day; DLL3 = delta-like protein 3; 
ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; ESR = erythrocyte sedimentation rate; 
HBcAb = Hepatitis B core antibody; HBsAb = Hepatitis B surface antibody, HBsAg,= Hepatitis B surface antigen; HCV = Hepatitis C virus; INR = international normalized ratio; 
LTFU = long-term follow-up; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; PD = progressive disease; PRO = patient reported outcomes; 
PT = prothrombin time; PTT = partial thromboplastin time; RF = rheumatoid factor; RECIST = Response Evaluation Criteria in Solid Tumors; RBC = red blood cell; 
WBC = white blood cell.
Table Footnotes
1)
EOT occurs 42 ±3 days after last dose, or within 7 days of documentation of the decision to discontinue treatment, whichever is later.
2)
Day 1 procedures may be performed within 1 day prior to dosing of study drug in Cycle 1; results from local clinical laboratory tests must be available prior to dose. 
Dexamethasone will be administered on Day -1 to Day 2 of rovalpituzumab dosing.
3)
Assessments are to occur during Cycles 1, 2, and 4, only.
4)
In Cycles 5 and higher, this visit may be reduced to a virtual visit consisting of Fluid Retention Questionnaire only if the previous 4 consecutive cycles lacked any clinically 
significant AEs. 
5)
The PK sample is to be drawn Cycles 1 and 2 only – omitted for retreatment subjects
6)
LTFU occurs every 6 weeks until 6 months, then every 12 weeks until PD or initiation of new anticancer therapy, whichever occurs first. Afterwards, Disease/Response 
Assessment consists of subsequent anticancer therapies and dates, date of progression (if not already captured on study), and survival status. Subjects will be followed for 
survival until death or study termination, whichever occurs first.
7)
Assessments after CXD1 can be done by MD or by PA/NP with MD supervision. Assessments during screening, C1D1, and EOT should be done by an MD.
8)
Medical and Surgical History includes descriptions of conditions or procedures, and dates of onset - offset.
9)
Malignancy History includes tumor type, stage, sites of metastases, mutational status. 
10) Prior Anticancer Treatments include recording of names of specific treatments, dates of administration, response to therapy, and DOR, if known
11) Vital signs include temperature, blood pressure, pulse, respirations, and weight. On treatment days, weight is only assessed once, pre-infusion. 
12) CBC includes WBC count with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), RBC count, platelet count, hemoglobin, and 
hematocrit.
13) Chemistries include electrolytes (sodium, potassium, chloride, and carbon dioxide), creatinine, calcium , phosphorus, magnesium, BUN, estimated glomerular filtration rate, 
glucose, albumin, total protein, amylase, lipase, and liver function tests (total and direct bilirubin, ALT, AST, alkaline phosphatase, lactate dehydrogenase).
14) Coagulation tests include PT, aPTT, PTT, and INR
15) Urinalysis includes dipstick results for color, appearance, specific gravity, pH, glucose, bilirubin, ketones, occult blood, and protein; as well as spot analysis of protein and
creatinine for ratio.
16) Hepatitis B and C tests include HBsAg, HBsAb, HBcAb and HCV antibody. Results that may be consistent with chronic or active infection must be confirmed by PCR tests 
for Hep B and/or C.
17) Pregnancy test consists of blood or urine testing for ∀-hCG in women of child-bearing potential. Repeat testing may be done as requested by the Investigator.


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18) ECG consists of a 12-lead study. ECGs will be done in triplicate at the indicated times.
19) ECHO includes assessment of left LVEF and pericardial effusion. The screening ECHO should be done any time before the first dose of study drug, either during screening or 
pre-dose on C1D1; all ECHOs after C1D1 should be conducted within 4 days before the next dosing.
20) Fluid Retention Questionnaire includes queries of daily weights and worsening or new edema or dyspnea.
21) Subjects will maintain a diary of daily weights.
22) Concomitant medications include names of all concomitant therapies, including dates of administration, dose regimen, route of administration, and purpose
23) CT imaging of the chest, abdomen, and pelvis, and neck (if indicated) for all subjects, for assessment via RECIST v1.1. Subjects who achieve a partial or complete response 
must undergo confirmatory assessment(s) as described in Section 7.3.
24) Standard of Care procedures completed prior to the subject signing ICF, but within the study screening window, may be used as screening procedures.
25) CT of the brain with intravenous contrast may be substituted at the discretion of the Investigator.
26) MRI of the brain is only required after screening when clinically indicated (e.g., if CNS progression is documented).
27) PRO assessments (questionnaires) are required for subjects in Part B of the study (only) at screening, and also on Cycle 2 Day 1, Cycle 2 Day 29, and EOT.
28) Tumor tissue assessment consists of procurement for DLL3 testing of archived, representative tumor tissue, or an optional fresh tumor biopsy, if accessible. With consent from 
the subject, tumor tissue may be obtained prior to the screening period and tested for DLL3 expression. Optional: collection of tumor tissue at progression to better understand 
mechanisms of resistance and expression of DLL3.
29) Optional collection of tumor tissue at progression
30) Inflammatory markers will be assessed locally and will include ESR, CRP, ANA, and RF.
31) Blood Tumor Markers include soluble tumor-specific biomarkers specific to the tumor type (Section 7.5).
32) Soluble Biomarkers consists of blood collection for possible future analysis of soluble factors such as chemokines or cytokines which may have prognostic or 
pharmacodynamic importance in cancer and/or with rovalpituzumab tesirine, e.g., soluble DLL3.
33) CTC assessment includes 1 sample collected from subjects with neuroendocrine prostate cancer for central assessment of CTC and a sample for exploratory analyses of CTC-
associated biomarkers such as DLL3 collected from subjects with large cell neuroendocrine carcinoma (cohort 4), neuroendocrine prostate cancer (cohort 5), and high-grade 
gastroenteropancreatic neuroendocrine carcinoma (cohort 6). Both CTC samples are collected at the following time points: C1D1, EOT, Long Term Follow-Up 2 (12 weeks), 
and time of progression (if not already collected).
34) Clinical assessments should include the following (refer also to Section 7.2.3): Serosal fluid assessment entails procurement, where feasible, of any pericardial, pleural and/or 
ascitic fluid collected as part of routine care (e.g., as part of a therapeutic thoracentesis, pericardiocentesis, or paracentesis), for possible PK, pharmacodynamic and/or 
biomarker testing.


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13.2
Schedule of Day 1 Peridosing Assessments
Predose
Dosing
Postdose
Time
–
0
+30 Minutes   
post SOI*
+2 Hours        
post SOI*
+4 Hours         
post SOI*
+6 Hours        
post SOI*
Window
–30 to 0 Minutes
–
±10 Minutes
±15 Minutes
±30 Minutes
±30 Minutes
Rovalpituzumab Tesirine Administration
X
Vital Signs1
X
X
X
X
Electrocardiogram2
X
X
Pharmacokinetic sample
X
X
X3
*SOI = Start of infusion 
1)
Vital signs according to Appendix 13.1.
2)
ECG (in triplicate) according to Appendix 13.1; up to 180 minutes predose.
3)
The 6 hour PK sample is to be drawn Cycles 1 and 2 only – omitted for retreatment subjects. 


