Clinical trial NCT03026166
Conditions: Small Cell Lung Cancer
Keywords: Cancer Extensive-Stage Small Cell Lung Cancer Nivolumab Ipilimumab Rovalpituzumab tesirine
Sponsor: AbbVie
Start date: 2017-03-30; Completion date: 2019-07-03
Enrollment: 42 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to assess the safety and efficacy of rovalpituzumab tesirine administered in combination with nivolumab or nivolumab and ipilimumab in participants with extensive-stage small cell lung cancer (SCLC).

Detailed description:
The study planned to enroll three cohorts with approximately 30 participants in each, including a dose-limiting toxicity (DLT) evaluation phase (the first 12 weeks of any treatment) and an expansion phase. Initially, up to 12 participants were to be enrolled into Cohort 1 in order to obtain 6 evaluable participants through the DLT evaluation period of 12 weeks. Safety data were reviewed by a Safety Monitoring Committee (SMC) for each cohort during the DLT evaluation phase before the next cohort opened. Once a new cohort was opened, the previously opened cohort was permitted to continue enrolling participants for the expansion phase for a total of 30 participants per cohort.

Only two of the planned three cohorts enrolled participants in the study based on the SMC recommendation after DLTs were identified in Cohort 2.

Arms: arm 1: Participants will receive 2 doses of 0.3 mg/kg rovalpituzumab tesirine by intravenous (IV) infusion 6 weeks apart (Day 1 of Cycles 1 and 3), and 2 doses of 360 mg nivolumab IV 3 weeks apart beginning on Cycle 2 (Day 1 of Cycles 2 and 3).

Participants will then receive maintenance therapy with 480 mg nivolumab IV once every 4 weeks from Cycle 4 until disease progression. arm 2: Participants will receive 2 doses of 0.3 mg/kg rovalpituzumab tesirine IV 6 weeks apart (Day 1 of Cycles 1 and 3), nivolumab 1 mg/kg every 3 weeks for 4 cycles beginning on Cycle 2 (Day 1 of Cycles 2-5), and ipilimumab 1 mg/kg IV every 3 weeks for 4 cycles beginning on Cycle 2 (Day 1 of Cycles 2-5).

After a 6-week washout, participants will then receive maintenance therapy with 480 mg nivolumab IV once every 4 weeks from Cycle 6 until disease progression. arm 3: Participants will receive 2 doses of 0.3 mg/kg rovalpituzumab tesirine IV 6 weeks apart (Day 1 of Cycles 1 and 3), nivolumab 1 mg/kg every 3 weeks for 4 cycles beginning on Cycle 2 (Day 1 of Cycles 2-5), and ipilimumab 3 mg/kg IV every 3 weeks for 4 cycles beginning on Cycle 2 (Day 1 of Cycles 2-5).

After an 8-week washout, participants will then receive maintenance therapy with 480 mg nivolumab IV once every 4 weeks from Cycle 6 until disease progression.
Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab intervention 3: Rovalpituzumab tesirine
Intervention descriptions: intervention 1: Administered by intravenous infusion intervention 2: Administered by intravenous infusion intervention 3: Administered by intravenous infusion

Protocol documents:
Prot_SAP_001.pdf: 
Page 1 of 125
CLINICAL PROTOCOL M16-300
Protocol Number
M16-300
Version and Date
Version 3, 01-DEC-2017
Protocol Title
A Phase 1/2 Study on the Safety of Rovalpituzumab Tesirine 
Administered in Combination with Nivolumab or Nivolumab and 
Ipilimumab for Adults with Extensive-Stage Small Cell Lung 
Cancer
Investigational Drugs
Rovalpituzumab tesirine (SC16LD6.5)
Nivolumab (BMS-936558, MDX1106, ONO-4538, Opdivo®)
Ipilimumab (MDX-010, Yervoy®)
Phase
1/2
EUDRA CT Number
2016-003686-26
CRO Medical Monitors
Sponsor
AbbVie*
1 North Waukegan Road
North Chicago, IL 60064
Sponsor Representative
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable 
regulatory requirements, including the archiving of essential documents.
*The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided 
within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the 
Competent Authority. “AbbVie” shall mean AbbVie Inc. or its affiliate AbbVie Stemcentrx LLC.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT03026166


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Synopsis
TITLE: 
A Phase 1/2 Study on the Safety of Rovalpituzumab Tesirine Administered in Combination with Nivolumab or 
Nivolumab and Ipilimumab for Adults with Extensive-Stage Small Cell Lung Cancer
PROTOCOL NUMBER: M16-300
PHASE OF DEVELOPMENT: 1/2
INVESTIGATORS AND STUDY CENTERS: Multicenter  
OBJECTIVES:
Primary:
!
To assess the safety of rovalpituzumab tesirine when administered in combination with nivolumab or 
nivolumab and ipilimumab in adult subjects with extensive-stage small cell lung cancer (SCLC)
Secondary:
!
To explore the efficacy of rovalpituzumab tesirine when administered in combination with nivolumab or 
nivolumab and ipilimumab in adult subjects with extensive-stage SCLC 
Exploratory:
!
To explore the expression of DLL3 and PD-L1 in SCLC and their relationship to clinical outcome during 
treatment
!
To explore the pharmacokinetics (PK) of and incidence of anti-therapeutic antibodies (ATA) against 
rovalpituzumab tesirine, nivolumab, and ipilimumab
!
To explore the effect of study drug regimen on disease and immune biomarkers
TEST PRODUCTS, DOSE, AND MODE OF ADMINISTRATION:
!
Rovalpituzumab tesirine 0.3 mg/kg will be administered intravenously (IV) on Day 1 of the first and third 
3-week cycle (q6wk x 2), or per other dosing regimen recommended by the safety monitoring committee 
(SMC)
!
Nivolumab 1 mg/kg or 360 mg IV q3wk or 480 mg IV q4wk as monotherapy
!
Ipilimumab 1 mg/kg or 3 mg/kg IV q3wk x 4 cycles
!
Dexamethasone 8 mg orally (PO) twice daily (BID) on Day –1, Day 1 (the day of dosing), and Day 2 of each 
cycle in which rovalpituzumab tesirine is administered.
STUDY DESIGN AND METHODOLOGY:
This is a multicenter study involving rovalpituzumab tesirine administered in combination with nivolumab or 
nivolumab and ipilimumab in subjects with SCLC. Planned cohorts are indicated below.
Cohort
Population
Rovalpituzumab 
tesirine
Nivolumab
Ipilimumab
1
2nd line or later 
SCLC 
(Platinum-
failure)
0.3 mg/kg q6wk x 
2
360 mg q3wk beginning on Week 
4 (Cycle 2) x 2 cycles, then 480 mg 
q4wk
–
2
2nd line or later 
SCLC 
(Platinum-
failure)
0.3 mg/kg q6wk x 
2
1 mg/kg q3wk x 4 cycles beginning 
on Week 4 (Cycle 2), then 480 mg 
q4wk (monotherapy) after 6 week 
washout
1 mg/kg q3wk x 4 
beginning on Week 4 
(Cycle 2)
3
2nd line or later 
SCLC 
(Platinum-
failure)
0.3 mg/kg q6wk x 
2
1 mg/kg q3wk x 4 cycles beginning 
on Week 4 (Cycle 2), then 480 mg 
q4wk (monotherapy) after 8 week 
washout
3 mg/kg q3wk x 4 
beginning on Week 4 
(Cycle 2)


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Initially, up to 12 subjects will be enrolled into Cohort 1 in order to obtain 6 evaluable subjects through the DLT 
evaluation period of 12 weeks, after which an SMC will perform a safety review of the data. The SMC may 
recommend further evaluation of the safety of a given combination or dose regimen, investigation of alternative 
dose regimens, a modification of the dosing interval, or a change in the maximum number of doses (or 
elimination) of any component of the regimen. Based on the tolerability of the initial 6 evaluable subjects in 
Cohort 1, enrollment may begin of up to 12 subjects into Cohort 2 to obtain 6 evaluable subjects through the DLT 
evaluation period of 12 weeks. Once Cohort 2 opens, Cohort 1 may continue enrolling (up to 30 subjects total). 
Similarly, Cohort 3 may enroll up to 12 subjects upon review of the tolerability of the first 6 evaluable subjects in 
Cohort 2. Once Cohort 3 is open, Cohort 2 may continue enrolling (up to 30 subjects total). Following completion 
of the DLT evaluation period and SMC review for a given cohort, the SMC may recommend that enrollment into 
the expansion of the cohort be initiated to gather additional safety data prior to escalation to the next cohort. 
Based on the tolerability of the initial 6 evaluable subjects in Cohort 3, Cohort 3 may continue enrolling (up to 
30 subjects total). If ≤1/6 subjects being evaluated in each cohort experience a DLT within the first 4 cycles of 
treatment (12 weeks), enrollment beyond 12 subjects may proceed. The SMC will meet at a frequency outlined in 
the SMC Charter and will periodically monitor the safety and tolerability of the dose regimen to endorse 
continued enrollment in the cohorts. In general, if a regimen appears intolerable, the dose of rovalpituzumab 
tesirine may be reduced to dose level -1, 0.2 mg/kg. Such changes will constitute a new cohort, and subsequent 
cohorts may then carry forward the tolerated dose. For instance, if Cohort 1 is not tolerated, a new Cohort 4 
consisting of rovalpituzumab tesirine 0.2 mg/kg and nivolumab 360 mg q3wk could be initiated; if tolerated, a 
new Cohort 5 consisting of rovalpituzumab tesirine 0.2 mg/kg, nivolumab 1 mg/kg and ipilimumab 1 mg/kg 
q3wk (nivolumab and ipilimumab doses from Cohort 2) could then be initiated.
For each cohort and dose regimen, up to 30 total subjects may be enrolled as part of an expansion phase after 
evaluation of the tolerability of the first 6 evaluable subjects. Details regarding enrollment priorities are discussed 
in Section 3.1.
MAJOR ELIGIBILITY CRITERIA:
Subjects with histologically or cytologically confirmed, 2nd line or later extensive-stage SCLC with evaluable or 
measurable disease; Eastern Cooperative Oncology Group (ECOG) 0-1; adequate hematologic, hepatic, and renal 
function; no active, known, or suspected autoimmune disease; and no prior exposure to an immuno-oncology or 
pyrrolobenzodiazepine (PBD)-based drug.
PLANNED SAMPLE SIZE:
Up to approximately 90 subjects (up to approximately 30 subjects per cohort) 
STUDY TESTS AND OBSERVATIONS:
Safety assessments (Section 2.4.1) include physical exam, vital signs, body weight, ECOG performance status, 
clinical adverse events (AEs), laboratory tests, electrocardiograms (ECGs), echocardiogram, Fluid Retention 
Questionnaire, and monitoring of concomitant medications.
Efficacy assessments will consist of radiographic imaging. Responses will be categorized by Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 (Eisenhauer, 2009). See Section 6.4.6 for imaging schedule per cohort.
Blood samples for PK, immunogenicity, biomarker, and pharmacodynamics (PD) assessments will be collected at 
protocol-defined time points to support the study endpoints. Sensitive, validated assays will be used to measure 
blood concentrations of rovalpituzumab tesirine antibody-drug conjugate (ADC) and related analytes of 
rovalpituzumab tesirine, such as total antibody and SC-DR002, as applicable. A validated immunoassay will be 
used to assess ATA against rovalpituzumab tesirine. Analogous assays may be performed for nivolumab and/or 
ipilimumab.
Pharmacodynamic and biomarker assessments will include analyses of tumor tissue for DLL3 and PD-L1 
expression, and of blood samples for tumor markers, circulating tumor cells (CTC), immune, and soluble 
biomarkers such as soluble DLL3.


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STATISTICAL METHODS:
As a general strategy, data will be analyzed by cohort and dose regimen. 
Safety analysis will include summaries by cohort and dose regimen of: AEs, laboratory measures, physical 
examinations, ECG, and vital signs using data from subjects in the Safety Analysis set. The incidence of DLTs 
will be summarized.
Objective response rate (ORR) will be reported with category counts, percentage and 95% confidence interval 
(CI). Duration of Response (DOR), progression-free survival (PFS) and overall survival (OS) will be evaluated 
using Kaplan-Meier.


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Table of Contents
Synopsis .....................................................................................................................................2
Definitions of Abbreviations and Terms....................................................................................12
1.
Introduction.................................................................................................................15
1.1
Small Cell Lung Cancer (SCLC)....................................................................................15
1.2
Delta-like Protein 3 and Rovalpituzumab Tesirine .........................................................15
1.3
Immune Checkpoints and Inhibitors of PD-1 and CTLA-4.............................................16
1.4
Rationale for the Study and Anticipated Risks ...............................................................17
2.
Objectives.....................................................................................................................18
2.1
Primary Objective..........................................................................................................18
2.2
Secondary Objective......................................................................................................18
2.3
Exploratory Objectives ..................................................................................................18
2.4
Endpoints ......................................................................................................................18
2.4.1
Safety Endpoints..............................................................................................18
2.4.2
Efficacy Endpoints ..........................................................................................19
2.4.3
Radiographic imaging, Pharmacokinetics, Biomarker, and Pharmacodynamic 
Endpoints ........................................................................................................19
3.
Investigational Plan .....................................................................................................20
3.1
Summary of Study Design.............................................................................................20
3.1.1
Definition of Dose-Limiting Toxicities ............................................................22
3.1.2
Retreatment .....................................................................................................23
3.2
Discussion and Rationale for Study Design....................................................................23
3.2.1
Study Design ...................................................................................................23
3.2.2
Method of Assigning Subjects to Cohorts ........................................................24
3.2.3
Rationale for Selection of Doses......................................................................24
3.2.4
Rationale for Nivolumab and Ipilimumab Combination Dose and Schedule.....24
3.2.5
Nivolumab Flat Dose Regimens.......................................................................25
3.2.6
Blinding...........................................................................................................26
4.
Study Population .........................................................................................................26
4.1
Inclusion Criteria...........................................................................................................26


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4.2
Exclusion Criteria..........................................................................................................28
4.3
Removal of Subjects from Therapy or Assessment ........................................................29
4.3.1
Discontinuation of Study Drug(s) ....................................................................30
4.3.2
Subject Discontinuation from Study.................................................................30
5.
Treatments...................................................................................................................31
5.1
Treatments Administered...............................................................................................31
5.1.1
Treatment Regimen Descriptions for Each Cohort ...........................................31
5.2
Investigational Product (Rovalpituzumab Tesirine)........................................................32
5.2.1
Description ......................................................................................................32
5.2.2
Packaging and Labeling...................................................................................32
5.2.3
Dosing and Administration ..............................................................................33
5.3
Investigational Product (Nivolumab; Opdivo®).............................................................33
5.3.1
Description, Packaging and Labeling ...............................................................33
5.3.2
Dosing and Administration ..............................................................................33
5.4
Investigational Product (Ipilimumab; Yervoy®) ............................................................33
5.4.1
Description, Packaging and Labeling ...............................................................33
5.4.2
Dosing and Administration ..............................................................................34
5.5
Dose Delays/Modifications (Nivolumab and Ipilimumab) .............................................34
5.5.1
Dose Delay Criteria (Nivolumab and Ipilimumab) ...........................................34
5.5.2
Criteria to Resume Nivolumab/Ipilimumab Dosing..........................................35
5.5.3
Rovalpituzumab Tesirine Dose Delays/Modifications......................................36
5.5.4
Permanent Treatment Discontinuation Criteria.................................................36
5.6
Required Premedication and Post-medication ................................................................38
5.7
Prior and Concomitant Therapy.....................................................................................38
5.7.1
Required Concomitant Therapy .......................................................................38
5.7.2
Allowed Concomitant Therapy ........................................................................39
5.7.2.1
Palliative Therapy...................................................................................................... 39
5.7.2.2
Surgical Resection Following Initial Response........................................................... 39
5.7.3
Prohibited Concomitant Therapy .....................................................................40
5.8
Treatment Compliance...................................................................................................40
5.9
Study Drug Accountability ............................................................................................40
5.10
Contraception Recommendations...................................................................................41


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5.11
Documentation of Non-Childbearing Status and Pregnancy Testing...............................41
6.
Study Activities............................................................................................................43
6.1
Enrollment.....................................................................................................................43
6.2
Prescreening Visit..........................................................................................................43
6.3
Screening Visit (Days -14 to -1) ....................................................................................43
6.4
Treatment Period...........................................................................................................45
6.4.1
Peridosing with Dexamethasone ......................................................................45
6.4.1.1
Day –1 (Day before Dosing) of Cycle 1 and Cycle 3 Only.......................................... 45
6.4.1.2
Day 1 (Day of Dosing) of Cycle 1 and Cycle 3 Only .................................................. 45
6.4.1.3
Day 2 (Day After Dosing) of Cycle 1 and Cycle 3 Only ............................................. 45
6.4.2
Day 1 Visit (±2 days) of Each Cycle................................................................45
6.4.3
Day 2 (Day After Dosing) of Cycle 1 and Cycle 3 Only...................................47
6.4.4
Days 8 and 15 Visits (± 2 days) of Cycle 1 and Cycle 3 ...................................47
6.4.5
Washout Period Safety Assessments................................................................48
6.4.6
Efficacy Assessment and Tumor Response ......................................................49
6.5
End of Treatment Visit ..................................................................................................50
6.6
Long-Term Follow-up; Every 6-12 weeks ±1 week .......................................................52
6.7
End of Study/End of Follow-Up ....................................................................................52
7.
Study Assessments .......................................................................................................52
7.1
Screening/Baseline Assessments....................................................................................52
7.2
Radiographic Response/Efficacy Assessments...............................................................53
7.2.1
Radiographic Disease Progression ...................................................................53
7.2.2
Central Radiographic Assessment....................................................................55
7.3
Pharmacokinetic Assessments .......................................................................................55
7.4
Pharmacodynamic and Biomarker Assessments.............................................................55
7.4.1
Tumor Tissue...................................................................................................55
7.4.2
56
7.4.3
Blood Soluble Markers ....................................................................................56
7.4.4
Flow Cytometry...............................................................................................56
7.4.5
Peripheral Blood RNA.....................................................................................56
7.4.6
Circulating Tumor Cells ..................................................................................56


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7.4.7
Cell-Free Circulating Tumor DNA...................................................................56
7.4.8
Genotyping......................................................................................................57
7.4.9
Serosal Fluid....................................................................................................57
7.5
Biospecimen Repository................................................................................................57
7.6
Adverse Event Collection ..............................................................................................57
7.7
Other Safety Assessments..............................................................................................58
7.7.1
Physical Examination ......................................................................................58
7.7.2
Vital Signs, Weight and Height........................................................................58
7.7.3
Clinical Laboratory Tests.................................................................................59
7.7.4
Electrocardiograms..........................................................................................59
7.7.5
Echocardiogram...............................................................................................60
7.7.6
ECOG Performance Status...............................................................................60
7.7.7
Fluid Retention Questionnaire with Daily Weight Diary ..................................60
7.8
Paraneoplastic Assessment ............................................................................................60
7.9
Appropriateness of Measurements .................................................................................60
8.
Complaints...................................................................................................................61
8.1
Medical Complaints.......................................................................................................61
8.1.1
Definitions.......................................................................................................61
8.1.1.1
Adverse Event ........................................................................................................... 61
8.1.1.2
Serious Adverse Events.............................................................................................. 62
8.2
Adverse Event Severity .................................................................................................63
8.2.1
Relationship to Study Drugs ............................................................................64
8.2.2
Deaths .............................................................................................................64
8.2.2.1
Eliciting Adverse Events............................................................................................ 65
8.2.2.2
Recording Adverse Events ......................................................................................... 65
8.2.2.3
Diagnosis vs. Signs or Symptoms............................................................................... 65
8.2.2.4
Recording Serious Adverse Events............................................................................. 65
8.2.2.5
Adverse Events Expected Due to SCLC or Progression of SCLC ............................... 66
8.2.2.6
Reporting Periods for Adverse Events and Serious Adverse Events ............................ 66
8.2.2.7
Serious Adverse Events Require Immediate Reporting............................................... 66
8.3
Toxicity Management....................................................................................................67
8.3.1
Management of Serosal Effusions/Serositis......................................................67
8.3.2
Management of Skin Reactions........................................................................68


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8.3.3
Management of Potential Drug-Induced Liver Injury.......................................69
8.3.4
Immune-Mediated Adverse Events ..................................................................71
8.3.5
Potential for Infusion-Related Reaction............................................................71
8.3.6
Sponsor Safety Reporting to Regulatory Authorities........................................73
8.3.7
Laboratory Test Result Abnormalities..............................................................73
8.3.8
Pregnancy........................................................................................................73
8.4
Product Complaint.........................................................................................................74
8.4.1
Definition ........................................................................................................74
8.4.2
Reporting.........................................................................................................74
9.
Data Quality Control and Quality Assurance ............................................................74
9.1
Site Training and Monitoring Procedures.......................................................................74
9.2
Data Management Procedures........................................................................................76
9.3
Access to Source Data ...................................................................................................76
9.4
Accuracy and Reliability of Data...................................................................................76
9.5
Quality Assurance Procedures .......................................................................................77
9.6
Data Handling and Recordkeeping.................................................................................77
9.6.1
Data Handling..................................................................................................77
9.6.2
Investigator Record Retention..........................................................................77
10.
Data Analysis and Statistical Methods........................................................................77
10.1
Determination of Sample Size .......................................................................................78
10.2
Analysis Populations .....................................................................................................78
10.3
Planned Analyses ..........................................................................................................78
10.3.1
Disposition of the Study Subjects.....................................................................78
10.3.2
Demographic and Baseline Characteristics.......................................................79
10.3.3
Exposure to Study Treatment...........................................................................79
10.3.4
Analysis of Efficacy Endpoints........................................................................79
10.3.5
Safety Analyses ...............................................................................................79
10.3.5.1 Treatment-Emergent Adverse Events ......................................................................... 79
10.3.5.2 Clinical Laboratory Evaluation................................................................................... 80
10.3.5.3 Vital Signs................................................................................................................. 80
10.3.5.4 ECOG Performance Status......................................................................................... 80
10.3.5.5 Electrocardiogram...................................................................................................... 80


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10.3.5.6 Echocardiogram......................................................................................................... 80
10.3.5.7 Concomitant Medications .......................................................................................... 80
10.3.6
Pharmacokinetic and Pharmacodynamics Analyses..........................................80
11.
Ethical and Regulatory Considerations......................................................................82
11.1
Ethical Conduct of the Study .........................................................................................82
11.2
Subject Information and Consent...................................................................................82
11.3
Biospecimens ................................................................................................................83
11.4
Investigator and Study Personnel Information................................................................83
11.5
Protocol Amendments and Study Termination...............................................................84
11.6
Study Documentation, Privacy and Records Retention...................................................84
11.7
Clinical Trial Agreement ...............................................................................................85
12.
References....................................................................................................................87
13.
Appendices...................................................................................................................89
13.1
Schedule of Assessments...............................................................................................90
13.1.1
Schedule of Assessments Cohort 1...................................................................90
13.1.2
Schedule of Assessments Cohort 2...................................................................95
13.1.3
Schedule of Assessments Cohort 3.................................................................100
13.2
Schedule Peridosing Assessments................................................................................105
13.3
Performance Status Scales Conversion ........................................................................106
13.4
New York Heart Association (NYHA) Classification ..................................................107
13.5
Response Evaluation Criteria for Solid Tumors (RECIST) v1.1...................................108
13.6
CTCAE v4.03 Grading of Some AEs Relevant to Rovalpituzumab Tesirine ................109
13.7
Guidance for Management of Immune-Mediated Adverse Events................................112
13.8
Paraneoplastic Assessment ..........................................................................................120
13.9
Fluid Retention Questionnaire .....................................................................................121
13.10 Adverse Events Expected Due to SCLC or Progression of SCLC ................................122
13.11 Investigator Signature Page .........................................................................................124
13.12 Document History .......................................................................................................125


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List of Tables
Table 1.
Planned Cohorts in the Study······································································ 21
Table 2.
Study Drug Dosing Schedule······································································ 32
Table 3.
Cohort 2 Washout Period Schedule ······························································ 48
Table 4.
Cohort 3 Washout Period Schedule ······························································ 48
Table 5.
Recommended Management of Photosensitivity··············································· 69
List of Figures
Figure 1.
Study Schema ························································································ 20
Figure 2.
Adverse Event Collection ·········································································· 58


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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
AST
aspartate aminotransferase
AT
aminotransferase
ATA
anti-therapeutic antibody
∀#
bioavailability
∀∃
bioequivalence
%-hCG
beta-human chorionic gonadotropin
BID
twice daily
BSA
Body surface area
BUN
blood urea nitrogen
Cavgss
average concentration in steady-state
CBC
complete blood count
CBR
clinical benefit rate
CFR
Code of Federal Regulations
CI
confidence interval
Cmaxss
steady-state peak concentration
Cmin1
minimum trough concentration following the first dose
CNS
central nervous system
CR
complete response
CRP
C-reactive protein
CT
computerized tomography
CTA
clinical trial agreement
CTC
circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte antigen 4
cTnT
cardiac troponin T
cTnI
cardiac troponin I
DILI
drug-induced liver injury
DLL3
delta-like protein 3
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form


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eGFR
estimated glomerular filtration rate
EOT
end of treatment
ESR
erythrocyte sedimentation rate
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
IB
Investigator's Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IHR
infusion or hypersensitivity reaction
IL
Interleukin
INR
international normalized ratio
IRB
Institutional Review Board
IV
intravenous(ly)
LDH
lactate dehydrogenase
LTFU
long-term follow-up
LVEF
left ventricular ejection fraction
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
NET
neuroendocrine tumor
NSCLC
Non-small cell lung cancer
NSE
neuron-specific enolase
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PBD
pyrrolobenzodiazepine
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PD
progressive disease
PD
pharmacodynamic
PD-1
programmed death receptor-1
PD-L1
anti-PD-L1 antibody
PD-L2
Anti-PD-L2 antibody
PET
positron emission tomography
PFS
progression-free survival


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PK
Pharmacokinetic(s)
PO
per os (by mouth/orally)
PPK
population pharmacokinetics
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
q2wk
every 2 weeks
q3wk
every 3 weeks
q4wk
every 4 weeks
q6wk
every 6 weeks
q12wk
every 12 weeks
QA
quality assurance
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate by Fridericia's formula
RBC
red blood cell
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RF
rheumatoid factor
RP2D
recommended phase 2 dose
SAE
serious adverse event
SCLC
small cell lung cancer
SD
stable disease
SMC
safety monitoring committee
SPF
sun protection factor
TEAE
treatment-emergent adverse event
TPC
tumor perpetuating cells
ULN
upper limit of normal
USP
United States Pharmacopeia


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1.
Introduction 
1.1
Small Cell Lung Cancer (SCLC)
Small cell lung cancer (SCLC) is an important unmet medical need, representing 15–20% of the 
220,000 annual new cases of lung cancer (Govindan, 2006; Siegel, 2012). These cancers arise 
from epithelial cells with neuroendocrine differentiation and typically are positive for both 
cytokeratin and neuroendocrine markers; however, the diagnosis is usually made by morphologic 
examination. Historically, SCLC has been divided into limited versus extensive-stage disease, 
the former being defined as disease limited to the chest that can be encompassed by a radiation 
field while the latter includes all other cases. Approximately one-third of newly diagnosed 
patients will have limited-stage disease while the rest will be extensive. Unlike non-small cell 
lung cancer (NSCLC), SCLC is rarely cured with local therapy (surgery and/or radiotherapy); 
systemic chemotherapy remains the cornerstone of therapy for all stages of disease. Standard 
initial therapy for all patients with a suitable performance status consists of a platinum salt 
(carboplatin or cisplatin) in combination with a second agent, usually etoposide. For patients 
with limited-stage disease, concurrent or sequential involved-field thoracic radiotherapy is 
indicated. Response rates to initial therapy are high, ranging from 70-90% for limited stage and 
60–70% for extensive-stage; however, recurrence rates remain high in the limited group and 
universal in the extensive group, leading to median survivals of only 14-20 months and 
9-11 months, respectively (Simon, 2004).
1.2
Delta-like Protein 3 and Rovalpituzumab Tesirine
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 SCLC, including its tumor 
perpetuating cells (TPCs), but with no detectable surface protein expression in normal tissues or 
non-neuroendocrine tumor (NET) types (Saunders, 2015; AbbVie 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 (Dunwoodie, 1997; Chapman, 2011).
Rovalpituzumab tesirine (SC16LD6.5) is a DLL3-targeted antibody-drug conjugate (ADC) 
consisting of the humanized DLL3-specific IgG1 monoclonal antibody SC16; the 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.


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In a Phase 1 study (SCRX16-001), rovalpituzumab tesirine 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) (39% [10/26] and 73% [19/26] by 
investigator review), respectively, in DLL3 ≥50% tumors dosed at 0.2-0.4 mg/kg. Median 
overall survival (OS) was 7.7 months in DLL3 ≥50% subjects at all dose levels, with a 1-year 
survival rate of 30%. In DLL3 ≥50% tumors in the third line setting, rovalpituzumab tesirine 
achieved a 33% (4/12) and 83% (10/12) central review-adjudicated confirmed ORR and CBR, 
respectively, with a median survival of 5.8 months and a 1-year survival rate of 37%. 
Rovalpituzumab tesirine was generally tolerated, with the most common Grade 3 or higher AEs 
of serosal effusions and thrombocytopenia occurring in 14% and 12% of subjects, respectively 
(AbbVie data on file). Therefore, rovalpituzumab tesirine appears to be an active anticancer 
therapy.
1.3
Immune Checkpoints and Inhibitors of PD-1 and CTLA-4
Immune checkpoint therapy targets regulatory pathways in T lymphocytes to enhance antitumor 
immune responses (Sharma, 2015). Agents inhibiting the interaction between programmed death 
receptor-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and their ligands have 
facilitated considerable progress in the treatment of many solid tumors: ipilimumab, a CTLA-4-
blocking antibody, has been approved for the treatment of unresectable or metastatic melanoma 
(Bristol-Myers Squibb [BMS], 2015), while nivolumab, a PD-1 blocking antibody, has been 
approved for treatment as a single agent for metastatic NSCLC after platinum-based 
chemotherapy, advanced renal cell carcinoma (RCC) after prior anti-angiogenic therapy, and as a 
single agent or in combination with ipilimumab for unresectable or metastatic melanoma 
(BMS, 2016).
In an ongoing Phase 1/2 study, nivolumab with or without ipilimumab showed antitumor activity 
with durable responses and manageable safety profiles in previously treated patients with SCLC: 
nivolumab 3 mg/kg q2wk achieved a PR and SD in 10% (10/98) and 22% (22/98), respectively, 
while the combination of nivolumab and ipilimumab (1 and 1 mg/kg, 1 and 3 mg/kg, or 3 and 
1 mg/kg, respectively) every 3 weeks (q3wk) x 4 followed by nivolumab 3 mg/kg q2wk achieved 
an ORR and SD in 23% (14/61) and 19% (10/54), respectively (Antonia, 2016). Treatment was 
generally well tolerated, with grade 3 or higher treatment-related AEs occurring in 13 (13%) 
patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 
3 mg/kg cohort, and 10 (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the 
most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase 
(none vs. 5 [8%] vs. none) and diarrhea (none vs. 3 [5%] vs. 1 [2%]). No patients in the 
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event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg 
plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 
1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who 
received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse 
events (myasthenia gravis and worsening of renal failure), and one patient who received 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. 
Nivolumab and the combination of nivolumab and ipilimumab, therefore, appear to have 
clinically significant therapeutic potential in SCLC (Antonia, 2016).
1.4
Rationale for the Study and Anticipated Risks
Although rovalpituzumab tesirine as well as the checkpoint inhibitors nivolumab and ipilimumab 
have demonstrated encouraging efficacy in SCLC, neither approach alone appears at this time 
sufficient to afford a complete clinical benefit or cure in the majority of patients, where medical 
need remains high. Their mechanisms of actions are complementary and toxicities generally 
non-overlapping, though, suggesting that combination therapy may be safe, and clinical benefit 
may be additive or even synergistic. Indeed, preliminary studies indicate that ADCs like 
rovalpituzumab tesirine may, at least in part, result in immunogenic cell death of tumors, 
complementing the immuno-regulatory effects of checkpoint inhibitors like nivolumab and/or 
ipilimumab (Gerber, 2016). However, no formal clinical studies have previously examined the 
tolerability of rovalpituzumab tesirine administered in combination with checkpoint inhibitors. 
This study will therefore explore the safety, tolerability, and antitumor activity of 
rovalpituzumab tesirine administered in combination with nivolumab with or without 
ipilimumab.  Upon completion of the study, decisions to further advance this program will also 
include review of the ORR rate. The lower bound value of the 95% confidence interval for the 
ORR rate observed will be compared to the ORR rate of 23% and used as one of the factors in 
making the decision.
The most frequent treatment-emergent adverse event (TEAE) terms considered related to 
rovalpituzumab tesirine have included fatigue (35%), peripheral edema (23%), and nausea 
(19%), while the most frequent, related TEAEs of Grade 3 or higher have included serosal 
effusions (14%), thrombocytopenia (12%), and skin reactions (8%). In addition, 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 AEs (AbbVie data on file).
Warnings for nivolumab include immune-mediated reactions, including pneumonitis, colitis, 
hepatitis, endocrinopathies, nephritis, rash, and encephalitis, as well as infusion reactions and 
embryo-fetal toxicity. The most common adverse reactions (≥20%) in patients with melanoma 
were fatigue, rash, musculoskeletal and back pain, pruritus, diarrhea, upper respiratory tract 


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infection, decreased appetite, and nausea as a single agent, and fatigue, rash, diarrhea, nausea, 
pyrexia, vomiting, and dyspnea when administered with ipilimumab. In metastatic non-small cell 
lung cancer (NSCLC), the most common adverse reactions (≥20%) were fatigue, 
musculoskeletal pain, decreased appetite, cough, and constipation. In advanced renal RCC, they 
were asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased 
appetite, back pain, and arthralgia (BMS, 2016).
Warnings for ipilimumab also include immune-mediated reactions, including hepatitis and 
endocrinopathies, as well as embryo-fetal toxicity. The most common adverse reactions (≥5%) 
have been fatigue, diarrhea, pruritus, rash, and colitis. At the 10 mg/kg dose (higher than 
anticipated in this study), additional common adverse reactions (≥5%) include nausea, vomiting, 
headache, weight loss, pyrexia, decreased appetite, and insomnia (BMS, 2015).
Accordingly, safety assessments will include regular assessments at protocol-specified time 
points of routine physical examination, laboratory and imaging tests, as well as echocardiograms, 
a Fluid Retention Questionnaire, daily weights, and spot urine protein testing.
2.
Objectives
2.1
Primary Objective
!
To assess the safety of rovalpituzumab tesirine when administered in combination with 
nivolumab or nivolumab and ipilimumab in adult subjects with extensive-stage SCLC
2.2
Secondary Objective
!
To explore the efficacy of rovalpituzumab tesirine when administered in combination with 
nivolumab or nivolumab and ipilimumab in adult subjects with extensive-stage SCLC
2.3
Exploratory Objectives
!
To explore the expression of DLL3 and PD-L1 in SCLC and their relationship to clinical 
outcome during treatment
!
To explore the pharmacokinetics (PK) of and incidence of anti-therapeutic antibodies (ATA) 
against rovalpituzumab tesirine, nivolumab, and ipilimumab
!
To explore the effect of study drug regimen on disease and immune biomarkers
2.4
Endpoints
2.4.1
Safety Endpoints
Analyses of the safety endpoints will include the following measurements or assessments:


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!
Adverse Events (AEs) and Dose-Limiting Toxicities (DLTs)
!
Vital signs (Section 7.7.2)
!
Body weight (Section 7.7.2)
!
Laboratory abnormalities (Sections 7.7.3 and 8.3.7)
!
Electrocardiographic parameters (e.g. QT interval corrected for heart rate [QTc], QT interval 
corrected for heart rate by Fridericia’s formula [QTcF]) (Section 7.7.4)
!
Echocardiography (Section 7.7.5)
!
Eastern Cooperative Oncology Group (ECOG) performance status (Section 7.7.6)
!
Monitoring of concomitant medications
2.4.2
Efficacy Endpoints
!
Response assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, 
including ORR and CBR
!
Duration of response (DOR)
!
Progression-free survival (PFS)
!
PFS status after 6 months from the initiation of study treatment 
!
OS
2.4.3
Radiographic imaging, Pharmacokinetics, Biomarker, and Pharmacodynamic 
Endpoints
Analyses of the endpoints will include the following assessments:
!
Specific PK parameters of rovalpituzumab tesirine, nivolumab, and ipilimumab
!
ATA incidence and timing
!
Tumor DLL3 and PD-L1 expression
!
!
Blood Soluble Markers
!
Immune Markers
!
Circulating Tumor Cells (CTCs)


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3.
Investigational Plan
3.1
Summary of Study Design
This is a multicenter study involving rovalpituzumab tesirine administered in combination with 
nivolumab or nivolumab and ipilimumab in subjects with SCLC. The study plans to include 
3 cohorts of up to approximately 30 subjects each (Table 1).  DLTs will be assessed during the 
DLT Evaluation Period (Section 3.1.1).
Figure 1.
Study Schema
*
Up to 12 DLL3+ subjects will be enrolled into each cohort in order to obtain 6 evaluable subjects at the end of 
the 12 week DLT period.
a.
Based on the tolerability of the initial 6 DLL3+ subjects in cohort 1, enrollment may begin of up to 12 DLL3+ 
subjects into cohort 2. The same strategy will be used for cohort 3 enrollment. If a regimen appears intolerable, 
the dose of rovalpituzumab tesirine may be reduced to 0.2 mg/kg, or 0.1 mg/kg. Such changes will constitute a 
new cohort, and subsequent cohorts may then carry forward the tolerated dose.
b.
For each cohort, up to 30 total subjects may be enrolled as part of an expansion phase after evaluation of the 
tolerability of the first 6 evaluable subjects.