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13.3
Previous Protocol (version 3.0) Cohort 3 (Glioblastoma) Specific Guidance
Protocol version 3.0 included eight separate cohorts enrolling in the following cancer types: 
1. Malignant melanoma 
2. Medullary thyroid cancer (MTC)
3. Glioblastoma (GBM)
4. Large cell neuroendocrine carcinoma (LCNEC) of the lung
5. Neuroendocrine prostate cancer (NEPC)
6. High-grade gastroenteropancreatic neuroendocrine carcinoma (GEP NEC) 
7. Other neuroendocrine carcinoma (NEC), and high grade neuroendocrine tumors (NET) 
8. Solid tumors other than the above
13.3.1 Efficacy Endpoint
Response will be assessed by radiographic imaging at protocol-specified time points. Tumor response 
assessments will be conducted every 6 weeks during active study treatment until 24 weeks, then 
every 12 weeks, thereafter. GBM cancer-specific assessments are described below, in Section 13.3.4.
For GBM subjects only, efficacy will be assessed using Response Assessment in Neuro-Oncology 
(RANO) criteria.
13.3.2 Inclusion Criteria
Measurable disease, defined as at least one tumor lesion ≥10mm in the longest diameter, or a lymph 
node ≥15mm in short-axis measurement, assessed by computerized tomography (CT) scan (by 
RECIST v1.1).  Subjects with GBM must have measurable disease by RANO criteria: Measurable 
disease is defined as bidimensionally contrast enhancing lesions with clearly defined margins by CT 
or magnetic resonance imaging (MRI) scan, with two perpendicular diameters of at least 10 mm, 
visible on two or more axial slices that are preferably, at most, 5 mm apart with 0 mm skip.
13.3.3 Study Activities
Subjects enrolled in cohort 3 (GBM) will follow the study activities for subjects in cohorts 1-8, as 
outlined in Section 6 of the protocol (version 4.0), as well as the Schedule of Assessments for cohort 
1-8 subjects (Table 13.1).  Specific considerations for cohort 3 subjects are provided in this 
section 13.3.
13.3.4 Blood Tumor Markers
Blood tumor markers are NOT collected for Cohort 3, Glioblastoma.
13.3.4 Response Assessment in Neuro-Oncology Criteria
Tumor assessments will be assessed using the RANO criteria as outlined below according to Wen, et 
al, "Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in 
Neuro-Oncology Working Group."


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Table 13-1
Criteria for Determining First Progression Depending on Time from Initial 
Chemoradiotherapy
First Progression
Definition
Progressive disease 
<12 weeks after 
completion of 
chemoradiotherapy
Progression can only be defined using diagnostic imaging if there is new 
enhancement outside of the radiation field (beyond the high-dose region or 80% 
isodose line) or if there is unequivocal evidence of viable tumor on 
histopathologic sampling (e.g., solid tumor areas [i.e., > 70% tumor cell nuclei in 
areas], high or progressive increase in MIB-1 proliferation index compared with 
prior biopsy, or evidence for histologic progression or increased anaplasia in 
tumor).
Note: Given the difficulty of differentiating true progression from 
pseudoprogression, clinical decline alone, in the absence of radiographic or 
histologic confirmation of progression, will not be sufficient for definition 
of progressive disease in the first 12 weeks after completion of concurrent 
chemoradiotherapy.
Progressive disease 
≥12 weeks after 
chemoradiotherapy 
completion
1.
New contrast-enhancing lesion outside of radiation field on decreasing, 
stable, or increasing doses of corticosteroids.
2.
Increase by ≥25% in the sum of the products of perpendicular diameters 
between the first post-radiotherapy scan, or a subsequent scan with smaller 
tumor size, and the scan at 12 weeks or later on stable or increasing doses of 
corticosteroids.
3.
Clinical deterioration not attributable to concurrent medication or comorbid 
conditions is sufficient to declare progression on current treatment but not for 
entry onto a clinical trial for recurrence.
4.
For patients receiving anti-angiogenic therapy, significant increase in 
T2/FLAIR non-enhancing lesion may also be considered progressive disease. 
The increased T2/FLAIR must have occurred with the patient on stable or 
increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy and not be a result of comorbid events 
(e.g., effects of radiation therapy, demyelination, ischemic injury, infection, 
seizures, postoperative changes, or other treatment effects).
FLAIR = fluid-attenuated inversion recovery
Pseudoprogression and Radiation Effects
The proposed new response criteria suggest that within the first 12 weeks of completion of 
radiotherapy, when pseudoprogression is most prevalent, progression can only be determined if the 
majority of the new enhancement is outside of the radiation field (for example, beyond the high-dose 
region or 80% isodose line) or if there is pathologic confirmation of progressive disease. It is 
recognized that the proposed histologic criteria have important limitations, but they provide guidance 
on the type of findings that are suggestive of progressive disease. For patients in whom 
pseudoprogression cannot be differentiated from true tumor progression, enrollment onto trials for 
recurrent gliomas should not be permitted. Patients who remain clinically stable and/or are suspected 
to have pseudoprogression based on metabolic or vascular imaging should continue with their current 
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Enhancement as a Result of Surgery and Other Therapies
Increased enhancement often develops in the wall of the surgical cavity 48 to 72 hours after surgery. 
To avoid interpretation of postoperative changes as residual enhancing disease, a baseline MRI scan 
should ideally be obtained within 24 to 48 hours after surgery and no later than 72 hours after 
surgery. The inclusion of diffusion weighted imaging in the immediate post-operative MRI scan can 
be helpful in determining whether new enhancement developing in the subsequent weeks or months 
is caused by sequelae of ischemia or by tumor recurrence. In addition, a transient increase in 
enhancement that can be difficult to distinguish from recurrent disease can also occur after locally 
administered therapies. These include chemotherapy wafers, immunotoxins delivered by convection 
enhanced delivery, regionally administered gene and viral therapies, immunotherapies, and focal 
irradiation with brachytherapy and stereotactic radiosurgery. Imaging modalities such as perfusion 
imaging, magnetic resonance spectroscopy, and positron emission tomography scans may sometimes 
be helpful in differentiating treatment effects from recurrent tumor. However, no imaging modality 
currently has sufficient specificity to conclusively differentiate recurrent tumor from treatment 
effects, and surgical sampling may occasionally be needed to obtain a definitive diagnosis.
Definition of Clinical Deterioration
The definition of clinical deterioration is left to the discretion of the treating physician, but it is 
recommended that a decline in the KPS from 100 or 90 to 70 or less, a decline in KPS of at least 20 
from 80 or less, or a decline in KPS from any baseline to 50 or less, for at least 7 days, be considered 
neurologic deterioration unless attributable to comorbid events or changes in corticosteroid dose. 
Similarly, a decline in the Eastern Cooperative Oncology Group and WHO performance scores from 
0 or 1 to 2 or 2 to 3 would be considered neurologic deterioration.
For those subjects who have measurable disease post resection, RANO criteria for assessment of CR, 
PR, SD and PD can be applied. See the below tables for the definitions to be used.
Definition of Radiographic Response
Radiographic response should be determined in comparison to the tumor measurement obtained at 
pretreatment baseline for determination of response, and the smallest tumor measurement at either 
pretreatment baseline should be used for determination of progression. Table 1 lists the criteria for 
radiographic changes after therapy. In the event that the radiographic changes are equivocal and it is 
unclear whether the patient is stable or has developed progressive disease, it is permissible to 
continue treatment and observe the patient closely, for example at 4-week intervals. If subsequent 
imaging studies demonstrate that progression has occurred, the date of progression should be the date 
of the scan at which this issue was first raised. The determination of radiographic response after 
treatment with agents that affect vascular permeability is particularly difficult. In these patients, 
consideration should be given to performing a second scan at 4 weeks to confirm the presence of 
response or stable disease. All measurable and nonmeasurable lesions should be assessed using the 


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same techniques as at baseline. Ideally, patients should be imaged on the same MRI scanner, or at 
least with the same magnet strength, for the duration of the study to reduce difficulties in interpreting 
changes.
Patients with nonmeasurable enhancing disease whose lesions have significantly increased in size and 
become measurable (minimal bidirectional diameter of ≥10 mm and visible on at least two axial 
slices that are preferably, at most, 5 mm apart with 0 mm skip) will also be considered to have 
experienced progression. The transition from a nonmeasurable lesion to a measurable lesion resulting 
in progression can theoretically occur with relatively small increases in tumor size (e.g., a 9 × 9 mm 
lesion [nonmeasurable] increasing to a 10 × 11 mm lesion [measurable]). Ideally, the change should 
be significant (>5 mm increase in maximal diameter or ≥25% increase in sum of the products of 
perpendicular diameters of enhancing lesions). In general, if there is doubt about whether the lesion 
has progressed, continued treatment and close follow-up evaluation will help clarify whether there is 
true progression. If there is uncertainty regarding whether there is progression, the patient may 
continue on treatment and remain under close observation (e.g., evaluated at 4-week intervals). If 
subsequent evaluations suggest that the patient is in fact experiencing progression, then the date of 
progression should be the time point at which this issue was first raised.


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Table 13-2
Criteria for Response Assessment Incorporating MRI and Clinical Factors
Response
Criteria
Complete Response
Requires all of the following: complete disappearance of all enhancing 
measurable and nonmeasurable disease sustained for at least 4 weeks; no new 
lesions; stable or improved nonenhancing (T2/FLAIR) lesions; patients must be 
off corticosteroids (or on physiologic replacement doses only); and stable or 
improved clinically.
Note:
Patients with nonmeasurable disease only cannot have a complete response; the 
best response possible is stable disease.
Partial Response
Requires all of the following: ≥50% decrease compared with baseline in the sum 
of products of perpendicular diameters of all measurable enhancing lesions 
sustained for at least 4 weeks; no progression of nonmeasurable disease; no new 
lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower 
dose of corticosteroids compared with baseline scan; the corticosteroid dose at 
the time of the scan evaluation should be no greater than the dose at time of 
baseline scan; and stable or improved clinically.
Note:
Patients with nonmeasurable disease only cannot have a partial response; the best 
response possible is stable disease.
Stable Disease
Requires all of the following: does not qualify for complete response, partial 
response, or progression; stable nonenhancing (T2/FLAIR) lesions on same or 
lower dose of corticosteroids compared with baseline scan. In the event that the 
corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging, and subsequent follow-up 
imaging shows that this increase in corticosteroids was required because of 
disease progression, the last scan considered to show stable disease will be the 
scan obtained when the corticosteroid dose was equivalent to the baseline dose.
Progression
Defined by any of the following: ≥25% increase in sum of the products of 
perpendicular diameters of enhancing lesions compared with the smallest tumor 
measurement obtained either at baseline (if no decrease) or best response, on 
stable or increasing doses of corticosteroids; significant increase in T2/FLAIR 
nonenhancing lesion on stable or increasing doses of corticosteroids compared 
with baseline scan or best response after initiation of therapy* not caused by 
comorbid events (e.g., radiation therapy, demyelination, ischemic injury, 
infection, seizures, postoperative changes, or other treatment effects); any new 
lesion; clear clinical deterioration not attributable to other causes apart from the 
tumor (e.g., seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection, and so on) or changes in corticosteroid dose; 
failure to return for evaluation as a result of death or deteriorating condition; or 
clear progression of nonmeasurable disease.
MRI = magnetic resonance imaging; FLAIR = fluid-attenuated inversion recovery
*
Stable doses of corticosteroids include patients not on corticosteroids.
Note:
All measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline.


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13.4
Performance Status Scales Conversion
ECOG
Karnofsky
Score
Description
Percent
Description
0
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction.
100
Normal, no complaints, no evidence of disease.
90
Able to carry on normal activity; minor signs or 
symptoms of disease.
1
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but ambulatory 
and able to carry out work of a light or 
sedentary nature (e.g., light housework, 
office work).
80
Normal activity with effort; some signs or 
symptoms of disease.
70
Cares for self, unable to carry on normal activity or 
to do active work.
2
In bed <50% of the time. Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities. Up and about more 
than 50% of waking hours.
60
Requires occasional assistance, but is able to care 
for most of his/her needs.
50
Requires considerable assistance and frequent 
medical care.
3
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours.
40
Disabled, requires special care and assistance.
30
Severely disabled, hospitalization indicated. Death 
not imminent.
4
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair.
20
Very sick, hospitalization indicated. Death not 
imminent.
10
Moribund, fatal processes progressing rapidly.
5
Dead.
0
Dead.


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13.5
New York Heart Association (NYHA) Classification
Class I
Patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II
Patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion.
Class III
Patients with marked limitation of activity; they are comfortable only at rest.
Class IV
Patients who should be at complete rest, confined to bed or chair; any physical activity brings on 
discomfort and symptoms occur at rest.


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13.6
Response Evaluation Criteria for Solid Tumors (RECIST) v1.1
Term
Definition
Complete response (CR)
Disappearance of all target lesions. Any pathological lymph nodes must have 
reduction in short axis to <10 mm.
Partial response (PR)
A ≥30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.
Progressive disease (PD)
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 0.5 cm. The appearance of one or 
more new lesions is also considered progression.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study.
New measureable lesions*
Always represents PD.
New nonmeasurable lesions
Always represents PD.
Non-index lesions
Changes contribute to defining best overall response of CR, PR, SD, and PD.
From RECIST v1.1 (Eisenhauer 2009) 
* Measureable lesion must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of 10 mm by CT scan (CT slice thickness ≤5 mm).


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13.7
Guidance for Subjects with Prostate Cancer
For subjects with prostate cancer, the following prostate-specific guidelines will apply.
Additional Study Population Criteria
The following additional inclusion criteria will be applied to the main study criteria (Section 4):
1.
Prostate cancer of predominantly small cell neuroendocrine (NEPC) and/or intermediate 
atypical carcinoma (IAC) histologic differentiation in a primary or metastatic tumor specimen.
2.
Progressive disease by PCWG3 (Scher 2016), RECIST v1.1 (Eisenhauer 2009), or both criteria 
during or within 4 weeks following completion of at least one prior systemic therapy delivered 
in the metastatic disease setting, including at least one of the following:
a.
Progression of nodal or visceral metastasis (computed tomography [CT] scan or magnetic 
resonance imaging [MRI] according to RECIST v1.1).
b. Development of new sites of visceral or nodal metastases. Previously normal (<1.0 cm) 
lymph nodes must have grown by ≥5 mm in the short axis from baseline or nadir and be 
≥1.0 cm in the short axis to be considered to have progressed. 
c.
Progression of bone disease (at least 2 new bone lesions as measured by bone scan).
3.
Surgically or medically castrated with serum testosterone <50 ng/dL (1.7 nM) at screening. Any 
medical castration therapy (subjects who have not undergone orchiectomy) must have been 
initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the duration 
of the study. Subjects with de novo primary small cell carcinoma of the prostate are exempt 
from this criterion.
Duration of Treatment
Subjects will be eligible to continue treatment until unacceptable toxicity, no longer clinically 
beneficial according to PCWG3, withdrawal of consent, or study termination, whichever occurs first. 
In accordance with PCWG3 guidelines, early changes in PSA should not be acted on without other 
evidence of PD, and treatment should be continued for at least 12 weeks to ensure adequate drug 
exposure. 
Allowed Concomitant Therapy
For prostate cancer subjects, ongoing treatment with luteinizing hormone-releasing hormone (LHRH) 
agonists or antagonists, denosumab, or bisphosphonates (e.g., zoledronic acid) is allowed. 


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13.7.1 Additional Assessments for Subjects with Prostate Cancer
!
Tumor assessments will be performed according to RECIST v1.1 for soft tissue lesions and/or the 
PCWG3 for bone lesions
!
PSA levels will be measured and monitored according to the PCWG3 guidance for PSA
PCWG3 Guidance for Bone Lesions
Assessment of bone lesions will be based on radionuclide scans. The outcome of bone scans should 
be recorded as either “new lesions” or “no new lesions.” 
!
For the first scheduled reassessment, new lesions will require a confirmatory bone scan 6 or more 
weeks later. If new lesions are confirmed, the subject will be defined as disease progression in 
accordance with PCWG3, with progression dated as of the first “new lesion” scan.
!
For subsequent scheduled reassessments, new lesions will define the subject as disease 
progression in accordance with PCWG3, with progression dated as of the scan. 
PCWG3 Guidance for PSA
A PSA progression is defined as the time from start of therapy to first PSA increase that is ≥25% and 
≥2 ng/mL above the nadir, and which is confirmed by a second PSA value at least 4 weeks later (i.e., 
a confirmed rising trend).