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Table 1.
Planned Cohorts in the Study
Cohort
Population
Rovalpituzumab tesirine
Nivolumab
Ipilimumab
1
2nd line or later 
SCLC (Platinum-
failure) 
(Section 4.1)
0.3 mg/kg q6wk x 2
360 mg q3wk beginning on 
Week 4 (Cycle 2) x 2 
cycles, then 480 mg q4wk
–
2
2nd line or later 
SCLC (Platinum-
failure) 
(Section 4.1)
0.3 mg/kg q6wk x 2
1 mg/kg q3wk x 4 cycles 
beginning on Week 4 
(Cycle 2), then 480 mg 
q4wk (monotherapy) after 
6 week washout
1 mg/kg q3wk x 4 
beginning on Week 4 
(Cycle 2)
3
2nd line or later 
SCLC (Platinum-
failure) 
(Section 4.1)
0.3 mg/kg q6wk x 2
1 mg/kg q3wk x 4 cycles 
beginning on Week 4 
(Cycle 2), then 480 mg 
q4wk (monotherapy) after 
8 week washout
3 mg/kg q3wk x 4 
beginning on Week 4 
(Cycle 2)
Initially, up to 12 subjects will be enrolled into Cohort 1 in order to obtain 6 evaluable subjects 
through the DLT evaluation period of 12 weeks If ≤1/6 subjects being evaluated has a DLT, 
enrollment beyond 12 subjects may proceed (i.e., enrollment into Cohort 1 expansion may 
begin). Subjects who are considered DLT-inevaluable (e.g., due to withdrawal from study before 
completing the DLT evaluation period; see Section 3.1.1) will be replaced if required.
Based on the tolerability of the initial 6 evaluable subjects enrolled in Cohort 1, enrollment may 
begin of up to 12 subjects into Cohort 2. Once Cohort 2 is open, Cohort 1 may continue enrolling 
(up to 30 subjects total).
Up to 12 DLL3+ subjects may be enrolled into Cohort 2 initially in order to obtain 6 evaluable 
subjects through the DLT evaluation period of 12 weeks. This will continue for Cohort 3 as well.
Safety will be monitored throughout the trial by the safety monitoring committee (SMC) 
consisting at least of the medical monitor and biostatistician. After enrollment of up to 
12 subjects in Cohort 1, the SMC will perform a safety review of the data. Based on the 
tolerability of the initial 6 evaluable subjects in Cohort 1, enrollment may begin of up to 
12 subjects in Cohort 2. Once Cohort 2 opens, Cohort 1 may continue enrolling (up to 
30 subjects total). Similarly, Cohort 3 may enroll up to 12 subjects upon review of the 
tolerability of the first 6 evaluable subjects in Cohort 2. Once Cohort 3 opens, Cohort 2 may 
continue enrolling (up to 30 subjects total). Based on the tolerability of the initial 6 subjects in 
Cohort 3, Cohort 3 may continue enrolling (up to 30 subjects total). The SMC may recommend 
further evaluation of the safety of a given combination or dose regimen, investigation of 
alternative dose regimens, a modification of the dosing interval, or a change in the maximum 
number of doses (or elimination) of any component of the regimen. In general, if a regimen 


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appears intolerable, the dose of rovalpituzumab tesirine may be reduced to dose level -1, 
0.2 mg/kg, or level -2, 0.1 mg/kg. Such changes will constitute a new cohort, and subsequent 
cohorts may then carry forward the tolerated dose. For instance, if Cohort 1 is not tolerated, a 
new Cohort 4 consisting of rovalpituzumab tesirine 0.2 mg/kg and nivolumab 360 mg q3wk 
could be initiated; if tolerated, a new Cohort 5 consisting of rovalpituzumab tesirine 0.2 mg/kg, 
nivolumab 1 mg/kg and ipilimumab 1 mg/kg (nivolumab and ipilimumab doses from Cohort 2) 
could then be initiated. 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. The SMC will meet at a frequency 
defined in the SMC Charter.
Tumor response will be assessed according to the imaging schedule in Section 6.4.6. Treatment 
decisions by the investigator will be based on RECIST v1.1.
Subjects will be eligible to continue treatment until unacceptable toxicity, progressive disease 
(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 q6wk until 24 weeks, then 
q12wk until disease progression or initiation of new anticancer treatment, whichever occurs first, 
and will afterwards be followed for survival until death or study termination, whichever occurs 
first.
Blood samples for PK, immunogenicity, biomarker and PD assessments will be collected at 
protocol-defined time points to support the study endpoints (Sections 7.3 and 7.4).
3.1.1
Definition of Dose-Limiting Toxicities
The DLT evaluation period is the first 12 weeks of treatment for all subjects. 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 (see 
Appendix 13.6)
!
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


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!
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(s) (e.g., disease 
progression)
!
≥Grade 3 isolated alkaline phosphatase, amylase, or lipase laboratory abnormality of any 
duration
!
≥Grade 3 endocrinopathies controlled by hormone replacement
!
Grade 3-4 electrolyte abnormalities 
3.1.2
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 
as defined by SD or better during the period of receiving rovalpituzumab tesirine, and then 
experience disease progression 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 maximum 
tolerated dose (MTD).
Retreatment with nivolumab, or nivolumab and ipilimumab will not be permitted.
3.2
Discussion and Rationale for Study Design
3.2.1
Study Design
This is the first formal clinical study of rovalpituzumab tesirine in combination with an inhibitor 
of PD-1 and CTLA-4. Cohort 1 will first assess the tolerability of doublet rovalpituzumab 
tesirine and nivolumab, a PD-1 inhibitor; if tolerated, Cohort 2 will assess the tolerability of 
triplet rovalpituzumab tesirine, nivolumab, and ipilimumab; if tolerated, Cohort 3 will assess the 
tolerability of the triplet with a higher dose of ipilimumab. Expanded enrollment to each cohort 
may occur in order to explore further the tolerability of one or more regimen(s).


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The evaluation of the study endpoints will inform the safety profile of rovalpituzumab tesirine in 
combination with nivolumab with or without ipilimumab, and may provide evidence of 
antitumor activity that could influence the trial design of subsequent studies in SCLC.
3.2.2
Method of Assigning Subjects to Cohorts
Upon approval of subject registration by the sponsor or designee, the subject will be enrolled to a 
cohort. The enrollment confirmation will be documented in the clinical trial master file.
3.2.3
Rationale for Selection of Doses
In a recent 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 recommended Phase 2 dose (RP2D) 
in SCLC was chosen as 0.3 mg/kg q6wk based on the toxicity and efficacy profile during 
multiple cycle dosing (AbbVie data on file). 
In an ongoing Phase 1 study, nivolumab 3 mg/kg q2wk, and nivolumab 1 mg/kg + ipilimumab 
3 mg/kg q3wk, were found to be tolerated in SCLC (Antonia, 2015). Since the toxicities of these 
therapies have been generally non-overlapping, the starting dose regimens in this study will 
therefore be rovalpituzumab tesirine 0.3 mg/kg q6wk + nivolumab 360 mg q3wk, 
rovalpituzumab tesirine 0.3 mg/kg q6wk + nivolumab 1 mg/kg q3wk + ipilimumab 1 mg/kg 
q3wk, and rovalpituzumab tesirine 0.3 mg/kg q6wk + nivolumab 1 mg/kg q3wk + ipilimumab 
3 mg/kg q3wk. In all dose levels, nivolumab will be administered at 480 mg q4wk when used as 
a single agent or after 2 cycles at 360 mg in Cohort 1.
3.2.4
Rationale for Nivolumab and Ipilimumab Combination Dose and Schedule
In CA209004, a Phase 1B dose-escalation study of nivolumab in combination with ipilimumab 
in subjects with unresectable stage III or IV malignant melanoma, the 3 mg/kg nivolumab and 
3 mg/kg ipilimumab cohort exceeded the MTD per protocol. While both Cohort 2 (1 mg/kg 
nivolumab + 3 mg/kg ipilimumab) and Cohort 2a (3 mg/kg nivolumab + 1 mg/kg ipilimumab) 
had similar clinical activity, a dose of 3 mg/kg of ipilimumab q3wk for a total of four doses and 
1 mg/kg nivolumab q3wk for four doses followed by nivolumab 3mg/kg q2wk until progression 
was chosen. Exposure-response analysis of nivolumab monotherapy across dose ranges of 
1 mg/kg to 10 mg/kg reveals similar clinical activity while exposure-response analysis of 
0.3 mg/kg, 3 mg/kg, and 10 mg/kg of ipilimumab monotherapy have demonstrated increasing 
activity with increase in dose in the phase 2 study CA184022 (Wolchok, 2009). Therefore, 
theoretically the selection of 3 mg/kg of ipilimumab (Cohort 2) may be more clinically impactful 
than selection of 3 mg/kg of nivolumab (Cohort 2a).


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Data from the phase III study CA209067 in subjects with advanced melanoma showed that the 
administration schedule of 1 mg/kg of nivolumab q3wk plus 3 mg/kg of ipilimumab q3wk for 
4 doses, followed by 3 mg/kg of nivolumab q2wk for cycle 3 and beyond is safe and well 
tolerated (Larkin, 2015). As described above, current data from study CA209032 showed safety 
and tolerability of this treatment schedule in heavily pretreated SCLC subjects.
3.2.5
Nivolumab Flat Dose Regimens
The safety and efficacy of 240 mg q2wk flat dose of nivolumab is similar to 3 mg/kg q2wk 
dosing regimen. A flat dose of nivolumab 240 mg q2wk was selected since it is identical to a 
dose of 3 mg/kg for subjects weighing 80 kg, the observed median body weight in nivolumab 
treated cancer patients. The 240 mg q2wk flat dose of nivolumab was recently approved by the 
FDA. Using a population pharmacokinetic (PPK) model, the overall distributions of nivolumab 
exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable after treatment with either 3 mg/kg or 
240 mg nivolumab. The predicted range of nivolumab exposures (median and 90% prediction 
intervals) resulting from a 240 mg flat dose across the 35 to 160 kg weight range is maintained 
well below the corresponding exposures observed with the well tolerated 10 mg/kg nivolumab 
q2wk dosage. Across the various tumor types in the clinical program, nivolumab has been shown 
to be safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between 
nivolumab exposure produced by 3 mg/kg and efficacy and safety has been found to be relatively 
flat. Given the similarity of nivolumab PK across tumor types and the similar exposures 
predicted following administration of 240 mg flat dose compared to 3 mg/kg q2wk regimen, it is 
expected that the safety and efficacy profile of 240 mg q2wk nivolumab will be similar to that of 
3 mg/kg nivolumab.


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3.2.6
Blinding
This is not a blinded trial.
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 3.1.2, subjects must meet all inclusion and
none of the exclusion criteria outlined in this section.
4.1
Inclusion Criteria
1)
Written informed consent.
a)
Must have signed and dated an IRB/IEC approved written informed consent form (ICF) 
in accordance with regulatory and institutional guidelines. This must be obtained before 
the performance of any protocol-related procedures that are not part of normal patient 
care.
b)
Must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
2)
Target population
a) Histologically or cytologically confirmed extensive-stage SCLC with PD after at least 
one platinum-based chemotherapeutic regimen.
b) Measurable disease, defined as at least 1 tumor lesion ≥10 mm in the longest diameter 
or a lymph node ≥15 mm in short-axis measurement assessed by computerized 
tomography (CT) scan (RECIST v1.1) or evaluable disease.
c) Availability of representative baseline tumor tissue (archived or on-study biopsy) 
suitable for immunohistochemistry testing. Up to the first 12 subjects of each study 
cohort must be DLL3 positive per IHC (Immunohistochemistry) assay criteria, based on 
central assessment prior to enrollment.
d) ECOG performance status of 0 or 1. See Appendix 13.3 for conversion of performance 
status using Karnofsky scales, if applicable.
e) Minimum life expectancy of at least 12 weeks.


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f)
Asymptomatic central nervous system (CNS) metastases, if present, must be stable, 
with or without previous treatment, in the absence of corticosteroids for at least 2 weeks 
prior to initiation of study drugs.
g) Recovery to Grade 1 of any clinically significant toxicity (excluding alopecia) prior to 
initiation of administration of study drugs.
h) Satisfactory laboratory parameters:
i.
Absolute neutrophil count (ANC) ≥1,000/&L.
ii.
White blood cell count (WBC) ≥2,500/&L.
iii.
Platelet count ≥100,000/&L.
iv.
Hemoglobin ≥9.0 g/dL.
v.
Total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for subjects with 
Gilbert’s disease.
vi.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤3.0 x ULN (≤5 x ULN if evidence of hepatic involvement by malignant disease).
vii.
Creatinine ≤1.5 x ULN or estimated glomerular filtration rate (eGFR) 
≥40 mL/min/1.73m2.
viii.
Albumin ≥3 g/dL.
iv.
Lipase ≤1.5 x ULN. Subjects with Lipase >1.5 x ULN may enroll if there are 
neither clinical nor radiographic signs of a pancreatitis.
x.
Amylase ≤1.5 ULN. Subjects with Amylase >1.5 x ULN may enroll if there are 
neither clinical nor radiographic signs of a pancreatitis
i)
At least two (2) weeks since last dose of any prior systemic anticancer therapy (e.g. 
chemotherapy, radiation, and/or surgery).
3)
Age and Reproductive Status
a)
Adult 18 years of age or older.
b)
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 an FSH level >40 IU/L.
OR


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!
Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy)
OR
!
Woman of Childbearing Potential practicing at least one protocol specified method 
of birth control, starting at Day 1 through at least 31 weeks following the last dose 
of study drugs (Section 5.10).
c)
If the subject is male and is sexually active with female partner(s) of childbearing 
potential, he must agree, from Day 1 through 31 weeks following last dose of study 
drugs, to practice the protocol specified methods of contraception (Section 5.10).
d) Females of childbearing potential must have a negative serum pregnancy test result at 
Screening and a negative urine pregnancy test prior to dosing on Day 1. Females of 
non-childbearing potential (either postmenopausal or permanently surgically sterile as 
defined in Section 5.10) at Screening do not require pregnancy testing.
4.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following criteria:
1)
Prior treatment with or exposure to:
a)
A pyrrolobenzodiazepine (PBD)-based drug (including rovalpituzumab tesirine unless 
undergoing retreatment in the context of this protocol) 
b)
Other monoclonal antibodies
c)
ADCs
d)
Radioimmmunoconjugates
e)
T-cell or other cell-based or biologic therapies
f)
Experimental anti-tumor vaccines; therapies that target any T cell co-stimulation or 
checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti 
CTLA-4 antibody, including ipilimumab; or other medicines specifically targeting 
T cells.
2)
Any significant medical condition, including any condition suggested by screening 
laboratory findings that, in the opinion of the investigator or sponsor, may place the subject 
at undue risk from the study and/or may interfere with interpretation of study results.
3)
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 (Appendix 13.4) within 6 months prior to their 
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4)
Recent or ongoing serious infection, including:
a)
Any active grade 3 or higher (per NCI CTCAE version 4.03) viral, bacterial, or fungal 
infection within 2 weeks of the first dose of the study drugs. 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 [PCR]) 
or active hepatitis C (by PCR) infection, or subjects taking hepatitis-related antiviral 
therapy within 6 months of first dose of study drugs.
5)
Previous malignancies (except non-melanoma skin cancers, and the following in situ 
cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) 
unless a complete remission was achieved at least 2 years prior to study entry AND no 
additional therapy is required during the study period.
6)
Active, known, or suspected autoimmune disease. Vitiligo, type I diabetes mellitus, residual 
hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted.
7)
A condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone 
equivalent) or other immunosuppressive medications within 14 days prior to administration 
of study drugs. Inhaled or topical steroids and adrenal replacement doses >10 mg daily 
prednisone equivalent are permitted in the absence of active autoimmune disease.
8)
Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during 
the study or for approximately 31 weeks after the last dose of study drugs.
9)
Male subject who is considering fathering a child or donating sperm during the study for 
approximately 31 weeks after the last dose of study drugs.
10) 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.
11) Known hypersensitivity to any corticosteroid or excipients contained in the drug 
formulations.
4.3
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 electronic case report form (eCRF). When a subject withdraws from treatment, all 


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safety data normally required at the end of the study (i.e. the End of Treatment (EOT) Visit and 
long-term follow-up [LTFU]) will be obtained if possible (Sections 6.5 and 6.6).
4.3.1
Discontinuation of Study Drug(s)
Treatment with study drug(s) may be discontinued for any of the following reasons:
!
PD
!
AE
!
Investigator decision
!
Subject decision, Non-AE
!
Other
4.3.2
Subject Discontinuation from Study
Any subject may be discontinued from the study for any of the following reasons:
!
Subject withdrawal of consent
!
AE
!
Death
!
Investigator decision
!
Lost to follow-up
!
Significant noncompliance to protocol
!
Study termination by sponsor


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5.
Treatments
5.1
Treatments Administered
!
Rovalpituzumab tesirine 0.3 mg/kg IV on Day 1 of the first and third 3-week cycle 
(q6wk x 2), or per other dosing regimen recommended by the SMC (all cohorts)
!
Nivolumab 360 mg IV q3wk x 2 cycles beginning on Week 4 (Cycle 2) (Cohort 1)
!
Nivolumab 1 mg/kg IV q3wk x 4 cycles (Cohorts 2 and 3)
!
Nivolumab 480 mg q4wk (all cohorts) – monotherapy to be given after a washout period 
from ipilimumab.  See study drug dosing schedule (Section 5.1.1)
!
Ipilimumab 1 mg/kg IV q3wk x 4 cycles beginning on Week 4 (Cycle 2) (Cohort 2)
!
Ipilimumab 3 mg/kg IV q3wk x 4 cycles beginning on Week 4 (Cycle 2) (Cohort 3)
!
Dexamethasone 8 mg orally (PO) twice daily (BID) on Day -1, Day 1 (the day of dosing), 
and Day 2 of each cycle in which rovalpituzumab tesirine is administered (all cohorts)
On applicable cycles, rovalpituzumab tesirine will be administered before nivolumab and 
ipilimumab. Similarly, on applicable cycles, nivolumab will be administered prior to ipilimumab.
Detailed information describing the preparation, administration, and storage of rovalpituzumab 
tesirine, nivolumab, and ipilimumab is located in the Pharmacy Binder.
5.1.1
Treatment Regimen Descriptions for Each Cohort
The schedule, dose, route, and cycle length for the treatment regimens in each of the three 
cohorts are summarized below in Table 2.