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13.8
CTCAE v4.03 Grading of Some Relevant AEs
Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Effusions
Ascites
Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated
Symptomatic; medical 
intervention indicated
Severe symptoms; invasive 
intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Pericardial effusion
–
Asymptomatic effusion size 
small to moderate
Effusion with physiologic 
consequences
Life-threatening consequences; 
urgent intervention indicated
Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
Pericardial tamponade
–
–
–
Life-threatening consequences; 
urgent intervention indicated
Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
Pleural effusion
Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated
Symptomatic; intervention 
indicated (e.g., diuretics or 
limited therapeutic 
thoracentesis)
Symptomatic with respiratory 
distress and hypoxia; surgical 
intervention, including chest 
tube or pleurodesis indicated
Life-threatening respiratory or 
hemodynamic compromise; 
intubation or urgent intervention 
indicated
Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough and marked chest 
discomfort.
Edema
Edema face
Localized facial edema
Moderate localized facial 
edema; limiting instrumental 
ADL
Severe swelling; limiting self-
care ADL
–
Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.
Edema limbs
5–10% inter-limb discrepancy in 
volume or circumference at point 
of greatest visible difference; 
swelling or obscuration of 
anatomic architecture on close 
inspection
>10–30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible difference; 
readily apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent deviation from 
normal anatomic contour; 
limiting instrumental ADL
>30% inter-limb discrepancy in 
volume; gross deviation from 
normal anatomic contour; 
limiting self-care ADL
–


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Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.
Edema 
cont.
Edema trunk
Swelling or obscuration of 
anatomic architecture on close 
inspection
Readily apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent deviation from 
normal anatomic contour; 
limiting instrumental ADL
Gross deviation from normal 
anatomic contour; limiting self-
care ADL
–
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area.
Localized edema
Localized to dependent areas, no 
disability or functional 
impairment
Moderate localized edema and 
intervention indicated; limiting 
instrumental ADL
Severe localized edema and 
intervention indicated; limiting 
self-care ADL
–
Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.
Periorbital edema
Soft or non-pitting
Indurated or pitting edema; 
topical intervention indicated
Edema associated with visual 
disturbance; increased 
intraocular pressure, glaucoma 
or retinal hemorrhage; optic 
neuritis; diuretics indicated; 
operative intervention indicated
–
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face.
Labs
Hypo-albuminemia
<LLN–3 g/dL; <LLN–30 g/L
<3–2 g/dL; <30–20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences; 
urgent intervention indicated
Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.
Neutrophil count 
decreased
<LLN–1500/mm3;
<LLN–1.5 x 10e9/L
<1500–1000/mm3; 
<1.5–1.0 x 10e9/L
<1000–500/mm3; 
<1.0–0.5 x 10e9/L
<500/mm3; <0.5 x 10e9/L
Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen.
Platelet count 
decreased
<LLN–75,000/mm3;
<LLN–75.0 x 10e9/L
<75,000–50,000/mm3; 
<75.0–50.0 x 10e9/L
<50,000–25,000/mm3;
<50.0–25.0 x 10e9/L
<25,000/mm3;<25.0 x 10e9/L
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.


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Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Skin 
Erythema multiforme
Target lesions covering <10% 
BSA and not associated with 
skin tenderness
Target lesions covering 10-30% 
BSA and associated with skin 
tenderness
Target lesions covering >30% 
BSA and associated with oral or 
genital erosions
Target lesions covering >30% 
BSA; associated with fluid or 
electrolyte abnormalities; ICU 
care or burn unit indicated
Definition: A disorder characterized by target lesions (a pink-red ring around a pale center).
Skin cont.
Palmar-plantar 
erythrodysesthesia 
syndrome
Minimal skin changes or 
dermatitis (e.g., erythema, 
edema, or hyperkeratosis) 
without pain
Skin changes (e.g., peeling, 
blisters, bleeding, edema, or 
hyperkeratosis) with pain; 
limiting instrumental ADL
Severe skin changes (e.g., 
peeling, blisters, bleeding, 
edema, or hyperkeratosis) with 
pain; limiting self-care ADL
–
Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet.
Photosensitivity
Painless erythema and erythema 
covering <10% BSA
Tender erythema covering 
10-30% BSA
Erythema covering >30% BSA 
and erythema with blistering; 
photosensitivity; oral 
corticosteroid therapy indicated; 
pain control indicated (e.g., 
narcotics or NSAIDs)
Life-threatening consequences; 
urgent intervention indicated
Definition: A disorder characterized by an increase in sensitivity of the skin to light.
Rash maculo-papular
Macules/papules covering <10% 
BSA with or without symptoms 
(e.g., pruritus, burning, tightness)
Macules/papules covering 
10-30% BSA with or without 
symptoms (e.g., pruritus, 
burning, tightness); limiting 
instrumental ADL
Macules/papules covering 
>30% BSA with or without 
associated symptoms; limiting 
self-care ADL
–
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the most common 
cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.
From CTCAE v4.03


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13.9
Fluid Retention Questionnaire
[EXAMPLE: Refer to the study binder for the actual document]
Fluid Retention Questionnaire for Study SCRX001-006
Subject ID:____________________
Over the past 7 days, or since the last time this questionnaire was asked:
1.
What have your daily weights been? 
!
Please weigh yourself at the same time each day and record the date and your weight 
for that day below. Weights should be taken without outer garments such as hats, 
coats or shoes. Measurements while in light indoor clothing only, or undergarments 
only, are acceptable; however, please try to use the same or similar clothing 
(including any accessories or jewelry) from day to day when measuring weights.
!
Please complete one questionnaire for every 7 day/1 week period.
Date (DD/MMM/YYYY)
Weight (circle one: lb or kg)
lb or kg
lb or kg
lb or kg
lb or kg
lb or kg
lb or kg
lb or kg
2.
Have you noticed any new or worsening edema – e.g., swelling of the ankles or legs 
during the days above? 
☐Yes or ☐No
3.
Have you noticed any new or worsening shortness of breath during the days above?
☐Yes or ☐No
4.
Please sign below to confirm that you have completed this questionnaire.
____________________________________________
Date: __________________


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13.10 Disease Related Events Associated with Solid Tumors
Abdominal pain
Asthenia
Back pain
Bone pain
Cough
Decreased appetite
Deep vein thrombosis
Dysphagia
Dysphonia 
Dyspnea
Esophageal obstruction
Fatigue
General physical health deterioration
Horner's syndrome
Ileus
Infection*
Jaundice
Lymphadenopathy
Malaise
Malignant pleural effusion
Malignant ascites
Metastasis
Nausea
Non-cardiac chest pain
Opportunistic infection*
Paraneoplastic syndrome
Pathological fracture 
Pneumonia*
Pruritus
Pulmonary embolism
Pyrexia
Sepsis*
Septic shock*
Small intestinal obstruction
Superior vena cava syndrome
Tumor pain
Vocal cord paralysis 
Vomiting
Weight decreased
* Includes life threatening or fatal events.


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13.11 Investigator Signature Page
Investigator Statement and Signature
I have read the attached protocol entitled “An Open-Label Study of Rovalpituzumab Tesirine in 
Subjects with Delta-Like Protein 3-Expressing Advanced Solid Tumors.”
I understand and agree to the provisions of the protocol. I accept the responsibilities included 
herein in my role as Principal Investigator for the study and I will ensure that all Subinvestigators 
and study personnel comply with the provisions of this protocol.
Investigator Signature
Date
Investigator Name, Printed


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13.12 Document History
Version
Date
Version 1
27 January 2016
Version 2
21 July 2016
Version 3
06 September 2017
Version 4
19 October 2018
13.12.1
Protocol Amendment Version 4.0: Summary of Change
Protocol Title:
An Open-Label Study of Rovalpituzumab Tesirine in 
Subjects with Delta-Like Protein 3-Expressing Advanced 
Solid Tumors
Protocol Number:
SCRX001-006
Amendment Version 4.0:
19 October 2018
Supersedes Amendment Version 3.0:
06 September 2017
Main Changes to the Protocol:
The main purposes of this amendment are:
1)
Close enrollment to Cohort 3 (Glioblastoma) 
2)
Clarify enrollment criteria for cohort 4 (large cell neuroendocrine carcinoma)
3)
Clarify response assessment schedule 
4)
Add guidance for the monitoring and management of Edema;
5)
Add guidance for the monitoring and management of Pneumonitis;
6)
Add guidance for the monitoring and management of Skin Reactions;
7)
Clarify photodocumentation requirements for skin reactions; 
8)
Clarify pregnancy reporting requirements for pregnant study subjects and partners;
9)
Clarify AE reporting requirements including for deaths related to disease progression;
10) Update PK sample collection requirements;
11) Clarify CTC sample collection;
12) Clarify research tests associated with tumor tissue specimens;
13) Clarify sample collection requirements for retreatment subjects;
14) Clarify sample collection schedule for Blood Inflammatory Markers, Blood Tumor Markers, and Soluble 
Biomarkers;
15) Clarify sample retention guidelines;
16) Clarify that CT imaging of the chest, abdomen, and pelvis, and neck (if indicated), for assessment via 
RECIST v1.1 should be completed for all subjects;
17) Updates to align with the Recommended Phase 2 Dose (RP2D);
18) Clarify that Standard of Care procedures completed prior to the subject signing ICF, but within the 
screening window, may be used as screening procedures;
19) Update sponsor name to AbbVie Inc.;
20) Update Medical Monitor contact phone number;
21) Remove AbbVie Safety contact phone number;
22) Clarify that the sponsor can close a cohort at their discretion;
23) Relocate the cohort 3 (Glioblastoma) inclusion criteria, study activities, response assessment criteria, and 
other applicable language to the Appendix;
24) Make administrative changes of typographical errors, minor language and word revision as needed 
throughout the document;
All substantive changes to protocol are summarized below; wherever possible, new text is bold and deleted text is 
shown by strike through text.
Additional editorial and administrative changes were made to reflect current administrative details, correct 
typographical errors, and add clarity; such changes are not itemized below.


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Section
Revision
Rationale
Cover Page
Revised Medical Monitor Contact Number:
, MD, PhD
Novella Clinical
1700 Perimeter Park Drive
Morrisville, NC 27560 USA
Phone: 
 
Updated to 
provide new 
Medical Monitor 
contact 
information.
Synopsis
The Synopsis has been updated to reflect the changes made throughout 
the protocol body.
Updated to align 
with the revised 
protocol body.
Definitions of 
Abbreviations 
and Terms
The List of Abbreviations has been updated to reflect the changes made 
throughout the protocol. 
Updated to align 
with the revised 
protocol body.
Section 1.2
Rovalpituzumab 
Tesirine
Revised Paragraph 2:
In a Phase 1 study (Study SCRX16-001), rovalpituzumab tesirine 
dosed at 0.2 – 0.4 mg/kg exhibited encouraging efficacy in recurrent 
SCLC, achieving a 31% (8/26) and 85% (22/26) central review-
adjudicated confirmed objective response rate (ORR) and clinical 
benefit rate (CBR), respectively, in subjects whose tumors expressed 
DLL3 in ≥ 50% of cells.  Median overall survival was 7.7 months in 
DLL3 ≥ 50% subjects at all dose levels, with a 1-year survival rate of 
30%%. The most frequent grade 3 or worse treatment-related 
adverse events in 74 patients 
with small-cell lung cancer were thrombocytopenia (11%), pleural eff 
usion (8%), and increased lipase (7%). Drug-related serious adverse 
events occurred in 28 (38%) of 74 patients. The recommended phase 
2 dose and schedule is 0.3 mg/kg every 6 weeks.% (AbbVie 
Stemcentrx, data on file). A Phase 1 study with rovalpituzumab tesirine, 
SCRX16 001, has demonstrated encouraging results with an objective 
response rate (ORR) of 44% and a clinical benefit rate (CBR) of 78% in 
relapsed or refractory DLL3hi (delta like protein 3 positive in ≥50% 
tumor cells) SCLC subjects treated in the expansion cohorts of 0.2 mg/kg 
Q3wk (every 3 weeks) and 0.3 mg/kg Q6wk (every 6 weeks). In all 
expansion cohort SCLC subjects, regardless of DLL3 expression, the 
ORR and CBR were 23% and 66%, respectively (Stemcentrx data on 
file). Therefore, rovalpituzumab tesirine appears to be an active 
anticancer therapy.
New Paragraph 3:
In a Phase 2 SCRX001-002 (TRINITY) study in patients with SCLC 
recurrent after at least two systemic chemotherapy regimens, 
rovalpituzumab tesirine dosed at 0.3 mg/kg every 6 weeks for two 
cycles (with an option for additional two cycles upon progression 
occurring ≥ 12 weeks after the second dose) had shown confirmed 
objective response rate of 16%, progression-free survival of 3.9 
months and overall survival of 5.6 months in 3rd line DLL3High 
patients.  Of note, prolonged stable disease with target lesion size 
reduction has been observed in a considerable number of patients 
receiving additional post-progression cycles of rovalpituzumab 
Updated the 
section based on 
updated 
data/information 
now available.


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tesirine. Drug related grade 3 or above treatment emergent adverse 
events that occurred in at least 10 subjects include thrombocytopenia 
(11%), photosensitivity reactions (7%), anemia (4%), fatigue (4%), 
and pleural effusion (4%). Adverse events leading to study treatment 
discontinuation occurred in7% of subjects (AbbVie Stemcentrx, data 
on file).
Section 3.1
Summary of 
Study Design
Revised Paragraph 1:
This is a multicenter, open-label study of rovalpituzumab tesirine in 
subjects with DLL3 expressing advanced solid tumors. The study will 
include 8 7 cohorts of subjects with the following cancers:
Revised Bullet 4:
Large cell neuroendocrine carcinoma (LCNEC) of any origin
Added Paragraph 2:
As of protocol version 4.0, cohort 3 (Glioblastoma) is closed to 
enrollment. Specific guidance for cohort 3 (Glioblastoma) subjects 
(protocol version 3.0) are provided in Appendix 13.3.
Updated to align 
with the closure of 
cohort 3 
(Glioblastoma).
Updated to allow 
enrollment of 
LCNEC from 
tumor types of any 
origin.
Updated to clarify 
closure of cohort 3 
(Glioblastoma) 
and note that 
specific guidance 
for glioblastoma 
subjects has been 
moved to the 
Appendix.
Section 4.1
Inclusion Criteria
Revised Bullet 3:
Measurable disease, defined as at least one tumor lesion ≥10 mm in the 
longest diameter, or a lymph node ≥15 mm in short-axis measurement, 
assessed by computerized tomography (CT) scan (by RECIST v1.1). 
Subjects with GBM must have measurable disease by RANO criteria: 
Measurable disease is defined as bidimensionally contrast enhancing 
lesions with clearly defined margins by CT or magnetic resonance 
imaging (MRI) scan, with two perpendicular diameters of at least 10 mm, 
visible on two or more axial slices that are preferably, at most, 5 mm 
apart with 0 mm skip.
Updated to align 
with the closure of 
cohort 3 
(Glioblastoma).
Section 4.3.1 
Contraception for 
Female Subjects
Removed Bullet 4:
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
Updated to align 
with current 
requirements for 
contraception.
Section 4.4.1 
Discontinuation 
of Study Drug
Revised Bullets 1-5:
• Progressive disease (PD) per RECIST 1.1
• Adverse event (AE)
• Investigator Physician decision
• Study terminated by sponsor Subject decision, Non AE
• Withdrawal by subject
• Other
Updated bullets to 
align with 
language present 
in EDC
Section 4.4.2
Subject 
Discontinuation 
from Study
Revised Bullets 1-2, 4, 6-7:
• Withdrawal by subject Subject withdrawal of consent
• AE
• Death
• Investigator Physician decision
• Lost to follow-up
• Significant noncompliance to protocol
• Study terminatedion by Sponsor
• Other
Updated bullets to 
align with 
language present 
in EDC