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Table 2.
Study Drug Dosing Schedule
Cohort
Study Drug(s)
Cycle
1
2
3
4
5
6+
1a
Rovalpituzumab tesirine 0.3 mg/kg
X
X
Nivolumab 360 mg q3wk
X
X
Nivolumab 480 mg q4wk
X
X
X
2b
Rovalpituzumab tesirine 0.3 mg/kg
X
X
Nivolumab 1 mg/kg
X
X
X
X
Ipilimumab 1 mg/kg
X
X
X
X
Nivolumab 480 mg q4wkd
X
3c
Rovalpituzumab tesirine 0.3 mg/kg
X
X
Nivolumab 1 mg/kg
X
X
X
X
Ipilimumab 3 mg/kg
X
X
X
X
Nivolumab 480 mg q4wke
X
a) Cycles 1–3 are 3 weeks. Cycles 4 and beyond are 4 weeks.
b) Cycles 1–5 are 3 weeks. Cycles 6 and beyond are 4 weeks
c) Cycles 1–5 are 3 weeks. Cycles 6 and beyond are 4 weeks
d)  Nivolumab 480 mg q4wk (monotherapy) to be started 6 weeks after Cycle 5 Day 1 in Cohort 2.
e)  Nivolumab 480 mg q4wk (monotherapy) to be started 8 weeks after Cycle 5 Day 1 in Cohort 3.
5.2
Investigational Product (Rovalpituzumab Tesirine)
5.2.1
Description
Rovalpituzumab tesirine (SC16LD6.5) drug product is provided in a sterile clear United States 
Pharmacopeia (USP) Type I 10 mL glass vial as a lyophilized powder containing 30 mg/vial. 
The lyophilized drug product is reconstituted with 3.2 mL sterile water for injection to deliver 
3 mL per vial of 10 mg/mL rovalpituzumab tesirine. The rovalpituzumab tesirine formulation 
consists of 10 mg/mL rovalpituzumab tesirine in 20 mM histidine hydrochloride, 0.175 M 
sucrose and 0.4 mg/mL polysorbate 20, pH 6.0. The lyophilized drug product is stored and 
shipped at 2-8°C prior to its use in clinical trials.
A description of the chemistry and formulation may be found in the Investigator's Brochure (IB).
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 
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5.2.3
Dosing and Administration
Dosing is based on subject actual body weight to the nearest tenth of a kilogram, assessed on 
Day 1 of each cycle, and administered according to the assigned dose. Detailed information 
describing the preparation, administration, and storage of rovalpituzumab tesirine is located in 
the Pharmacy Binder.
Subjects must meet all of the following on each dosing day before receiving rovalpituzumab 
tesirine:
!
ANC ≥1,000/&L
!
Platelet count ≥100,000/&L
!
Resolution to Grade 0 or 1, or to baseline grade if pre-existing, of any clinically-significant 
clinical or laboratory AE (excluding alopecia) occurring during the previous cycle, including 
findings indicative of pleural or pericardial effusions.
5.3
Investigational Product (Nivolumab; Opdivo®)
5.3.1
Description, Packaging and Labeling 
Nivolumab, available in the United States as Opdivo, is a sterile, preservative-free, non-
pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) 
particles. Opdivo injection for intravenous (IV) infusion is supplied in single-dose vials. Each 
mL of Opdivo solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), 
polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and 
Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust 
pH to 6 (BMS, 2016). Additional details or updates may be found in the most recent Prescribing 
Information.
5.3.2
Dosing and Administration
Detailed information describing the preparation, administration, and storage of nivolumab is 
located in the Pharmacy Binder.
5.4
Investigational Product (Ipilimumab; Yervoy®)
5.4.1
Description, Packaging and Labeling
Ipilimumab, available in the United States as Yervoy, is a sterile, preservative-free, clear to 
slightly opalescent, colorless to pale yellow solution for IV infusion, which may contain a small 
amount of visible translucent-to-white, amorphous ipilimumab particulates. It is supplied in 


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single-use vials of 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following 
inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), 
polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride 
(3.15 mg), and Water for Injection, USP at a pH of 7 (BMS, 2015). Additional details or updates 
may be found in the most recent Prescribing Information.
5.4.2
Dosing and Administration
Detailed information describing the preparation, administration, and storage of ipilimumab is 
located in the Pharmacy Binder.
5.5
Dose Delays/Modifications (Nivolumab and Ipilimumab)
5.5.1
Dose Delay Criteria (Nivolumab and Ipilimumab)
Dose reductions for nivolumab and ipilimumab are not permitted in this study. Nivolumab 
monotherapy or both nivolumab together with combination therapy should be delayed for the 
following:
!
Any Grade ≥1 pneumonitis
!
Any Grade ∋2 non-skin, drug-related AE, with the following exceptions:
(
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay.
!
Grade 2 drug-related creatinine, AST, ALT, or total bilirubin abnormalities
!
Any Grade ≥3 skin drug-related AE
!
Any Grade 3 drug-related laboratory abnormality with the following exceptions:
(
Grade 3 or 4 lymphopenia does not require a dose delay
(
Any Grade 3 drug-related amylase and/or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay.
Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. In the event of isolated CNS 
progression during study treatment, study drug(s) may be withheld while palliative treatment is 
administered, e.g. a standard course of whole brain radiotherapy 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 disease progression. If more than 6 weeks 
have elapsed since the previous dose of study drug(s), the subject should undergo a radiographic 
tumor assessment before restarting study drugs. If additional sites of PD are present, the subject 


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will be required to discontinue study drugs (but may be eligible for re-treatment as per 
Section 3.1.2).
If the decision is made to resume nivolumab and/or ipilimumab dosing, the subject should restart 
treatment on the next regularly scheduled dosing visit. Skipped doses are not to be replaced. If
treatment is delayed >6 weeks, the subject must be permanently discontinued from all study 
therapy, except as specified in Dose Discontinuation Criteria. Tumor assessments for all subjects 
should continue as per protocol even if dosing is delayed.
5.5.2
Criteria to Resume Nivolumab/Ipilimumab Dosing
Subjects will be permitted to resume therapy at the same dose level(s) following resolution of the 
AE to ≤Grade 1 or to baseline within 6 weeks after the last dose, with the exception of subjects 
who meet criteria for permanent discontinuation as specified in Section 5.5.4 (Dose 
discontinuation criteria below). Subjects who meet criteria for permanent discontinuation must 
not receive further study therapy.
Subjects may resume treatment with nivolumab and/or ipilimumab when the drug-related AE(s) 
resolve(s) to Grade ) 1 or baseline, with the following exceptions:
!
Subjects may resume treatment in the presence of Grade 2 fatigue.
!
For subjects with Grade 2 AST, ALT, or total bilirubin elevations, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete.
!
Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 5.5.4) should have treatment permanently discontinued.
!
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Subjects with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for re-treatment if discussed with and 
approved by the sponsor and/or medical monitor.
!
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the sponsor and/or medical 
monitor.
!
Dose delay of nivolumab or ipilimumab that results in treatment interruption of >6 weeks 
requires treatment discontinuation, with exceptions as noted in Section 5.5.4. However, if the 
toxicity resolves to ≤Grade 1 or baseline >6 weeks after the last dose, but the subject does not 
otherwise meet the criteria for permanent discontinuation (Section 5.5.4), and the investigator 


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believes that the subject is deriving clinical benefit, then the subject may be eligible to 
resume the study drug(s) following the approval of the sponsor and/or medical monitor.
5.5.3
Rovalpituzumab Tesirine Dose Delays/Modifications
In general, if a subject has a clinically significant, unresolved AE on the next scheduled dosing 
day, treatment with rovalpituzumab tesirine may be delayed for up to 21 days. The AE must 
resolve to baseline or ≤Grade 1 prior to proceeding with treatment, unless the AE is determined 
to be clearly unrelated to rovalpituzumab tesirine. In cases of treatment delays of >21 days for 
unresolved adverse events, the medical monitor should be contacted regarding the subject's 
continuation of treatment.
If rovalpituzumab tesirine is delayed at Cycle 3 Day 1, nivolumab and/or ipilimumab are not 
required to be delayed.
In general, subjects who experience a clinically-significant Grade 3 or 4 AE (unless the AE is 
determined to be clearly unrelated to rovalpituzumab tesirine) should have a dose reduction(s) of 
rovalpituzumab tesirine in subsequent treatment cycles to dose level –1 or –2, or as suggested 
upon discussion with the medical monitor and/or sponsor. If the clinically-significant Grade 3 or 
4 AE recurs after dose reduction, rovalpituzumab tesirine should be permanently discontinued.
5.5.4
Permanent Treatment Discontinuation Criteria
Subjects meeting any of the following criteria will be required to permanently discontinue all 
assigned study drug(s).
!
PD (see details regarding continuing treatment beyond initial assessment of progression per 
RECIST v1. 1). See Section 7.2.1 for additional details.
!
Clinical deterioration, as assessed by the investigator
!
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within 6 weeks OR requires 
systemic treatment
!
Any Grade ∋2 drug-related pneumonitis or interstitial lung disease that does not resolve 
following dose delay and systemic steroids (also see Pulmonary Adverse Event Management 
Algorithm);
!
Any Grade 3 non-skin, drug-related AE lasting >7 days or recurs, with the following 
exceptions:
–
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation


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–
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation
–
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
o
Grade 3 drug-related thrombocytopenia >7 days or associated with bleeding 
requires discontinuation
o
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation
o
In most cases of Grade 3 AST or ALT elevation, study drug(s) will be 
permanently discontinued. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug(s), a discussion between 
the investigator and the Medical Monitor/designee must occur
!
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
(
Grade 4 neutropenia )7 days
(
Grade 4 lymphopenia or leukopenia
(
Isolated Grade 4 amylase and/or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis
(
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset
!
Any AE, laboratory abnormality, or intercurrent illness, which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued treatment.
!
Any dosing delay of nivolumab or ipilimumab lasting >6 weeks after the last dose, with the 
following exceptions:
(
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related AEs 
are allowed. Prior to re-initiating treatment in a subject with a dosing interruption lasting 
>6 weeks after the last dose and with no more than 3 missed doses, the medical monitor 
must be consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted.
(
Dosing interruptions >6 weeks after the last dose, which occur for nondrug-related 
reasons, may be allowed if approved by the medical monitor. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting >6 weeks after the last dose and 


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with no more than 3 missed doses, the medical monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted, and subjects 
must otherwise meet the criteria for continued treatment at the time re-initiation of study 
therapy is considered.
5.6
Required Premedication and Post-medication 
All subjects enrolled will receive premedication consisting of dexamethasone orally (PO) at 
8 mg BID given on Day –1, Day 1 (the day of dosing), and Day 2 of each rovalpituzumab 
tesirine 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., intravenous, IV) administration may be substituted for per 
os (by mouth/orally, PO) at the discretion of the investigator.
On Day 1 of each rovalpituzumab tesirine cycle, the first dose of dexamethasone of the day must 
be taken at least 30 minutes, but no more than 4 hours, prior to the rovalpituzumab tesirine 
infusion. In the event that a subject arrives for administration of study drugs on Day 1, but has 
not taken any or all required dexamethasone doses on Day –1 and/or Day 1, study drug 
administration may proceed, at the investigator’s discretion, after administration of a parenteral 
corticosteroid dose equivalent to the total missed dexamethasone dose prior to administration of 
study drugs. For instance, subjects who missed 1, 2, or 3 dexamethasone doses could receive 
43 mg, 85 mg, or 128 mg methylprednisolone IV, respectively, prior to proceeding with 
administration of study drugs. If a subject misses any dose(s) of dexamethasone prior to these 
visits, the medical monitor may be consulted if additional guidance is needed.
5.7
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements) that the subject is receiving at the time of enrollment, or receives 
during the study, must be recorded along with the reason for use, date(s) of administration 
including start and end dates, and dosage information including dose, route and frequency.
Any concomitant therapy given for a study protocol-related AE should be recorded from the time 
of informed consent.
5.7.1
Required Concomitant Therapy
Other than dexamethasone (Section 5.6), there are no required concomitant therapies. However, 
due to the potential for rovalpituzumab tesirine-related skin photosensitivity, subjects should be 


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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.
5.7.2
Allowed Concomitant Therapy
Standard supportive care for drug-related toxicity is permitted, including growth factors and 
blood product transfusions per 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 per 
local institutional standards. Other prescribed medications for non-neoplastic conditions are 
allowed, as well as vitamins and nutritional supplements.
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 (Section 8.3.1), 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.
5.7.2.1
Palliative Therapy
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted if the 
following criteria are met:
!
The subject is considered to have progressed at the time of palliative therapy and meets 
criteria to continue with treatment beyond progression (Section 7.2.1).
!
The case is discussed with the sponsor, medical monitor (or designee). Palliative therapy 
must be clearly documented as such in the study record.
5.7.2.2
Surgical Resection Following Initial Response
Investigators may choose to resect solitary lesions and render the subject free of macroscopic 
disease. Subjects enrolled in this study may have such lesions surgically resected only following 


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consultation with the medical monitor and following the Week 12 re-staging assessments. If 
tumor shrinkage of the solitary lesion is noted on the re-staging assessment (e.g., Week 12), it is 
highly encouraged that surgical resection be delayed until subsequent confirmatory scans 
confirm response, and/or fail to demonstrate further shrinkage. Subjects with a PR who go on to 
have surgical resection of remaining disease will be considered a PR. Tumor tissue of any 
resected solitary lesion should be submitted to AbbVie. Detailed instructions of the obtaining, 
processing, labeling, handling, storage and shipment of these specimens will be provided in a 
separate Laboratory Manual.
5.7.3
Prohibited Concomitant Therapy
Subjects may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, or systemic anti-neoplastic therapy during the study, other than as allowed in 
Sections 4 and 5.7.2. Subjects may not have received any systemic anticancer therapy 
(e.g. chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer 
agents) within two weeks of the Screening Visit.
5.8
Treatment Compliance
Study drug administration must be performed by study site staff and documented in source 
documents and the eCRFs.
5.9
Study Drug Accountability
The director of the medical institution should appoint a study drug management director. The 
investigator and the study drug management director will maintain accurate records of receipt 
and the condition of all study drugs including dates of receipt. In addition, accurate records will 
be kept of the weight used to calculate each dispensed rovalpituzumab tesirine dose, and when 
and how much study drug is dispensed and used by each subject in the study. Any reasons for 
departure from the protocol dispensing regimen must also be recorded.
Drug accountability records and inventory will be available. Remaining study drugs (all used, 
partially used, and unused vials) will be returned to AbbVie or its specified designee/depot or 
destroyed at the site according to applicable regulations.
Study drugs must not be used for any purpose other than the present study.
Further instructions about study drug accountability are detailed in the Pharmacy Binder.


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5.10
Contraception Recommendations
If female, subject must be either postmenopausal or permanently surgically sterile (refer to 
inclusion criteria for definitions of both), OR a Woman of Childbearing Potential, practicing at 
least one of the following methods of birth control, on Cycle 1 Day 1 (or earlier) through at least 
31 weeks after the last dose of study drug.
If subject is a Woman of Childbearing Potential practicing acceptable birth control, one of the 
following methods must be followed starting on Day 1 (or earlier) through at least 31 weeks 
following the last dose of study drugs:
(
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 has received medical 
assessment of the surgical success and is the sole sexual partner of the woman of child 
bearing potential 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.  (Note: periodic abstinence [e.g., calendar, 
ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable).
Male subjects who are sexually active with a woman of childbearing potential, even if the male 
subject has undergone a successful vasectomy, must agree from Study Day 1 through at least 
31 weeks 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 31 weeks after the 
last dose of study drug.
5.11
Documentation of Non-Childbearing Status and Pregnancy Testing
For each female subject, the Investigator will document non-childbearing status (surgically 
sterile or post-menopausal for at least 1 year) or potential childbearing status.


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Should a female study subject become pregnant or suspect she is pregnant while participating in 
this study, she should inform the treating Investigator immediately (Section 8.3.8).
For female subjects of childbearing potential, the laboratory will perform pregnancy testing 
according to Appendix 13.1.  A serum pregnancy test will be performed at Screening and the 
results must be available prior to the administration of the first dose of investigational product on 
C1D1.  Subjects with borderline pregnancy tests at Screening must have a serum pregnancy test 
≥3 days later to document continued lack of a positive result.  Urine pregnancy tests will be 
performed at Day 1 of each cycle and again at the End of Treatment Visit.
Females of non-childbearing potential (either postmenopausal or permanently surgically sterile) 
as defined in Section 4 at Screening do not require pregnancy testing.  Post-menopausal female 
subjects ≤55 years of age must have an FSH level >40 IU/L and will have FSH performed at 
Screening and assessed by the Investigator.