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Table 5-1
Toxicities 
Requiring Dose 
Reduction
Updated Serosal Effusions and Edema, Toxicities Requiring 2 Dose Level 
Reductions at First Occurrence, and Toxicities Requiring 
Discontinuation of Investigational Product at First Occurrence 
Subsections:
Toxicities Requiring 1 Dose Level Reduction at First Occurrence
# 2nd occurrence = 2nd dose level reduction
# Discontinue after 2 dose level reductions 
Serosal Effusions and 
Edema
!
Grade 2 or higher pericardial effusion
!
Grade 2 3 or higher pleural effusion 
!
Grade 2 3 or higher ascites
!
Grade 2 3 or higher peripheral edema
Hematology
!
Grade 3 thrombocytopenia (platelets <50.0–
25.0 × 109 /L)
!
Grade 4 neutropenia (ANC <0.5 × 109 /L)
lasting more than 7 days
!
Grade 3 or higher febrile neutropenia (with 
ANC <1.0 × 109 /L) (concurrent fever ≥38.3° 
C)
Laboratory Abnormalities
!
Clinically significant Grade 3 or higher non-
hematologic laboratory abnormality that 
does not resolve to Grade 0/1 or baseline 
within 7 days
!
Any other Grade 3 or 4 laboratory 
abnormality considered clinically significant 
and treatment-related; adjustments to these 
guidelines may occur based on the clinical 
judgment of the Investigator and with 
approval of the Medical Monitor and 
Sponsor
!
Grade 2 hypoalbuminemia
Other Adverse Events
!
Grade 3 photosensitivity reaction 
(Section 5.5.2)
!
Grade 3 or Grade 4 nonlaboratory treatment-
related toxicity, with the exception of 
fatigue, asthenia, nausea, or other 
manageable constitutional symptom
Toxicities Requiring 2 Dose Level Reductions at First Occurrence
# Discontinue at second occurrence 
!
Grade 3 serosal effusions (pleural effusions, pericardial effusions, 
and ascites) and edema
!
Grade 2 capillary syndrome
!
Grade 4 thrombocytopenia/ Grade 3 thrombocytopenia with bleeding/ 
Need for platelet transfusion
!
Grade 4 febrile neutropenia
!
Grade 4 (>20.0 × ULN) ALT or AST or Grade 3 (>5.0–20.0 × ULN) 
ALT or AST elevation with concomitant total bilirubin Grade 2 or 
Updated to align 
with recent safety 
updates


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higher (>1.5 ULN)
!
Grade 3 or higher hypoalbuminemia (<2 g/dL)
!
Grade 2 pneumonitis
Toxicities Requiring Discontinuation of Investigational Product at First 
Occurrence
!
Grade 4 photosensitivity or skin reaction (Section 5.5.2)
!
Drug induced liver injury is confirmed (refer to Section 5.5.3 for 
definition)
!
Life threatening Infusion related reaction or hypersensitivity
!
Grade ≥3 pneumonitis
Section 5.5.2
Skin Reactions
Added Paragraph 1:
Photosensitivity was reported in patients treated with Rova-T 
including severe events.  Photosensitivity reactions may occur hours 
to days after sun exposure. The median time to onset was 30 days 
(range 1 to 247 days). Patients should be advised to avoid direct and 
indirect sun exposure as much as possible during Rova-T treatment 
and for 30 days after the last dose. If unavoidable, patients should 
wear protective clothing and sunglasses, and use a broad-spectrum 
sunscreen and lip balm (SPF 30 or greater). 31 – 90 days after last 
dose, the patient may resume outdoor activities with appropriate sun 
protection including broad brimmed hat, protective clothing and 
sunscreen SPF 30 or higher. Skin reactions should be evaluated 
promptly and treated with topical or systemic steroids as indicated 
(refer to Table 5-2). Rova-T dose should be delayed, reduced or
discontinued as necessary (refer to Table 5-1).
Revised Paragraph 2:
All cutaneous reactions which develop during treatment warrant 
prompt evaluation. Skin toxicity with rovalpituzumab tesirine may 
consist of photosensitivity but possibly other reactions such as palmar-
plantar erythrodysesthesia or erythema multiforme. As such, development 
of a cutaneous reaction during treatment warrants prompt evaluation by 
the Investigator or designee:
Revised Bullets 1 and 2 :
• If clinically consistent with photosensitivity, the AE may should be 
reported as such (using medically accurate and descriptive AE 
terminology), and managed as described below in Table 5 2. 
• If notFor clinically more severe cases of photosensitivity or ifIf not  
clinically not consistent with photosensitivity, the following should be 
done, : PhotodocumentationPphotodocumentation to facilitate later 
review by the Sponsor or designee may occur.
Revised Sub Bullet 1:
• Formal evaluation by a dermatologist, including possible skin biopsy to 
rule out alternative etiologies, such as erythema multiforme which may 
warrant discontinuation of study drug, and to facilitate the most 
appropriate terminology for AE reporting, is recommended.
Added Sub Bullet 2:
• Photodocumentation of skin toxicity, if available, may be requested 
by the TAMD. The investigative site will take measures to protect the 
Updated to align 
with recent safety 
updates
Updated to align 
with recent safety 
updates
Clarifies 
photodocumentati
on guidelines for 
photosensitivity
Clarifies 
photodocumentati
on guidelines for 
photosensitivity
Clarifies 
photodocumentati
on guidelines for 
photosensitivity


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identity of the patient. These measures include taking the photograph 
very close to the affected skin region to exclude facial features, or if 
facial features cannot be excluded due to the location of the skin 
reaction, covering identifying features (such as the eyes) with a black 
rectangle.
Section 5.5.4
Monitoring and 
Management of 
Edema
Added New Section; refer to protocol body Section 5.5.4
Update to align 
with recent safety 
updates
Section 5.5.5 
Monitoring and 
Management of 
Pneumonitis
Added New Section; refer to protocol body Section 5.5.5
Update to align 
with recent safety 
updates
Section 6.3.2 
Day 1 (±2 Days)
Revised Bullet 13:
• Blood sample for PK – Should be drawn within 30 minutes prior to the 
infusion, and then post infusion at 30 minutes after start of infusion (±10 
minutes). In Cycles 1 and, 2, and 4 of subjects in Part A, an additional 
sample will be taken at 6 hour (±30 minutes). The 6 hour PK sample is 
required for Cycles 1 and 2 only - omitted for retreatment subjects.
Revised Bullet 18:
• Circulating tumor cells (CTCs), collected at Cycle 1 Day 1. (Section 
7.5.5)
Clarify PK sample 
collection  
Clarify CTC 
sample collection
Section 6.3.4
Day 3 (Window 
+1 Day) of 
Cycles 1, 2, and 4 
Only
Revised Bullet 2:
• Blood sample for PK for Cycles 1 and 2 only – omitted for 
retreatment subjects
Clarify PK sample 
collection
Section 6.3.5
Days 8 and 15 
(±2 Days) and 29 
(±3 Days)
Revised Bullet 8:
• Blood sample for PK for Cycles 1 and 2 only – omitted for 
retreatment subjects
Clarify PK sample 
collection
Section 6.3.7
Within 7 Days 
Prior to the Next 
Dose
Removed Section:
The following assessments should be performed within the time frame 
and at a frequency determined by the subject’s dosing schedule:
• Disease assessment consisting of CT scans of the chest, abdomen, and 
pelvis (and neck if indicated; Section 7.3)
• MRI of the brain if clinically indicated (e.g., if CNS progression has 
been documented previously). CT of the brain with intravenous contrast 
may be substituted at the discretion of the Investigator.
• Blood inflammatory markers (Section 7.5.2)
• Blood tumor markers (Section 7.5.3)
• Soluble biomarkers (Section 7.5.4)
• CTCs (Section 7.5.5)
• Prostate cancer subjects only: 99 mTc Bone Scintigraphy, as clinically 
indicated in accordance with the institutional standard of care, but at a 
minimum of every 12 weeks (Section 7.3).
Corrected the 
sample collection 
to align with 
protocol schedule 
of assessments. 
Moved scans to a 
new section 6.3.7 
to align with 
updated guidance. 
Section 6.3.7
Disease 
Assessment
Added Section:
• Disease assessment consisting of CT scans of the chest, abdomen, 
and pelvis (and neck if indicated; Section 7.3). Tumor response will 
be assessed every 6 weeks counting from Cycle 1 Day 1, preferably 
before each dosing if possible, until 24 weeks, then every 12 weeks, 
thereafter.
• MRI of the brain – if clinically indicated (e.g., if CNS progression 
has been documented previously). CT of the brain with intravenous 
Clarify response 
assessment 
schedule to allow 
for consistency in 
response 
assessment 
collection


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contrast may be substituted at the discretion of the Investigator. CNS 
lesion will be assessed every 6 weeks counting from Cycle 1 Day 1, 
preferably before each dosing if possible, until 24 weeks, then every 
12 weeks, thereafter.
• Prostate cancer subjects only: 99 mTc Bone Scintigraphy, will be 
assessed every 6 weeks counting from Cycle 1 Day 1, preferably 
before each dosing if possible, until 24 weeks, then every 12 weeks, 
thereafter (Section 7.3).).
Section 7.1
Screening/Baselin
e Assessments
Added a Note to the Section:
Only subjects who meet all inclusion and exclusion criteria specified in 
Section 4 (and Appendix 13.6, for prostate cancer subjects) will be 
enrolled in this study. 
Absence of active CNS tumor or metastases will be confirmed by MRI of
the brain. CT of the brain with intravenous contrast may be substituted at 
the discretion of the Investigator.
Demographics include age, gender, and race.
Subject medical history includes a thorough review of significant past 
medical history, current conditions, smoking history, any diagnosis and 
treatment for prior malignancies, including response to treatment, and any 
concomitant therapies.
Malignancy history should include tumor type, stage, grade and grading 
system, sites of metastases, and mutational status. The latter should 
include, at least, status of BRAF for melanoma subjects, and RET for 
MTC subjects.
Standard of Care procedures completed prior to the subject signing 
ICF, but within the study screening window, may be used as 
screening procedures.
Clarify window 
associated with 
SOC screening 
assessments.
Section 7.3
Radiographic 
Response/Efficac
y Assessments
Revised Paragraph 2:
Diagnostic quality, spiral CT scans are recommended; other methods may 
be used if performed consistently throughout the study for each individual 
subject. Positron emission tomography (PET) and/or 
octreotide/somatostatin scans may be used in an ancillary manner; 
however, no decisions relating to PD may be made based on PET or 
octreotide/somatostatin scans alone. Clinical response will be determined 
by the Investigator at each assessment according to RECIST v1.1 
(Appendix 13.5; Eisenhauer 2009), and/or for prostate cancer subjects, 
PCWG3 criteria (Appendix 13.6). GBM will be assessed using RANO 
criteria (refer to Appendix 13.7).
Updated to align 
with the removal 
of cohort 3 
(Glioblastoma)
Section 7.4 
Pharmacokinetic 
Assessments
Revised Paragraphs 1-2:
Blood samples for PK and ATA testing will be collected at the time 
points throughout the study as indicated in Appendices 13.1 and 13.2 for 
incorporation into an integrated population PK analysis. A population PK 
analysis may be reported separately.
Sensitive, qualified assays will be used to measure blood plasma
concentrations of rovalpituzumab tesirine ADC (SC16LD6.5) and).  
Plasma concentrations of rovalpituzumab total antibody and blood 
concentrations of SC-DR002, the small molecule component of 
rovalpituzumab tesirine, may also be measured if deemed necessary 
and appropriate. A qualified immunoassay will be used to assess ATA 
against rovalpituzumab tesirine.
Clarify PK sample 
collection
Section 7.5
Pharmacodynami
c and Biomarker 
Assessments
Added Paragraph 2:
AbbVie (or people or companies working with AbbVie) will store the
samples in a secure storage space with adequate measures to protect 
confidentiality. The samples may be retained while research on 
rovalpituzumab tesirine (or drugs of this class) or this disease and 
related conditions continues, but for no longer than 20 years after 
Clarify sample 
retention 
guidelines


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study completion, or per local requirement.
Section 7.5.1 
Tumor Tissue
Revised Paragraphs 1-2:
Tumor tissue, consisting of a representative archived specimen, or a fresh 
tumor biopsy, will be assessed at baseline for expression of DLL3 by 
methods such as but not necessarily limited to immunohistochemistry 
(Section 7.1.1). Additional studies, such as routine hematoxylin and eosin 
for morphology and histological classification, IHC for confirmation of 
diagnosis (e.g., for synaptophysin, chromogranin-A, or CD56 for 
neuroendocrine tumors, or HMB45, S100, or MART-1 for melanoma), or 
scoring of immune infiltrates (e.g., IHC for CD3+, CD4+, CD8+, and 
Foxp3+ cells) may be performed. Tumor material may also be utilized 
for exploratory research that includes assessments of nucleic acid or 
protein based biomarkers of drug sensitivity, resistance, or disease 
biology and development of a companion diagnostic assay. When 
fresh tumor biopsies are performed, tissue may also be collected for 
exploratory studies, such as but not necessarily limited to assays of drug 
sensitivity or resistance.
At PD, an optional tumor biopsy may be performed for the assessment of 
expression of DLL3 and/or execution of additional studies, such as but 
not necessarily limited to scoring of immune infiltrates or assessment of 
molecular pathways related to the response to rovalpituzumab tesirine. 
Tumor material may also be utilized for exploratory research that 
includes assessments of nucleic acid or protein based biomarkers of 
drug sensitivity, resistance, or disease biology and development of a 
companion diagnostic assay. Additional instructions will be provided in 
the laboratory manual.
Clarify potential 
uses for collected 
tumor tissue 
specimens
Table 7-1
Disease-Specific 
Blood Tumor 
Markers
Revised Table Note:
Note: Blood tumor markers are NOT collected for Cohort 3, 
Glioblastoma, or Cohort 8, Other Solid Tumors.
Updated to align 
with the removal 
of cohort 3 
(Glioblastoma)
Section 7.5.5 
Circulating 
Tumor Cells
Revised Section:
At the indicated times, blood samples from subjects with neuroendocrine 
prostate cancer will be collected for assessment and characterization of 
CTC as a possible reflection of disease burden for central processing at 
all sites. A second sample for exploratory analyses of CTC-associated 
biomarkers, such as DLL3, will be collected from subjects with large cell 
neuroendocrine carcinoma (cohort 4), neuroendocrine prostate 
cancer (cohort 5), and high-grade gastroenteropancreatic 
neuroendocrine carcinoma (cohort 6) at specific sites based on 
feasibility.
Clarify CTC 
sample collection
Section 8.1.1.1
Adverse Events
Revised Paragraph 3:
Worsening in severity of a reported AE should be reported as a new AE. 
Laboratory abnormalities and changes in vital signs are considered to be 
AEs only if they result in discontinuation from the study, necessitate 
therapeutic medical intervention (including interruption/dose reduction 
of study drug, starting or discontinuing medication, etc.), [meets 
protocol specific criteria (refer to Sections 5.5 and 8.1 regarding toxicity 
management)] and/or if the Investigator considers them to be AEs.
Clarify medical 
intervention as it 
requires to AEs
Section 8.1.4
Deaths
Revised Paragraph 2:
Deaths that occur during the protocol specified AE reporting period 
(Section 8.1.5) that are more likely related to PD will therefore be 
considered as an expected AE and will not be subject to expedited 
reporting. to regulatory agencies. These SAEs events should be captured
reported as “disease progressionmalignant neoplasm progression” and 
also recorded on the AE eCRF. After the AE reporting period, deaths 
attributed to PD under study should be recorded only on the end of study 
Clarify reporting 
requirements for 
deaths related to 
disease 
progression