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6.
Study Activities
6.1
Enrollment
Subjects who provide informed consent will be screened for eligibility. Once screening 
procedures have been completed, and for those subjects who meet all of the entry criteria, a 
Registration and Enrollment Form will be completed and submitted to the sponsor or designee to 
confirm eligibility. Approved subjects will then be enrolled into a treatment cohort. Refer to the 
Study Binder for the enrollment form, contact numbers, and other details of enrollment.
Safety assessments (Section 2.4.1) will include physical examinations, vital signs, body weight, 
ECOG performance status, AE assessments, laboratory tests (Section 7.7.3), ECGs, 
echocardiograms, Fluid Retention Questionnaire, concomitant medications, AEs, and 
concomitant therapies will be recorded from Day 1 (pre-dose) through the safety reporting period 
At the same time, subjects will maintain a diary of daily weights. Any protocol-related AE 
should be recorded from the time of informed consent as well as any concomitant therapies given 
for treatment of the AE.
Study activities are listed by visit in this section and descriptions of all study assessments are 
presented in Section 7. A schedule of events is provided in Appendix 13.1.
Subjects undergoing retreatment as described in Section 3.1.2 will follow the same study 
schedule from Screening through EOT and LTFU.
6.2
Prescreening Visit
Informed consent for the prescreening portion of this study will be obtained in order to collect 
and test an archived or fresh tumor tissue specimen for DLL3 expression (Section 7.4.1). Up to 
the first 12 subjects enrolled into each cohort must test positive for the expression of DLL3, per 
IHC assay criteria. Demographic information will be collected at this visit (Section 7.1).
6.3
Screening Visit (Days -14 to -1)
Informed consent for the main portion of this study will be obtained prior to the performance of 
any study procedures and may occur within 30 days prior to the Day 1 Visit. All other screening 
procedures must occur within 14 days prior to Day 1. Imaging performed as standard of care 
within 14 days prior to Day 1 will be accepted.
The following assessments will occur during Screening:
!
Informed consent – omitted for retreatment subjects


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!
Demographics (Section 7.1) – omitted for retreatment subjects
!
Confirmation of study eligibility per inclusion/exclusion criteria (Section 4); if prescreening 
visit was not conducted, testing of an archived or fresh tumor tissue specimen for DLL3 
expression will be conducted during the Screening Visit. Upon enrollment into the study, 
remaining tumor tissue will be analyzed for PD-L1 expression.
!
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 7.7.1)
!
Vital signs (Section 7.7.2)
!
Height (Section 7.7.2) (For adult subjects (≥18 years), measurements of height obtained 
within 6 months prior to Screening Visit may be utilized)
!
Urinalysis (Section 7.7.3)
!
Triplicate electrocardiogram (ECG)
!
ECOG performance status (Section 7.7.6 and Appendix 13.3)
!
Procedure-related AEs (Section 7.6)
!
Procedure-related concomitant medications
!
Disease assessment consisting of CT scans of the chest, abdomen, and pelvis (and neck if 
indicated) (Section 7.2) – may be omitted for all subjects if recent scans demonstrating PD 
are within 14 days prior to dosing of study drugs.
!
Magnetic resonance imaging (MRI) of the brain – may be omitted for all subjects if recent 
scans are taken within 14 days prior to dosing of study drugs. CT of the brain with IV 
contrast may be substituted at the discretion of the investigator. (Section 7.2)
!
Paraneoplastic Assessment (Appendix 13.8)
!
Blood sample collection for:
(
Complete blood count (CBC) with differential (Section 7.7.3)
(
Serum chemistries (Section 7.7.3)
(
Coagulation tests (Section 7.7.3)
(
Hepatitis B and C tests (Section 7.7.3) – omitted for retreatment subjects
(
Pregnancy test (serum) (Section 7.7.3) for women of child-bearing potential


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(
Blood 
 (Section 7.4.2)
(
Blood soluble markers (Section 7.4.3)
(
Flow cytometry (Section 7.4.4)
(
Peripheral blood RNA (Section 7.4.5)
(
Genotyping (Section 7.4.8)
(
Endocrinology tests, including ACTH, thyroid stimulating hormone (TSH), and free 
thyroxine (T4)
6.4
Treatment Period
Treatment will be administered in 3-4 week cycles.
6.4.1
Peridosing with Dexamethasone
6.4.1.1
Day –1 (Day before Dosing) of Cycle 1 and Cycle 3 Only
!
Subjects will take dexamethasone 8 mg PO BID (Section 5.6).
!
Dexamethasone may be taken at home or in the clinic.
6.4.1.2
Day 1 (Day of Dosing) of Cycle 1 and Cycle 3 Only
!
Subjects will take dexamethasone 8 mg PO BID (the first dose of the day should be at least 
30 minutes, but no more than 4 hours, prior to the rovalpituzumab tesirine dose); this dose of 
dexamethasone will be taken in the clinic.
!
All subjects will receive 0.3 mg/kg of rovalpituzumab tesirine at Cycle 1 Day 1 and Cycle 3 
Day 1 (Week 7).
6.4.1.3
Day 2 (Day After Dosing) of Cycle 1 and Cycle 3 Only
!
Subjects will take dexamethasone 8 mg PO BID (Section 5.6)
6.4.2
Day 1 Visit (±2 days) of Each Cycle
If Screening activities occur within 1 calendar 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, local safety labs (CBC with differential, chemistries, coagulation tests, 
urinalysis, and pregnancy test), and disease assessment with tumor response on cycles where 
imaging is required.
Day 1 procedures may be performed up to 2 calendar days prior to dosing of study drugs. Results 
from local clinical laboratory tests (at least CBC with differential and serum chemistry panel) 


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and disease assessment with tumor response on cycles where imaging is required must be 
available prior to dose administration. All assessments must occur prior to dosing 
(Appendix 13.1). Imaging report confirming measurable or evaluable disease from the central 
reader will be provided to determine eligibility prior to enrollment.
The following will be performed on the Day 1 Visit of each cycle:
!
Physical examination (Section 7.7.1)
!
Vital signs – within 30 minutes prior to the infusion, and then post-infusion at 30 minutes 
(±10 minutes), 2 hour (±15 minutes), and 4 hour (±30 minutes) for Cycles 1 and 3 only. For 
all other cycles, vital signs should be collected at least 30 minutes (±10 minutes), but no 
longer than 4 hours prior to infusion (Section 7.7.2). Post-infusion vitals do not need to 
include weight. Weight needs to be collected only once prior to infusion and does not need to
be collected within 30 minutes prior to infusion.
!
Urinalysis (Section 7.7.3)
!
Pregnancy test (urine) (Section 7.7.3) for women of child-bearing potential
!
Triplicate ECG prior to infusion of rovalpituzumab tesirine and then post-infusion at 
30 minutes ± 10 minutes (only done on Cycles 1 and 3) (Section 7.7.4). Triplicate ECG 
should be performed prior to PK draw.
!
Echocardiogram (only performed at Cycles 1and 3 (cycles where rovalpituzumab tesirine is 
administered) (Section 7.7.5)
!
ECOG performance status (Appendix 13.3)
!
Fluid Retention Questionnaire with daily weight diary accountability (Cycles 1, 2, 3, and 4) 
(Section 7.7.7)
!
Record all AEs and SAEs (Section 7.6)
!
Record concomitant medications
!
Blood sample collection for:
(
CBC with differential (Section 7.7.3)
(
Serum chemistries (Section 7.7.3)
(
Coagulation tests (Section 7.7.3)
(
Rovalpituzumab tesirine PK (Section 7.3)

Prior to infusion – on Cycle 1 Day 1, Cycle 3 Day 1, and Cycle 5 Day 1


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
Post-infusion at 30 minutes (± 10 minutes), 2 hours (± 15 minutes), and 4 hours 
(± 30 minutes) – only on Cycle 1 and Cycle 3.
(
Rovalpituzumab tesirine ATA –prior to infusion only on Cycle 1 Day 1, Cycle 3 Day 1, 
and Cycle 5 Day 1
(
Nivolumab PK and ATA – all cycles (prior to infusion)
(
Ipilimumab PK and ATA (Cohorts 2 and 3 only) – on Cycle 1 Day 1, Cycle 2 Day 1, 
Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 6 Day 1 (prior to infusion)
(
Endocrinology tests, including ACTH, thyroid stimulating hormone (TSH), and free 
thyroxine (T4)
(
Blood 
 (Section 7.4.2)
(
Blood soluble markers (Section 7.4.3)
(
Flow Cytometry (Section 7.4.4)
(
Peripheral blood RNA (Section 7.4.5)
(
CTCs – (C1D1 and C5D1 pre-infusion only) (Section 7.4.6)
(
Plasma for ctDNA (Cycle 1 Day 1, pre-dose only) (Section 7.4.7)
!
Administration of study drugs (Section 5.1); on applicable cycles, rovalpituzumab tesirine 
will be administered before nivolumab and ipilimumab. Similarly, on applicable cycles, 
nivolumab will be administered prior to ipilimumab.
!
Serosal fluid collection, if applicable (Section 7.4.9)
6.4.3
Day 2 (Day After Dosing) of Cycle 1 and Cycle 3 Only
!
Record AEs and SAEs (Section 7.6) – may be collected by telephone.
!
Record concomitant medications – may be collected by telephone.
!
A single rovalpituzumab tesirine PK draw will be obtained 24 hours (± 2 hours) after start 
time of infusion of rovalpituzumab tesirine on Day 1.
6.4.4
Days 8 and 15 Visits (± 2 days) of Cycle 1 and Cycle 3
The following assessments will be performed at Cycle 1 (Day 8), Cycle 1 (Day 15), Cycle 3 
(Day 8) and Cycle 3 (Day 15) (± 2 days):
!
Physical examination (Section 7.7.1)
!
Vital signs (Section 7.7.2)
!
Urinalysis (Section 7.7.3)


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!
Fluid Retention Questionnaire with daily weight diary accountability (Section 7.7.7)
!
Record AEs and SAEs (Section 7.6)
!
Record concomitant medications
!
Serosal fluid collection, if applicable (Section 7.4.9)
!
Blood sample collection for:
(
CBC with differential (Section 7.7.3)
(
Serum chemistries (Section 7.7.3)
(
Rovalpituzumab tesirine PK
6.4.5
Washout Period Safety Assessments
After the last dose of ipilimumab has been administered on Cycle 5 Day 1 in Cohorts 2 and 3, the 
subject will undergo a washout period for 6 weeks if in Cohort 2, and 8 weeks if in Cohort 3.  
During the washout period, subjects will have a Safety Visit in clinic and telephone follow-up 
calls as described in Table 3 and Table 4.
Table 3.
Cohort 2 Washout Period Schedule
Study Drug
Cycle 5 
Day 1
Washout Period
Week 1
Week 2a
Week 3
Week 4a
Week 5
Cycle 6 
Day 1b
Nivolumab 1 mg/kg
X
Safety  
Visit
Phone 
Follow-
up
Ipilimumab 1 mg/kg
X
Nivolumab 480 mg q4wk
X
a.
Window for visit/telephone follow-up is ±3 days.
b.
Window for visit is ±2 days.
Table 4.
Cohort 3 Washout Period Schedule
Study Drug
Cycle5 
Day 1
Washout Period
Week 
1
Week 
2a
Week 
3
Week 
4a
Week 
5
Week 
6a
Week 
7
Cycle 6 
Day 1b
Nivolumab 1 mg/kg
X
Safety
Visit
Phone 
Follow 
Up 
Visit
Safety 
Visit
Ipilimumab 3 mg/kg
X
Nivolumab 480 mg q4wk
X
a.
Window for visit/telephone follow-up is ±3 days.
b.
Window for visit is ±2 days.
Safety Visit
The following will be performed during the Safety Visit:


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!
Physical examination (Section 7.7.1)
!
Vital signs (Section 7.7.2)
!
ECOG performance status (Appendix 13.3)
!
Record AEs and SAEs (Section 7.6)
!
Record concomitant medications
!
Blood samples for:
!
CBC with differential (Section 7.7.3)
!
Serum chemistries (Section 7.7.3)
Telephone Follow-up Calls
The following will be reviewed during the telephone follow-up call:
!
Any new or ongoing AEs
!
Any new concomitant medications
6.4.6
Efficacy Assessment and Tumor Response
On applicable cycles, disease assessment will occur at least 3 days, but no greater than 7 days, 
prior to day of dosing.
Cohort 1 Imaging Schedule:
!
Prior to Cycle 3 Day 1 (6 weeks after Screening imaging)
!
Prior to Cycle 5 Day 1 (7 weeks after Cycle 3 Day 1 imaging)
o
If response is noted (CR or PR) on Cycle 5 Day 1 scan, a mandatory 4 week follow up 
scan will be performed to confirm response. The 4 week follow up scan may be omitted 
if no response is noted on Cycle 5 Day 1 scan.
!
Prior to Cycle 7 Day 1 (8 weeks after Cycle 5 Day 1 imaging)
!
After Cycle 5 Day 1, imaging will be collected every 8 weeks (at least 3 days, but no greater 
than 7 days, prior to day of dosing) during the maintenance therapy stage of the study.
Cohort 2 Imaging Schedule:
!
Prior to Cycle 3 Day 1 (6 weeks after Screening imaging)
!
Prior to Cycle 5 Day 1 (6 weeks after Cycle 3 Day 1 imaging)


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!
Prior to Cycle 6 Day 1 (6 weeks after Cycle 5 Day 1 imaging given washout period)
!
Prior to Cycle 8 Day 1 (8 weeks after Cycle 6 Day 1 Imaging)
!
After Cycle 8 Day 1, imaging will be collected every 8 weeks (at least 3 days, but no greater 
than 7 days, prior to day of dosing) during the maintenance therapy stage of the study. 
Cohort 3 Imaging Schedule:
!
Prior to Cycle 3 Day 1 (6 weeks after Screening imaging)
!
Prior to Cycle 5 Day 1 (6 weeks after Cycle 3 Day 1 imaging)
o
If response is noted (CR or PR) on Cycle 5 Day 1 scan, a mandatory 4 week follow up 
scan will be performed to confirm response. The 4 week follow up scan may be omitted 
if no response is noted on Cycle 5 Day 1 scan.
!
Prior to Cycle 6 Day 1 (8 weeks after Cycle 5 Day 1 imaging given washout period)
!
Prior to Cycle 8 Day 1 (8 weeks after Cycle 6 Day 1 imaging)
!
After Cycle 8 Day 1, imaging will be collected every 8 weeks (at least 3 days, but no greater
than 7 days, prior to day of dosing) during the maintenance therapy stage of the study.
Disease assessment will consist of the following:
!
CT scans of the chest, abdomen, and pelvis (and neck if indicated) (Section 7.2)
!
MRI of the brain – if clinically indicated (e.g. if CNS progression has been documented 
previously). CT of the brain with IV contrast may be substituted at the discretion of the study 
doctor.
Tumor response will be determined and categorized by RECIST v1.1 (Eisenhauer, 2009).
6.5
End of Treatment Visit
The EOT Visit occurs within 7 days of documentation of the decision to discontinue treatment. 
The following procedures will be performed at the EOT Visit:
!
Physical examination (Section 7.7.1)
!
Vital signs (Section 7.7.2)
!
Urinalysis (Section 7.7.3)
!
Pregnancy test (urine) (Section 7.7.3) for women of childbearing potential
!
Triplicate ECG (Section 7.7.4)


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!
Echocardiogram (Section 7.7.5)
!
ECOG performance status (Appendix 13.3)
!
Record AEs and SAEs (Section 7.6)
!
Fluid Retention Questionnaire with daily weight diary accountability (Section 7.7.7) if EOT 
occurs prior to Cycle 5
!
Record concomitant medications
!
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 7.2)
!
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 IV contrast may be substituted at the discretion of the 
investigator (Section 7.2).
!
Blood samples for:
(
CBC with differential (Section 7.7.3)
(
Serum chemistries (Section 7.7.3)
(
Coagulation tests (Section 7.7.3)
(
Rovalpituzumab tesirine PK and ATA
(
Nivolumab PK and ATA
(
Ipilimumab PK and ATA
(
Blood 
(Section 7.4.2)
(
Plasma for ctDNA (Cycle 1 Day 1, pre-dose only) sample
(
Blood soluble markers (Section 7.4.3)
(
Flow Cytometry (Section 7.4.4)
(
Peripheral blood RNA (Section 7.4.5)
(
CTCs (Section 7.4.6)
(
Endocrinology Tests, including ACTH, thyroid stimulating hormone (TSH), and free 
thyroxine (T4)
!
(Optional) fresh tumor tissue, collected at disease progression (Section 7.4.1)
!
Serosal fluid, if applicable (Section 7.4.9)


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6.6
Long-Term Follow-up; Every 6-12 weeks ±1 week
For all subjects who discontinue study drugs for reasons other than disease progression (e.g. due 
to an AE), the first follow-up visit will occur at 6 weeks (±1 week) after the last dose of study 
drugs, then q6wk (±1 week) until 6 months, then q12wk (±1 week) until disease progression, 
initiation of new anticancer therapy, or withdrawal/ termination from the study. Procedures to be 
conducted on follow-up visits include:
!
Record AEs and SAEs (Section 7.6)
!
Disease response assessment consisting of CT scans of the chest, abdomen, and pelvis (and 
neck if indicated) (Section 7.2)
!
MRI of the brain – if clinically indicated (e.g. if CNS progression has been documented 
previously). CT of the brain with IV contrast may be substituted at the discretion of the 
investigator (Section 7.2).
!
(Optional) fresh tumor tissue, collected at disease progression (Section 7.4.1)
!
Blood samples for:
(
Blood soluble markers (Section 7.4.3)
Survival status will be followed until death or study withdrawal/termination, whichever occurs 
first.
At progression, an optional collection of fresh tumor tissue may be conducted (Section 7.4.1).
After disease progression, subjects who are not retreated will be followed for subsequent 
anticancer therapies and dates, as well as survival status, q6wk (± 1 week) for 24 weeks 
(6 months), then q12wk (± 1 week) until death or study termination, whichever occurs first.
6.7
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.
7.
Study Assessments
7.1
Screening/Baseline Assessments
Only subjects who meet all of the inclusion and none of the exclusion criteria specified in 
Section 4 will be enrolled in this study.


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Screening radiographic assessment must include brain MRI and CT of the chest, abdomen and 
pelvis (and neck if indicated). CT of the brain with IV contrast may be substituted at the 
discretion of the investigator. Presence of measureable or evaluable disease at baseline will have 
to be confirmed by the central reader to determine subject eligibility for the study.
Demographics include age, gender, race, smoking history, and status.
Subject medical and surgical history includes a thorough review of significant past medical and 
surgical history, current conditions, any treatment for prior malignancies and response to prior 
treatment, and any concomitant therapies.
Malignancy history should include diagnosis date, tumor type, mutational status, stage, sites of 
metastases, and prior therapies including dates of treatment and reasons for treatment 
discontinuation, responses and dates of progression, as available and applicable.
7.2
Radiographic Response/Efficacy Assessments
Treatment response will be assessed by radiographic tumor evaluations at protocol-specified 
time points. Radiographic tumor evaluations include:
!
Diagnostic quality, spiral CT scans of the chest, abdomen and pelvis (and neck if indicated)
!
MRI of the brain, if indicated. CT of the brain with IV contrast may be substituted at the 
discretion of the investigator.
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) scans may be used in an ancillary manner; however, no decisions relating to PD may be 
made based on PET scans alone. Clinical response will be determined by the investigator at each 
assessment according to RECIST v1.1 (Appendix 13.5; Eisenhauer, 2009).
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.
7.2.1
Radiographic Disease Progression
Radiographic disease progression will be defined by RECIST v1.1 (Appendix 13.5).


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Accumulating evidence indicates that a minority of subjects with solid tumors treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD. Subjects will be 
permitted to continue on treatment with nivolumab and/or ipilimumab beyond initial 
RECIST v1.1-defined PD as long as they meet the following criteria:
!
Investigator-assessed clinical benefit and without rapid disease progression
!
Continue to meet all other study protocol eligibility criteria
!
Subject tolerates study drug
!
Subject has stable performance status
!
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases).
The assessment of clinical benefit should take into account whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment. All decisions to 
continue treatment beyond initial progression must be discussed with the medical monitor (or 
designee), and an assessment of the risk/benefit of continuing with study therapy must be 
documented in the study records.
The tumor burden volume from the time of initial progression should be used as the reference 
baseline for comparison with the post-progression assessment. Any new lesion considered 
non-measurable at the time of initial progression may become measurable, and therefore, must 
be included in the tumor burden measurement as follows:
For solid tumors: New lesions are considered measurable at the time of initial progression if the 
longest diameter is at least 10 mm (except for pathological lymph nodes, which must have a 
short axis of at least 15 mm).
For statistical analyses that include the investigator-assessed progression date, subjects who 
continue treatment beyond the initial investigator-assessed, RECIST v1.1-defined progression 
will be considered to have investigator-assessed PD at the time of the initial progression event.
Subjects should continue to receive monitoring according to the on-treatment assessments in 
Appendix 13.1. Radiographic assessment by CT (preferred) or MRI described in Section 7.2 and 
Appendix 13.1 is required when subjects continue post-progression treatment. For subjects that 
discontinue post-progression treatment with study therapy, no additional radiographic 
assessments will be required.


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7.2.2
Central Radiographic Assessment
Radiological scans will be collected for assessment by a Central Radiographic Assessment 
Reader. Within 24 hours of each subject’s disease assessment, the appropriate scans should be sent 
by overnight courier or electronically to the central facility. The central reader will make the 
definitive decision on tumor burden (including measurable disease) and tumor response, which will 
be relayed to the investigator. All decisions on treatment eligibility, continuation, discontinuation, 
and retreatment will be made based on the tumor response adjudicated by the central reader.
7.3
Pharmacokinetic Assessments
Blood samples for PK and ATA testing will be collected at the time points throughout the study 
as indicated in Section 6.4, Appendix 13.1, and Appendix 13.2.
Sensitive, validated assays will be used to measure blood concentrations of rovalpituzumab 
tesirine ADC and related analytes of rovalpituzumab tesirine, such as total antibody and SC-
DR002, as applicable. A validated immunoassay will be used to assess ATA against 
rovalpituzumab tesirine. Analogous assays may be performed for nivolumab and/or ipilimumab.
7.4
Pharmacodynamic and Biomarker Assessments
Blood and/or tissue samples for PD and biomarker testing will be collected at the time points 
throughout the study as indicated in Appendix 13.1. PD and biomarker assessments will include 
analysis of tumor tissue including but not limited to DLL3 and PD-L1 expression, and of blood 
samples for tumor markers, CTC, immune, and soluble biomarkers such as DLL3. See the 
Laboratory Manual for additional details.
7.4.1
Tumor Tissue
Tumor tissue, consisting of a representative archived specimen or a fresh tumor biopsy, will be 
assessed for expression of DLL3 and PD-L1 by methods such as, but not necessarily limited to, 
immunohistochemistry. Additional studies, such as routine hematoxylin and eosin for 
morphology and histological classification, immunohistochemistry for confirmation of diagnosis 
 
 may be performed.
At disease progression, an optional tumor biopsy may be performed for the assessment of 
expression of DLL3 and/or PD-L1, 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. Any remaining tissue may be utilized for additional 
biomarker research and exploratory studies including, but not necessarily limited to, assessment 


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of tissue for nucleic acid or protein based biomarkers to understand drug sensitivity and 
resistance, biology of SCLC, and to develop new diagnostic tests.
7.4.2
At the indicated times, blood will be collected for testing of
 
 
7.4.3
Blood Soluble Markers
At the indicated times, blood samples will be collected for possible testing of biomarkers that 
may be related to the PD effects of rovalpituzumab tesirine, nivolumab and/or  ipilumumab, such 
as, but not necessarily limited to, soluble DLL3, or circulating chemokines or cytokines
 
 
 
7.4.4
Flow Cytometry
At the indicated times, blood will be collected for flow cytometry peripheral blood mononuclear 
cells (PBMCs) for characterization of immune subsets.
7.4.5
Peripheral Blood RNA
Peripheral blood RNA consists of whole blood RNA for assessment of analytes that may reflect 
the PD effects of rovalpituzumab tesirine, nivolumab, and/or ipilimumab, 
 
7.4.6
Circulating Tumor Cells
At the indicated times, blood samples will be collected for assessment and characterization of 
CTCs as a possible reflection of disease burden. This will include a sample for exploratory 
analyses of CTC-associated biomarkers, such as DLL3, implemented only at specific sites based 
on feasibility.
7.4.7
Cell-Free Circulating Tumor DNA
At the indicated times, blood samples will be collected for possible assessment and 
characterization of cell free circulating tumor DNA (ctDNA) to potentially assess tumor burden, 
response to treatment, and PD, and to characterize tumor mutations.


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7.4.8
Genotyping
At screening, a blood and/or tumor sample will be collected for possible assessment of genes for 
genetic lesions and/or polymorphisms which may influence the safety or efficacy response to the 
study drugs. Such genes may include but are not necessarily limited to 
 
7.4.9
Serosal Fluid
Any pericardial, pleural and/or ascitic fluid collected as part of routine care (e.g. as part of a 
therapeutic thoracentesis, pericardiocentsis, or paracentesis) will be procured, where feasible, for 
possible PK, PD, and/or biomarker testing. See the Laboratory Manual for additional details.
7.5
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 for up to, but no 
longer than, 20 years from the end of the main portion of the study. If additional written consent 
is not provided, any remaining biological samples will be destroyed by sponsor or its designee 
following study completion.
7.6
Adverse Event Collection
All AEs reported from the time of study drug administration until 100 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 2.


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Figure 2.
Adverse Event Collection
*Only if considered by the investigator to be causally related to study-required procedures.
7.7
Other 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; Fluid Retention Questionnaire with daily weight 
diary; ECOG performance status; disease assessments; and diagnostic testing including 
laboratory testing, radiographic imaging, ECGs, and echocardiograms.
Safety will be monitored over the course of the study by an SMC.
7.7.1
Physical Examination
Physical examinations will include assessments of the head and neck, heart, lungs, abdomen, 
extremities, neurological, and skin. Complete (comprehensive) physical exam performed at 
Screening only.  A symptom-directed physical examination, including disease progression, will 
be performed at all other designated visits.
7.7.2
Vital Signs, Weight and Height
Vital signs will include heart rate, respirations, blood pressure, and temperature. 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 6 months prior to Screening Visit
may be utilized. In the event of an infusion reaction or hypersensitivity reaction (IHR), 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 


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acceptable; but every effort should be made to measure subjects in the same or similar clothing, 
including any accessories or jewelry, at each assessment.
7.7.3
Clinical Laboratory Tests
Laboratory assessments will be performed to evaluate safety at scheduled time points 
(Appendix 13.1) during the course of the study. The following assessments will be performed at 
the local laboratory:
!
CBC, including white blood cell 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), eGFR, glucose, calcium, magnesium, phosphorus, 
albumin, total protein, amylase, lipase, and liver function tests (total and direct bilirubin, 
ALT, AST, alkaline phosphatase, and lactate dehydrogenase [LDH]).
!
Coagulation tests, including prothrombin time (PT), partial thromboplastin time (PTT) or 
activated partial thromboplastin time (aPTT), and INR.
!
Endocrine tests, including adrenocorticotropic hormone (ACTH), thyroid stimulating 
hormone (TSH), and free thyroxine (T4).
!
Urinalysis, including dipstick results for color, appearance, specific gravity, pH, glucose, 
bilirubin, ketones, occult blood, and protein; as well as spot protein and creatinine.
!
Hepatitis B and C tests include hepatitis B surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), hepatitis 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 PCR tests for Hepatitis B and/or C, 
respectively.
!
Pregnancy test, consisting of blood or urine testing for beta-human chorionic gonadotropin 
(%-hCG). Repeat testing may be performed per the investigator.
7.7.4
Electrocardiograms
Throughout the study, subjects will be monitored for changes in cardiac conduction through 
ECGs (Appendix 13.1). ECGs consist of triplicate 12-lead studies, performed within a 5 minute 
window after at least 10 minutes of quiet rest in a supine position and should be done prior to 
blood sample for pharmacokinetics, when applicable.


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7.7.5
Echocardiogram
Echocardiograms will be performed at the indicated times to assess any pericardial effusions, if 
present, as well as cardiac function (left ventricular ejection fraction [LVEF]). Echocardiograms 
will only be performed at cycles 1 and 3 (cycles where rovalpituzumab tesirine is administered).  
Echocardiograms must be reviewed prior to rovalpituzumab tesirine infusions to rule out 
pericardial effusions.  Echocardiograms may be performed up to 72 hours prior to 
rovalpituzumab tesirine administration.
7.7.6
ECOG Performance Status
ECOG performance Status (Appendix 13.3) will be evaluated at protocol-specific time points 
(Appendix 13.1).
7.7.7
Fluid Retention Questionnaire with Daily Weight Diary
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 via 
telephone.
Throughout the treatment period (starting with Day 1 pre-dose through the end of Cycle 4), 
subjects will maintain a diary of daily weights.
7.8
Paraneoplastic Assessment
Paraneoplastic assessment includes documentation of the presence of an SCLC-related 
paraneoplastic syndrome, if present (Appendix 13.8).
7.9
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 (Appendix 13.6).
Response will be assessed according to RECIST v1.1 (Eisenhauer, 2009), which includes 
standard criteria for evaluating response in solid tumors. 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 
drugs. PK assessments for drug activity are also common in clinical studies.


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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 in combination 
with nivolumab alone or combined with nivolumab and ipilimumab. Complaints associated with 
any component of this investigational regimen must be reported to the sponsor (Section 8.2.2.7).
For product complaints, please refer to Section 8.4.
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 adverse event to study drugs, and any 
action(s) taken. For serious adverse events (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 Event
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 


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considered to be adverse events only if they result in discontinuation from the study, necessitate 
therapeutic medical intervention, and/or if the investigator considers them to be AEs.
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, adverse events with onset or worsening reported by a subject from the time that the 
first dose of study drug is administered until 100 days have elapsed following discontinuation of 
study drug administration will be considered as treatment-emergent adverse events.
8.1.1.2
Serious Adverse Events 
If an AE meets any of the following criteria, it is to be reported to AbbVie or designee as an SAE 
within 24 hours of the site being made aware of the 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, admission to an 
outpatient facility, hospitalization for respite care, or admission 
within the follow-up period for salvage therapy.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.


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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.
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
8.2
Adverse Event Severity
The investigator will rate the severity of each AE according to the NCI CTCAE Version 4.03.
For AEs not captured by the Common Terminology Criteria, the following should be used:
Grade 1
The AE is transient and easily tolerated by the subject (mild).
Grade 2
The AE causes the subject discomfort and interrupts the subject's usual 
activities (moderate).
Grade 3/4
The AE causes considerable interference with the subject's usual activities 
and may be incapacitating or life-threatening (severe).
Grade 5
The AE resulted in death of the subject (severe).


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8.2.1
Relationship to Study Drugs
The investigator will use the following definitions to assess the relationship of the AE to the use 
of rovalpituzumab tesirine, nivolumab, or ipilimumab:
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.
If an investigator’s opinion of no reasonable possibility of being related to study drug is given, 
another cause of event must be provided by the investigator for the SAE.
8.2.2
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 that are more likely related 
to disease progression will therefore be considered as expected AE and will not be subject to 
expedited reporting.
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 subject 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 subject 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 


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becomes available (e.g., after autopsy), "unexplained death" should be replaced by the 
established cause of death.
8.2.2.1
Eliciting Adverse Events
An open-ended or non-directed method of questioning should be used at each study visit to elicit 
the reporting of AEs.
8.2.2.2
Recording Adverse Events
The following information should be recorded on the AEs and medical history eCRF:
!
Description using standard medical terminology, including any onset and resolution dates
!
Whether the AE met serious criteria
!
Grade or Severity
!
Relationship to study drug(s) or alternate causality
!
Outcome
8.2.2.3
Diagnosis vs. Signs or Symptoms
In general, the use of a unifying diagnosis is preferred to the listing of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
practice. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
the individual symptom should be reported as a separate AE.
For infusion-related reactions, if multiple signs or symptoms occur with a given infusion-related 
event, each sign or symptom may be recorded separately with its own level of severity.
8.2.2.4
Recording Serious Adverse Events
For SAEs, record the event(s) on both the eCRF and an SAE form.
The following should be considered when recording SAEs:
!
Death is an outcome of an event. The event that resulted in the death should be recorded and 
reported on both the SAE form and the eCRF.
!
For hospitalizations, surgical or diagnostic procedures, the illness leading to the surgical or 
diagnostic procedure should be recorded as the SAE, not the procedure itself. The procedure 
should be captured in the narrative as part of the therapeutic action taken in response to the 
illness.


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8.2.2.5
Adverse Events Expected Due to SCLC or Progression of SCLC
AEs that may be expected from primary SCLC lesions, compression of adjacent thoracic
structures or distant metastases are presented in Appendix 13.10, Adverse Events Expected Due 
to SCLC or Progression of SCLC of the protocol.
These AEs may occur alone or in various combinations and are considered expected AEs in 
SCLC subjects.
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 should be collected under the 
unifying diagnosis of "malignant neoplasm progression"; symptoms of progression may be 
subsumed under this diagnosis.
8.2.2.6
Reporting Periods for Adverse Events and Serious Adverse Events
The safety reporting period for all AEs and SAEs is from the time of study drug administration 
(Cycle 1 Day 1) until 100 days following discontinuation of study drug administration. In 
addition, protocol related serious adverse events and protocol-related nonserious adverse events 
will be collected from the time the subject signed the study-specific informed consent, only if 
considered by the Investigator to be causally related to study-required procedures. All SAEs that 
occur after the safety reporting period and are considered study treatment-related in the opinion 
of the investigator should also be reported to the sponsor or designee.
Each SAE must be followed until the SAE returns to baseline (resolves or recovers to baseline) 
or the SAE stabilizes (resolves or recovers with sequelae); the SAE is considered not recovered 
or not resolved by the investigator; or the subject dies (the SAE end date is equal to the date of 
death). SAE outcome may not be possible to collect when a subject withdraws consent.
Additionally, all SAEs that occur after the safety reporting period (as defined above) that are 
considered study treatment-related by the investigator, should also be reported to the sponsor or 
its designee.
All non-serious AEs will be followed through the safety reporting period.
8.2.2.7
Serious Adverse Events Require Immediate Reporting
In the event of an SAE, whether associated with study drug or not, the investigator will notify 
Clinical Pharmacovigilance within 24 hours of the site being made aware of the SAE by entering 
the SAE data into the electronic data capture (EDC) system. SAEs that occur prior to the site 
having access to the RAVE® system, or if RAVE is not operable, should be documented on the 


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SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical Pharmacovigilance 
within 24 hours of the site being made aware of the SAE.
Email (preferred):
                                    and
                                    
Fax:
                        
For general or specific patient safety concerns, please contact the Medical Director listed below:
In emergency situations involving study subjects when the primary Therapeutic Area Medical 
Director (TA MD) 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:   
8.3
Toxicity Management
Subjects will be monitored continuously for toxicity while on study treatment. Toxicity will be 
assessed using the NCI CTCAE Version 4.03. Adjustments to these guidelines may occur based 
on the clinical judgment of the investigator with notification to the TA MD.
8.3.1
Management of Serosal Effusions/Serositis
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, 
development of any of these events or worsening from baseline warrants prompt evaluation by 
the investigator or designee. Alternative causes, such as infection, congestive heart failure, 
disease progression, and in particular an immune-mediated AE (as might be caused by a 
checkpoint inhibitor; see Section 8.3.3), should be ruled out. When appropriate, a unifying 


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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 during treatment with rovalpituzumab tesirine. The investigator should 
consider initiation of prednisone 1-2 mg/kg/day or equivalent, initiating a taper after 
improvement to Grade 1 or less, over the following 2-4 weeks.
!
Until clinical experience suggests otherwise, guidance for dose delay and/or reduction of 
rovalpituzumab tesirine, as well as criteria for ongoing dosing, should follow Section 5.2.3
and Section 5.5.
8.3.2
Management of Skin Reactions
Skin reactions have been described during single-agent treatment with rovalpituzumab tesirine, 
nivolumab and ipilimumab. For rovalpituzumab tesirine, these have consisted primarily of 
photosensitivity, although other reactions such as palmar-plantar erythrodysesthesia and 
erythema multiforme have been reported. In contrast, for nivolumab and ipilimumab, immune-
mediated dermatitis or rash has been described (Section 8.3.3 and Appendix 13.7). As such, 
development of a skin reaction during treatment warrants prompt evaluation by the investigator 
or designee:
!
If clinically consistent with photosensitivity, the AE may be reported as such (using 
medically accurate and descriptive AE terminology), and managed as described in Table 5.
!
If not clinically consistent with photosensitivity, the following should be done:
(
Photo documentation to facilitate later review by the sponsor or designee.
(
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(s), and to facilitate the most appropriate terminology for AE reporting.
(
Immune-mediated skin reactions should consider the guidance of Appendix 13.7.