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(EOS) eCRF.
Section 8.1.6 
Adverse Event 
Reporting
Removed AbbVie Safety Contact Number:
For safety concerns, contact the Oncology Safety Management Team at:
AbbVie Oncology Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:
Revised Medical Monitor Contact Number:
, MD, PhD
Novella Clinical
1700 Perimeter Park Drive
Morrisville, NC 27560 USA
Phone: 
 
Updated to 
provide current 
AbbVie Safety 
contact 
information
Updated to 
provide new 
Medical Monitor 
contact 
information.
Section 8.1.7
Pregnancy 
Reporting
Revised Paragraph 3:
Information regarding a pregnancy occurrence in a study subject and the 
outcome of the pregnancy will be collected. In the event of a pregnancy 
occurring in the partner of an enrolled subject, written informed consent 
for release of medical information from the partner must be obtained prior 
to the collection of any pregnancy-specific information, and the 
pregnancy will be followed to outcome. In the event a study subject or 
the partner of an enrolled subject delivers a baby, they will be asked 
to provide information including the following will be requested: date 
of delivery, birth weight and length, boy or girl, problems during 
pregnancy or delivery, and if the baby has any birth defects.
Clarify pregnancy 
reporting 
requirements for 
study subject or 
pregnant partner
Section 8.2.3
Events 
Commonly 
Associated in 
Study Population 
with Advanced 
Solid Tumors 
and/or 
Progression of 
Underlying 
Malignancy
Revised Paragraph 2:
A list of AEs associated with advanced solid tumors is provided in 
Appendix 13.10. These AEs are preferred terms coded according to the 
latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary; the AEs may occur alone or in various 
combinations and are considered expected for reporting purposes for this 
protocol. Although exempted from expedited reporting to Health 
Authorities and IRBs as individual cases, if these AEs meet serious 
criteria these SAEs must be reported to AbbVie within 24 hours of the 
site being made aware of the SAE (as required in Section 8.1.6). For 
deaths related to disease progression (coded to malignant neoplasm 
progression), the date and cause of death will be recorded on the 
appropriate case report form (CRF), but the event will not be expedited as 
an Individual Case Safety Report (ICSR) to regulatory authorities 
(Section 8.1.4).
Clarify reporting 
requirements for 
AEs related to 
disease 
progression
Section 8.3
Appropriateness 
of Measurements
Revised Paragraph 2:
Response will be assessed according to RECIST v1.1 (Eisenhauer 2009), 
which includes standard criteria for evaluating response in solid tumors. 
Prostate cancer is assessed by PCWG3 criteria and GBM will be assessed 
according to RANO Criteria. The intervals of evaluation in this protocol 
are appropriate for disease management.
Updated to align 
with the removal 
of cohort 3 
(Glioblastoma)
Section 10.1
Revised Paragraph 2:
Updated to align 


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Determination of 
Sample Size
In Part B, up to approximately 174 subjects may be enrolled, including 
approximately 19 subjects in each of the 56 disease-specific cohorts. The 
rationale for the sample size is based on the assumption that an ORR of 
around 15% would be indicative of efficacy worthy of further 
investigation given the advanced cancers and extensive treatment history 
in this study population. Additionally, an ORR below 5% would provide 
evidence of an ineffective treatment. The goal of the efficacy analyses is 
to provide a preliminary signal that the response rate may potentially be 
within that target range.
with the removal 
of cohort 3 
(Glioblastoma)
Section 10.3.8
Pharmacokinetic 
and 
Pharmacodynami
cs Analysis
Revised Paragraph 1:
Data from the Pharmacokinetic-Evaluable Set will be used in the analysis 
of PK and Pharmacodynamics endpoints. The PK of rovalpituzumab 
tesirine will be estimated from concentration-time data using non-
compartmental methods. The reporting of PK parameters will be 
determined based on the final parameter analysis on the available data. 
The PK parameters that may to be assessed may include, as appropriate:
Revised Bullets 2, 5, 6, and 8:
• Cmax     Maximum plasma concentration 
• AUC0 %     Area under the plasma concentration-time curve within a 
dosing interval
• Tmax     Time of Cmax 
• Ctrough     Plasma concentrations at trough
• T1t1/2     (Apparent) Terminal terminal half-life 
• AR
Accumulation ratios for exposure related PK parameters
• CL     Plasma clearance 
• VssVdβ     Steady state vVolume of distribution
Revised Continued Paragraph 1:
The above parameters will be summarized by descriptive statistics using 
the five number summary
Clarify PK sample 
analysis
Section 11.6
Protocol 
Amendments and 
Study 
Termination
Revised Paragraph 2:
The Sponsor may close a cohort at their discretion, or terminate the 
study at any time. The IRB/IEC must be advised in writing of study 
completion or early termination.
Clarify Sponsor 
option for cohort 
closure
Appendix 13.1
Schedule of 
Assessments
Revised Appendix 13.1.
Revised Footnote 19:
ECHO includes assessment of left LVEF and pericardial effusion. The 
screening ECHO should be done any time before the first dose of study 
drug, either during screening or pre-dose on C1D1; all ECHOs after
C1D1 should be conducted within 4 days before the next dosing.
Revised Footnote 23:
CT imaging of the chest, abdomen, and pelvis, and neck (if indicated) for 
all subjects, for assessment via RECIST v1.1. Subjects who achieve a 
partial or complete response must undergo confirmatory assessment(s) as 
described in Section 7.3.
Updated to align 
with the revised 
protocol body
Clarify collection 
requirements for 
the screening 
ECHO
Clarify collection 
requirements for 
CT imaging of the 
chest, abdomen, 
pelvis, and neck 
(if indicated)


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Revised Footnote 33:
CTC assessment includes 1 sample collected from subjects with 
neuroendocrine prostate cancer for central assessment of CTC, 
implemented at all sites, and a second sample for exploratory analyses of 
CTC-associated biomarkers such as DLL3, implemented only at specific 
sites based on feasibility collected from subjects with large cell 
neuroendocrine carcinoma (cohort 4), neuroendocrine prostate 
cancer (cohort 5), and high-grade gastroenteropancreatic 
neuroendocrine carcinoma (cohort 6). Both CTC samples are 
collected at the following time points: C1D1, EOT, Long Term 
Follow-Up 2 (12 weeks), and time of progression (if not already 
collected).
Clarify CTC 
sample collection
Appendix 13.2
Schedule Day 1 
Peridosing 
Assessments
Revised Footnote 3;
The 6 hour PK sample PK sample is to be drawn Cycles 1 and, 2, and 4 
only. – omitted for retreatment subjects.
Updated to align 
with the revised 
protocol body
Appendix 13.3
Previous Protocol
(version 3.0) 
Cohort 3 
(Glioblastoma) 
Specific 
Guidance
Added New Appendix; refer to Appendix 13.3
Moved cohort 3 
(Glioblastoma) 
guidance 
associated with 
protocol version 3 
to the appendix as 
a reference for 
those GBM 
subjects still on 
study