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Table 5.
Recommended Management of Photosensitivity
CTCAE v4.03
Treatment Recommendations
Dose 
Modifications
Grade 1
Painless erythema and erythema covering 
<10% body surface area (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 x 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 x 7 days
Hospitalization
Reduce dose
8.3.3
Management of 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.
Potential DILI is defined as:
!
ALT or AST elevation >3 times (3 x) ULN; and
!
Total bilirubin >2 times (2 x) 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 x 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 eCRF. If symptoms persist or repeat testing shows AT >3 x ULN for subjects with normal 
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before drug exposure, close observation should be initiated. If close monitoring is not possible, 
study drugs should be discontinued.
Close observation includes:
!
Repeating liver enzyme and serum bilirubin tests two or three 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 drugs should be considered if potential DILI is suspected and:
!
ALT or AST >8 x ULN
!
ALT or AST >5 x ULN for more than 2 weeks
!
ALT or AST >3 x ULN and (TBL >2 x ULN or INR >1.5)
!
ALT or AST >3 x 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. Retreatment of subjects who develop possible DILI and have previously 
discontinued study drugs may only be permitted upon approval by the sponsor and medical 
monitor.


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8.3.4
Immune-Mediated Adverse Events
General guidelines for immune-mediated AEs, which have been described during treatment with 
nivolumab and/or ipilimumab, but not (to date) with rovalpituzumab tesirine, may be found in 
Appendix 13.7.
General principles include that differential diagnoses should be diligently evaluated according to 
standard medical practice, and consultation with a medical or surgical specialist, especially prior 
to an invasive diagnostic or therapeutic procedure, is recommended. These evaluations, in 
addition to the guidelines of Appendix 13.7 may be supplemented by discussions with the 
medical monitor. Non-inflammatory etiologies should be considered and appropriately treated.
8.3.5
Potential for Infusion-Related Reaction
No infusion-related AEs with rovalpituzumab tesirine have been reported to date. However, as 
rovalpituzumab tesirine is administered via IV infusion, appropriate precautions should be taken 
during infusion of the drug with regular monitoring of vital signs per local institutional 
standards. In the event of a suspected infusion reaction, the infusion should be stopped at least 
temporarily and institutional standard supportive care administered.
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they 
are unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, 
arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the Medical Monitor and reported as an SAE if 
criteria are met. Infusion reactions should be graded according to NCI CTCAE version 4.03 
guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
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For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for ≤24 hours).
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms.
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the infusion 
is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% of 
the original infusion rate. Monitor subject closely. If symptoms recur then no further nivolumab 
or ipilimumab will be administered at that visit. Administer diphenhydramine 50 mg IV, and 
remain at bedside and monitor the subject until resolution of symptoms. The amount of study 
drug infused must be recorded on the electronic case report form (eCRF). The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 
30 minutes before additional nivolumab or ipilimumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be 
used.
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., renal impairment, pulmonary infiltrates]). Grade 4: (life-threatening; pressor or ventilator 
support indicated).
Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Subject should be monitored until the 
investigator is comfortable that the symptoms will not recur. Nivolumab or ipilimumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms. 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine, or corticosteroids).


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8.3.6
Sponsor Safety Reporting to Regulatory Authorities
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor or 
designee (Section 8.2.2.7).
The sponsor or designee will report all SAEs to the appropriate regulatory authorities as required 
per local regulatory reporting requirements. In the United States, endpoints that assess disease-
related mortality or major morbidity as well as other SAEs that are not study endpoints (but are 
known consequences of the underlying disease or condition that are anticipated to occur in the 
study population), should not be reported to Food and Drug Administration (FDA) as individual 
IND safety reports (per the final rule amending the IND safety reporting requirements under the 
Code of Federal Regulations 21 CFR 312.32 and FDA guidance, Safety Reporting Requirements 
for INDs and bioequivalence/ bioavailability (BE/BA) Studies, (FDA, 2012).
8.3.7
Laboratory Test Result Abnormalities
Any laboratory test result abnormality should be reported as an AE or SAE, as appropriate, if it:
!
is clinically significant or meets the definition of an SAE
!
required the subject to have study drugs discontinued or interrupted
!
required the subject to receive specific corrective therapy
Wherever possible, the clinical rather than laboratory term should be used by the reporting 
investigator (e.g. "anemia" rather than "low hemoglobin").
8.3.8
Pregnancy
Pregnancy in a study subject must be reported to the sponsor within 1 working day 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 5.10) should be 
taken throughout the study and for at least 31 weeks following 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 
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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 a SAE and must 
be reported to AbbVie within 24 hours of the site becoming aware of the event.
8.4
Product Complaint
8.4.1
Definition
A Product Complaint is any Complaint related to the biologic or drug component of the products.
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, or packaging issues.
Any information available to help in the determination of causality to the events outlined directly 
above should be captured.
8.4.2
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.
9.
Data Quality Control and Quality Assurance
9.1
Site Training and Monitoring Procedures
A Study Binder with instructions for study compliance and eCRF 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:


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!
The protocol, study objectives, eligibility requirements, study procedures, registration and 
withdrawal processes
!
Current IB
!
Recording and reporting AEs and SAEs
!
Enrollment goals and study timelines
!
The eCRF completion process and source documentation requirements
!
Monitoring requirements
!
Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and approval 
process
!
Informed consent process
!
GCP guidelines and related regulatory documentation requirements
!
Key study team roles and responsibilities
!
Investigational product storage, accountability, labeling, dispensing, and recordkeeping
!
Subject coding
!
Study samples/specimen collection, handling, and shipping
!
Protocol compliance
!
Clinical study record keeping, 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, eCRFs, 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 (QA) auditors, or representatives of regulatory authorities.


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9.2
Data Management Procedures
The sponsor or its designee will provide eCRF Completion Guidelines for data entry. Study-
specific data management procedures will be maintained in the Data Management Plan. Queries 
resulting from edit checks and/or data verification procedures will be posted 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 eCRFs and related source documents 
will be reviewed in detail by the sponsor’s representative(s) at each site visit. Original source 
documents or certified copies must be provided to the sponsor’s representative 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 eCRFs 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.


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9.5
Quality Assurance Procedures
The sponsor's QA 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 QA group or its designee as part of the written record.
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 eCRFs and in all required reports. The 
eCRFs should be captured in the sponsor Electronic Data Capture (EDC) system within 
five (5) business days of the subject's visit to the site. Data reported on the eCRF that is derived 
from source documents should be consistent with the source documents or the discrepancies 
must be explained.
Any change or correction to an eCRF must be maintained in an audit trail within EDC system. 
Data changes may only be made by those individuals so authorized. Prior to database lock the 
investigator must review and approve the completed eCRFs 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 subject 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 two (2) years after the last approval of 
a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or for at least two (2) years after the relevant authority 
has been informed of the discontinuation of clinical development of the study drugs. 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 shall 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.
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.


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10.1
Determination of Sample Size
Up to approximately 90 subjects are expected to participate in this three-cohort trial (up to 
approximately 30 per cohort).
The primary objective of this study is to determine the tolerability, adverse event profile, and any 
DLTs for rovalpituzumab tesirine when given in combination with nivolumab or nivolumab and 
ipilimumab intravenously in adult subjects with extensive-stage small cell lung cancer. Safety 
will be monitored throughout the trial by the safety monitoring committee (SMC). The sample 
size for this study is based on the need to establish safety of the regimens being evaluated and 6 
subjects is the minimum number required for the clinical safety evaluation of each cohort and 12 
subjects may need to be enrolled in order to evaluate safety after 12 weeks in at least 6 subjects. 
Enrollment of a minimum of 6 subjects and a maximum of 30 subjects per cohort will allow for a 
preliminary evaluation of efficacy.
10.2
Analysis Populations
The following populations will be considered:
!
Full Analysis Set: all enrolled subjects who receive any amount of study drugs.
!
Safety Set: all subjects who receive any amount of study drugs.
!
PK-Evaluable Set: all subjects who receive at least one dose of study drugs and for whom a 
baseline measurement and at least one blood sample following a dose of study treatment are 
available.
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 cohort of the number of subjects 
enrolled, the number of subjects treated, the number of subjects for whom study drugs were 
permanently discontinued (including the reasons for discontinuation), and the number of subjects 
who discontinued early from the study.


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10.3.2 Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by cohort. Results will be reported 
using subjects in the full analysis set.
10.3.3 Exposure to Study Treatment
Frequency distributions of the number of received doses will be presented by cohort. Treatment 
duration for all enrolled subjects will be described by cohort.
10.3.4 Analysis of Efficacy Endpoints
ORR is defined as the proportion of subjects whose best overall response is either CR or PR 
according to RECIST v1.1. The number and percentage of responders along with the 
corresponding 95% confidence interval (CI) will be provided for each cohort.
CBR will be analyzed in a way similar to the analysis of the ORR (described above).
DOR will be summarized for responders (i.e., subjects with CR or PR only) by cohort. PFS and 
OS will be summarized by cohort. Median DOR, PFS, and OS will be obtained by using the 
Kaplan-Meier approach. The PFS rate at additional time points may also be evaluated (e.g., 26, 
39, and 52 weeks). Details of the analysis of efficacy endpoints will be described in the 
Statistical Analysis Plan.
10.3.5 Safety Analyses
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.
At least 1 laboratory or other safety-related assessment subsequent to at least 1 dose of study 
drug is required for inclusion in the analysis of a specific safety parameter. To assess change 
from baseline, a baseline measurement is also required.
10.3.5.1 Treatment-Emergent Adverse Events
TEAEs reported during the study will be coded using a MedDRA dictionary. Incidence of 
TEAEs will be summarized by cohort.


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10.3.5.2 Clinical Laboratory Evaluation
Laboratory parameters will be summarized by 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. A listing will be 
provided for out of normal range as well as clinically significant abnormal lab values.
10.3.5.3 Vital Signs
Vital signs, including pulse, blood pressure, temperature, height, and body weight will be 
summarized by cohort and time point. For each assessment of vital signs, change and percent 
change in vital signs from baseline will be summarized by cohort.
10.3.5.4 ECOG Performance Status
ECOG performance status will be summarized for each visit by cohort. Shifts from baseline to 
the best and worst post-baseline score may be tabulated.
10.3.5.5 Electrocardiogram
ECG status will be summarized for each scheduled visit by cohort. Shifts from baseline may be 
tabulated. Additionally, ECG parameters will be described using the five-number summary 
(mean, standard deviation, median, minimum, and maximum).
10.3.5.6 Echocardiogram
Change from baseline of echocardiogram parameters will be described using the five-number 
summary (mean, standard deviation, median, minimum, and maximum).
10.3.5.7 Concomitant Medications
Concomitant medications will be classified according to the anatomical therapeutic chemical 
(ATC) codes in the World Health Organization Drug (WHODRUG) dictionary. The incidence 
rate of each coded concomitant medication will be tabulated by cohort. The table will be sorted 
by the incidence use of the entire sample.
10.3.6 Pharmacokinetic and Pharmacodynamics Analyses
Concentrations of rovalpituzumab tesirine, nivolumab, and ipilimumab will be summarized using 
descriptive statistics.


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Data from the PK-Evaluable set may also be used in the analysis of PK and exposure-PD 
analyses. In addition, the PK of rovalpituzumab tesirine, may also be characterized using 
population methods.
The incidence and timing of ATAs to study drugs will be summarized by descriptive statistics. 
The possible effects of ATA on PK, efficacy and safety may be explored.
The five-number summary will be used to describe absolute and percent change from baseline in 
IHC, blood soluble markers (such as soluble DLL3 or 
 and CTCs. 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 Statistical Analysis Plan.


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11.
Ethical and Regulatory Considerations
GCP requires that the clinical protocol, any protocol amendments, the IB, the ICF and all other 
forms of subject information related to the study (e.g., advertisements used to recruit subjects) 
and any other necessary documents be reviewed by an IEC/IRB. The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted. IEC/IRB 
approval of the protocol, ICF, and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation of any 
changes made to the study design. The investigator will be required to submit, maintain and 
archive study essential documents according to ICH GCP.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required by local regulations. 
During the conduct of the study, the investigator should promptly provide written reports 
(e.g. ICH Expedited Reports, and any additional reports required by local regulations) to the 
IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to subjects. 
Written documentation of the submission to the IEC/IRB should also be provided to the sponsor.
11.1
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical study 
conduct and the ethical principles that have their origin in the Declaration of Helsinki.
11.2
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject, and 
answer all questions regarding this study. Prior to any study-related screening procedures being 
performed on the subject, the informed consent statement will be reviewed and signed and dated 
by the subject, the person who administered the informed consent, and any other signatories 
according to local requirements. A copy of the informed consent form will be given to the 
subject and the original will be placed in the subject's medical record. An entry must also be 
made in the subject's dated source documents to confirm that informed consent was obtained 
prior to any study-related procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for treating 
and/or compensating subjects who are harmed as a consequence of participation in the study can 
be found in the ICF.


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In the event a subject withdraws consent to participate from the study, stored biomarker samples 
will continue to be used for research and analysis. In the event that a subject would like to 
withdraw consent for research using these samples, the subject may request that their samples be 
withdrawn. Once AbbVie receives the request, remaining biomarker samples will be destroyed. 
If the subject changes his/her consent, and the samples have already been tested, those results 
will still remain as part of the overall research data.
An ICF, approved by an IRB/IEC, must be voluntarily signed and dated before samples are 
collected for optional exploratory research. The nature of the testing should be explained and the 
subject given an opportunity to ask questions. The informed consent must be signed before the 
samples are collected and any testing is performed. If the subject does not consent to provide 
samples for the optional exploratory research, it will not impact their participation in the study.
In the event a subject withdraws from the main study, optional exploratory research samples will 
continue to be stored and analyzed unless the subject specifically withdraws consent for the 
optional samples. If consent is withdrawn for the optional sampling, the subject must inform 
their study doctor, and once AbbVie is informed, the optional samples will be destroyed. 
However, if the subject withdraws his/her consent and the samples have already been tested, 
those results will still remain as part of the overall research data.
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 information 
relating to clinical samples, including, if applicable, the labeling of clinical samples with the 
subject’s unique code.
11.4
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 Study Binder. 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 


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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 Principal Investigator and Subinvestigator (as designated on the Form FDA 1572) will 
provide a signed Financial Disclosure Form in accordance with 21 CFR 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 one (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 
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.
11.5
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 terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination.
11.6
Study Documentation, Privacy and Records Retention
To protect the safety of subjects 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 


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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, eCRFs 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.
11.7
Clinical Trial Agreement
A separate written Clinical Trial Agreement (CTA) 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 CTA 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 drugs, the publication of clinical trial data, and other relevant provisions.
The investigator and the institution shall collect and record all data and results of the study, 
including all information, eCRFs, laboratory work sheets, slides, biospecimens, findings and 
reports ("Results") as required by this protocol, the Sponsor’s instructions and the CTA. 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 drugs. 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 two (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 CTA 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 


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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
Antonia S, Bendell J, Taylor M, Calvo E, Jaeger D, De Braud F, et al. Phase I/II study of 
nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer 
(SCLC): CA209-032. J Clin Oncol, abstract, 2015;33(suppl):7503.
Antonia S, Lopez-Martin J, Bendell J, Ott P, Taylor M, Eder J, et al. Nivolumab alone and 
nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a 
multicenter, open-label, phase 1/2 trial. Lancet Oncol, 2016;17:883-95.
Bristol-Myers Squibb. Opdivo Prescribing Information. January 2016.
Bristol-Myers Squibb. Yervoy Prescribing Information. October 2015.
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.
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.
Gerber HP, Sapra P, Loganzo F, May C. Combining antibody-drug conjugates and immune-
mediated cancer therapy: What to expect? Biochem Pharmacol, 2016;102:1-6.
Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in 
the United States over the last 30 years: Analysis of the surveillance, epidemiologic, and 
end results database. J Clin Oncol, 2006; 24 (28): 4539-44.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob J, Cowey C, Lao C, et al. Combined nivolumab 
and ipilimumab or monotherapy in untreated melanoma. NEJM, 2015;373:23-34.
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.


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Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: A cancer journal for clinicians. 
2012; 62 (1):10-29.
Sharma P, Allison J. The future of immune checkpoint therapy. Science, 2015;348:56-61.
Simon M, Argiris A, Murren J. Progress in the therapy of small cell lung cancer. Crit Rev Oncol 
Hematol. 2004 Feb;49(2):119-33.
Wolchok J, Hoos A, O’Day S, Weber J, Hamid O, Lebbé C, et al. Guidelines for the evaluation 
of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res 2009;15:7412-20.


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13.
Appendices
13.1
Schedule of Assessments
13.2
Schedule of Day 1 Peridosing Assessments
13.3
Performance Status Scales Conversion
13.4
New York Heart Association (NYHA) Classification
13.5
Response Evaluation Criteria for Solid Tumors (RECIST) v1.1
13.6
CTCAE v4.03 Grading of Some Relevant AEs
13.7
Guidance for Management of Immune-Mediated Adverse Events
13.8
Paraneoplastic Assessment
13.9
Fluid Retention Questionnaire
13.10 Adverse Events Expected Due to SCLC or Progression of SCLC
13.11 Investigator Signature Page
13.12 Document History


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13.1
Schedule of Assessments
13.1.1 Schedule of Assessments Cohort 1
Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
EOT2 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk4 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 83
(±2 d)
Day 153
(±2 d)
Location
Clinic Visit
X
X
X
X
X
X
X
Telephone Follow-Up
X5
Investigator  present
X
X
X
X
X
X
Screening, 
Baseline, and 
Safety 
Assessments
Informed Consent
X6
X7
Demographics
X
X
Inclusion/Exclusion Criteria8
X
Medical and Surgical History9
X
Malignancy History10
X
Prior Anticancer Treatments11
X
Physical examination
X
X
X
X
X
Vital Signs12
X
X
X
X
X
Height
X
Complete Blood Count with 
differential13
X
X
X
X
X
Serum Chemistries14
X
X
X
X
X
Coagulation Tests15
X
X
X
Urinalysis16
X
X
X
X
X
Endocrinology Tests17
X
X
X
Hepatitis B and C tests18
X
Pregnancy Test19
X
X
X
Electrocardiogram (ECG)
X
X20
X


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Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
EOT2 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk4 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 83
(±2 d)
Day 153
(±2 d)
Echocardiogram
X21
X
Performance Status (ECOG)
X
X
X
Study 
Assessments
Fluid Retention Questionnaire22
X
X
X
X
Adverse Events
X23
X
X
X
X
X
X
Concomitant Medications24
X25
X
X
X
X
X
CT Scan26
X
X27
X
X
MRI Brain28
X
X29
X
X
Paraneoplastic Assessment
X
Disease Assessment
X
Treatment
Dexamethasone 
X
X
X
Rovalpituzumab tesirine (0.3 
mg/kg)
X30
Nivolumab (360 mg)
X31, 32
Nivolumab (480 mg)
X33
Response 
Assessment
Survival Status
X
Response Assessment
X27
X
X
PK and PD
Pharmacokinetics
X34
X35
X35
X35
X34
Rovalpituzumab tesirine anti-
therapeutic antibodies (ATA)
X36
X
Nivolumab ATA
X37
X
Tumor Tissue38
X
X
X39
X39
Blood 
X
X
X
Blood Soluble Markers41
X
X
X
X
Flow cytometry42
X
X
X
Peripheral blood RNA43
X
X
X


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Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
EOT2 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk4 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 83
(±2 d)
Day 153
(±2 d)
Circulating Tumor Cells44
X45
X
Genotyping46
X
Serosal Fluid47
X
X
X
X
Cell Free Circulating Tumor 
DNA (ctDNA) 48
X
X
Table Notes
*       Cycles 1 – 3 are 3 weeks. Cycles 4 and beyond are 4 weeks. 
1)
Only applies to Cycle 1 and Cycle 3 when rovalpituzumab tesirine is administered.
2)
EOT occurs within 7 days of documentation of the decision to discontinue treatment.
3)
Visits on Days 8 and 15 should be done during Cycles 1 and 3 only (may be omitted during cycles that do not include rovalpituzumab tesirine).
4)
LTFU includes the 100 day follow up for safety; LTFU also occurs q6wk (±1 week) until 6 months, then q12wk (±1 week) until disease progression, initiation of new 
anticancer therapy, or withdrawal/termination from the study. 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. After disease progression, 
subjects who are not retreated will be followed (Section 6.6).
5)
This may be a telephone follow-up or performed in clinic.
6)
Prescreening ICF only.
7)
Informed consent for the main portion of this study will be obtained prior to the performance of any study procedures and may occur within 30 days prior to the Day 1 Visit. 
All other screening procedures must occur within 14 days prior to Day 1.
8)
Confirmation of study eligibility per inclusion/exclusion criteria.
9)
Medical and Surgical History includes descriptions of conditions or procedures, and dates of onset - offset.
10) Malignancy History includes tumor type, stage, sites of metastases, mutational status.
11) Prior Anticancer Treatments include names of specific treatments, dates of administration, response to therapy, and DOR, if known.
12) All vitals should be measured after subject has been sitting/resting for at least 5 minutes. Vital signs include temperature, blood pressure, pulse, respiration rate, and weight. 
Vital signs should be collected at least 30 minutes (but no longer than 4 hours) pre-infusion and then 30 minutes (±10 minutes), 2 hours (±15 minutes), and 4 hours (±30 
minutes) post-infusion for Cycles 1 and 3 only. Weight needs to be collected only once prior to infusion and does not need to be collected within 30 minutes prior to infusion. 
All other cycles, vitals should be collected at least 30 minutes (but no longer than 4 hours) pre-infusion.


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13) CBC includes white blood cell count with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), red blood cell (RBC) count, platelet count, 
hemoglobin, and hematocrit.
14) Chemistries include electrolytes (sodium, potassium, chloride, and carbon dioxide), creatinine, BUN, eGFR, magnesium, calcium, phosphorus, glucose, albumin, total 
protein, amylase, lipase, and liver function tests (total and direct bilirubin, ALT, AST, alkaline phosphatase, LDH).
15) Coagulation tests include PT, PTT or aPTT, and INR.
16) Urinalysis includes dipstick results for color, appearance, specific gravity, pH, glucose, bilirubin, ketones, occult blood, and protein; as well as spot urine protein and 
creatinine.
17) Endocrinology Tests include ACTH, thyroid stimulating hormone (TSH), and free thyroxine (T4).
18) 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 Hepatitis B and/or C.
19) Screening pregnancy test consists of serum testing for β-hCG in women of childbearing potential (Section 5.10 for definition). Urine pregnancy test will be performed at Day 
1 of all cycles prior to dosing. Repeat testing may be done per the investigator.
20) ECGs consist of 12-lead studies taken in triplicate, performed within a 5 minute window after at least 10 minutes of quiet rest in a supine position. ECGs will be performed 
prior to infusion (prior to blood sample collection for pharmacokinetics) and 30 minutes ± 10 minutes post-infusion, when applicable.
21) Echocardiogram includes assessment of LVEF and pericardial effusion, if present; performed only on Cycles 1 and 3 when rovalpituzumab tesirine is administered. ECHO 
may be performed up to 72 hours prior to Rova-T administration.
22) Fluid Retention Questionnaire includes diary of daily weights and queries for worsening/ new edema or dyspnea; Fluid Retention Questionnaire will be administered on 
Cycles 1, 2, 3, 4 and EOT visit if occurs prior to Cycle 5. Subjects should record daily weight from Day 1 through the end of Cycle 4.
23) Procedure-related AEs (only).
24) Concomitant Medications include names of all concomitant therapies, including dates of administration, dose regimen, route of administration, and purpose.
25) Procedure related concomitant medications (only).
26) CT imaging of the chest, abdomen, and pelvis, and neck (if indicated), for assessment via RECIST v1.1. 
27) On applicable cycles, disease assessment will occur at least 3 days but no greater than 7 days prior to day of dosing. See Section 6.4.6 for imaging schedule per cohort.
28) CT of the brain with IV contrast may be substituted at the discretion of the investigator.
29) MRI brain is only required after screening if clinically indicated (e.g. if CNS progression is documented).
30) Cycles 1 and 3 only.
31) Nivolumab will be administered after rovalpitzumab tesirine on applicable cycles.
32) Cycles 2 and 3 only.
33) Cycles 4 and beyond.
34) See Appendix 13.2 for rovalpituzumab tesirine and nivolumab PK time points.
35) Rovalpituzumab tesirine single PK will be collected at Cycle 1: Day 2, Day 8, Day 15, Cycle 3: Day 2, Day 8, and Day 15.


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36) Prior to infusion on Cycles 1, 3, 5 only.
37) Prior to infusion for all cycles.
38) Tumor Tissue consists of procurement of archived, representative tumor tissue, or an optional fresh tumor biopsy, if accessible for DLL3 and PD-L1 testing. Any remaining 
tissue may be utilized for additional biomarker research and exploratory studies including, but not necessarily limited to, assessment of tissue for nucleic acid or protein based 
biomarkers to understand drug sensitivity and resistance, biology of SCLC, and to develop new diagnostic tests. With consent from the subject, tumor tissue may be obtained 
prior to the screening period (during the prescreening portion of the study) and tested for DLL3 and PD-L1 expression. Up to the first 12 subjects enrolled into each cohort 
must be DLL3 positive.  For any subjects who did not complete a prescreening visit, this will be done at screening.
39) Optional collection of tumor tissue at progression.
40)
41) Blood soluble markers sample will be tested for various soluble markers that may include but are not limited to chemokines or cytokines, soluble DLL3, and soluble tumor-
specific biomarkers such as 
  Samples will be collected pre-dose at designated visits, and again during retreatment cycles at predose of C1D1, C2D1, 
C3D1.
42) Flow cytometry consists of the collection of blood for characterization of immune cell subsets. Samples will be collected pre-dose at designated visits.
43) Peripheral blood RNA consists of whole blood RNA for assessment of analytes that may reflect the PD effects of rovalpituzumab tesirine and/or nivolumab, including 
 
. Samples will be collected pre-dose at designated visits.
44) CTC collection includes a sample for exploratory analyses of CTC-associated biomarkers such as DLL3, implemented only at specific sites based on feasibility.
45) CTC collection to occur pre-dose on Day 1 of Cycles 1 and 5.
46) Genotyping includes blood and/or tumor sample for possible  assessment of  genes for genetic lesions and/or polymorphisms which may influence the safety or efficacy 
response to the study drugs. Such genes may include but are not necessarily limited to 
47) Serosal Fluid 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, 
pericardiocentsis, or paracentesis), for possible PK, PD, and/or biomarker testing.
48) ctDNA collection to occur pre-dose on Day 1 of Cycle 1and EOT .


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13.1.2 Schedule of Assessments Cohort 2
Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
Washout 
Period Safety 
Assessment2
EOT3 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk5 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 84
(±2 d)
Day 154
(±2 d)
Location
Clinic Visit
X
X
X
X
X
X7
X
X
Telephone Follow-Up
X6
X7
Investigator  present
X
X
X
X
X
X
Screening, 
Baseline, and 
Safety 
Assessments
Informed Consent
X8
X9
Demographics
X
X
Inclusion/Exclusion Criteria10
X
Medical and Surgical History11
X
Malignancy History12
X
Prior Anticancer Treatments13
X
Physical examination
X
X
X
X
X14
X
Vital Signs15
X
X
X
X
X14
X
Height
X
Complete Blood Count with 
differential17
X
X
X
X
X14
X
Serum Chemistries18
X
X
X
X
X14
X
Coagulation Tests19
X
X
X
Urinalysis20
X
X
X
X
X
Endocrinology Tests21
X
X
X
Hepatitis B and C tests22
X
Pregnancy Test23
X
X
X
Electrocardiogram (ECG)
X
X24
X
Echocardiogram
X25
X
Performance Status (ECOG)
X
X
X14
X
Study 
Assessments
Fluid Retention Questionnaire26
X
X
X
X
Adverse Events
X27
X
X
X
X
X16
X
X


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Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
Washout 
Period Safety 
Assessment2
EOT3 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk5 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 84
(±2 d)
Day 154
(±2 d)
Concomitant Medications28
X29
X
X
X
X
X16
X
CT Scan30
X
X31
X
X
MRI Brain32
X
X33
X
X
Paraneoplastic Assessment
X
Disease Assessment
X
Treatment
Dexamethasone 
X
X
X
Rovalpituzumab tesirine (0.3 
mg/kg)
X34
Nivolumab (1 mg/kg)
X35, 36
Nivolumab (480 mg)
X37, 38
Ipilimumab (1 mg/kg)
X39,40
Response 
Assessment
Survival Status
X
Response Assessment
X31
X
X
PK and PD
Pharmacokinetics
X41
X42
X42
X42
X41
Rovalpituzumab tesirine anti-
therapeutic antibodies (ATA)
X43
X
Nivolumab ATA
X44
X
Ipilimumab ATA
X45
X
Tumor Tissue46
X
X
X47
X47
Blood 
 
X
X
X
Blood Soluble Markers49
X
X
X
X
Flow cytometry50
X
X
X
Peripheral blood RNA51
X
X
X
Circulating Tumor Cells52
X53
X
Genotyping54
X
Serosal Fluid55
X
X
X
X


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Clinical Protocol M16-300
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Final Protocol
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Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
Washout 
Period Safety 
Assessment2
EOT3 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk5 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 84
(±2 d)
Day 154
(±2 d)
Cell Free Circulating Tumor DNA 
(ctDNA) 56
X
X
Table Notes
*       Cycles 1 – 5 are 3 weeks. Cycles 6 and beyond are 4 weeks.
1)
Only applies to Cycle 1 and Cycle 3 when rovalpituzumab tesirine is administered.
2)
Washout Period will occur after Cycle 5 Day 1 and will consist of both telephone follow-up calls and in clinic visits (Section 6.4.5).
3)
EOT occurs within 7 days of documentation of the decision to discontinue treatment.
4)
Visits on Days 8 and 15 should be done during Cycles 1 and 3 only (may be omitted during cycles that do not include rovalpituzumab tesirine).
5)
LTFU includes the 100 day follow up for safety; LTFU also occurs q6wk (±1 week) until 6 months, then q12wk (±1 week) until disease progression, initiation of new 
anticancer therapy, or withdrawal/termination from the study. 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. After disease progression, 
subjects who are not retreated will be followed (Section 6.6).
6)
This may be a telephone follow-up or performed in clinic.
7)
The Safety Visit in clinic should occur 2 weeks (±3 days) after Cycle 5 Day 1.  The telephone follow-up call should occur 4 weeks (±3 days) after Cycle 5 Day 1.
8)
Prescreening ICF only.
9)
Informed consent for the main portion of this study will be obtained prior to the performance of any study procedures and may occur within 30 days prior to the Day 1 Visit. 
All other screening procedures must occur within 14 days prior to Day 1.
10) Confirmation of study eligibility per inclusion/exclusion criteria.
11) Medical and Surgical History includes descriptions of conditions or procedures, and dates of onset - offset.
12) Malignancy History includes tumor type, stage, sites of metastases, mutational status.
13) Prior Anticancer Treatments include names of specific treatments, dates of administration, response to therapy, and DOR, if known.
14) To be performed at in clinic visit only.
15) All vitals should be measured after subject has been sitting/resting for at least 5 minutes. Vital signs include temperature, blood pressure, pulse, respiration rate, and weight. 
Vital signs should be collected at least 30 minutes (but no longer than 4 hours) pre-infusion and then 30 minutes (±10 minutes), 2 hours (±15 minutes), and 4 hours 
(±30 minutes) post-infusion for Cycles 1 and 3 only. Weight needs to be collected only once prior to infusion and does not need to be collected within 30 minutes prior to 
infusion. All other cycles, vitals should be collected at least 30 minutes (but no longer than 4 hours) pre-infusion.
16) To be performed during both telephone follow-up and in clinic visit.


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Final Protocol
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17) CBC includes white blood cell count with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), red blood cell (RBC) count, platelet count, 
hemoglobin, and hematocrit.
18) Chemistries include electrolytes (sodium, potassium, chloride, and carbon dioxide), creatinine, BUN, eGFR, magnesium, calcium, phosphorus, glucose, albumin, total protein, 
amylase, lipase, and liver function tests (total and direct bilirubin, ALT, AST, alkaline phosphatase, LDH).
19) Coagulation tests include PT, PTT or aPTT, and INR.
20) Urinalysis includes dipstick results for color, appearance, specific gravity, pH, glucose, bilirubin, ketones, occult blood, and protein; as well as spot urine protein and 
creatinine.
21) Endocrinology Tests include ACTH, thyroid stimulating hormone (TSH), and free thyroxine (T4).
22) 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 Hepatitis B and/or C.
23) Screening pregnancy test consists of serum testing for β-hCG in women of childbearing potential (Section 5.10 for definition). Urine pregnancy test will be performed at 
Day 1 of all cycles prior to dosing. Repeat testing may be done per the investigator.
24) ECGs consist of 12-lead studies taken in triplicate, performed within a 5 minute window after at least 10 minutes of quiet rest in a supine position. ECGs will be performed 
prior to infusion (prior to blood sample collection for pharmacokinetics) and 30 minutes ± 10 minutes post-infusion, when applicable.
25) Echocardiogram includes assessment of LVEF and pericardial effusion, if present; performed only on Cycles 1 and 3 when rovalpituzumab tesirine is administered. ECHO 
may be performed up to 72 hours prior to rovalpituzumab tesirine administration.
26) Fluid Retention Questionnaire includes diary of daily weights and queries for worsening/ new edema or dyspnea; Fluid Retention Questionnaire will be administered on 
Cycles 1, 2, 3, 4 and EOT visit if occurs prior to Cycle 5. Subjects should record daily weight from Day 1 through the end of Cycle 4.
27) Procedure-related AEs (only).
28) Concomitant Medications include names of all concomitant therapies, including dates of administration, dose regimen, route of administration, and purpose.
29) Procedure related concomitant medications (only).
30) CT imaging of the chest, abdomen, and pelvis, and neck (if indicated), for assessment via RECIST v1.1.
31) On applicable cycles, disease assessment will occur at least 3 days but no greater than 7 days prior to day of dosing. See Section 6.4.6 for imaging schedule per cohort.
32) CT of the brain with IV contrast may be substituted at the discretion of the investigator.
33) MRI brain is only required after screening if clinically indicated (e.g. if CNS progression is documented).
34) Cycles 1 and 3 only.
35) Nivolumab (1 mg/kg) will be administered after rovalpitzumab tesirine on applicable cycles.
36) Cycles 2 – 5 only.
37) Nivolumab 480 mg (monotherapy) to be started 6 weeks after Cycle 5 Day 1.
38) Cycles 6 and beyond.
39) Ipilimumab will be administered after rovalpitzumab tesirine and nivolumab on applicable cycles.


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40) Cycles 2 – 5 only.
41) See Appendix 13.2 for rovalpituzumab tesirine, nivolumab, and ipilimumab PK time points.
42) Rovalpituzumab tesirine single PK will be collected at Cycle 1: Day 2, Day 8, Day 15, Cycle 3: Day 2, Day 8, and Day 15.
43) Prior to infusion on Cycles 1, 3, 5 only.
44) Prior to infusion for all cycles.
45) Prior to infusion on Cycles 1 – 6 only.
46) Tumor Tissue consists of procurement of archived, representative tumor tissue, or an optional fresh tumor biopsy, if accessible for DLL3 and PD-L1 testing. Any remaining   
tissue may be utilized for additional biomarker research and exploratory studies including, but not necessarily limited to, assessment of tissue for nucleic acid or protein based 
biomarkers to understand drug sensitivity and resistance, biology of SCLC, and to develop new diagnostic tests. With consent from the subject, tumor tissue may be obtained 
prior to the screening period (during the prescreening portion of the study) and tested for DLL3 and PD-L1 expression. Up to the first 12 subjects enrolled into each cohort 
must be DLL3 positive.  For any subjects who did not complete a prescreening visit, this will be done at screening.
47) Optional collection of tumor tissue at progression.
48)
49) Blood soluble markers sample will be tested for various soluble markers that may include but are not limited to chemokines or cytokines, soluble DLL3, and soluble tumor-
specific biomarkers such as 
  Samples will be collected pre-dose at designated visits, and again during retreatment cycles at pre-dose of C1D1, C2D1, 
C3D1.
50) Flow cytometry consists of the collection of blood for characterization of immune cell subsets.  Samples will be collected pre-dose at designated visits.
51) Peripheral blood RNA consists of whole blood RNA for assessment of analytes that may reflect the PD effects of rovalpituzumab tesirine, nivolumab and/or ipilimumab, 
including 
.  Samples will be collected pre-dose at designated visits.
52) CTC collection includes a sample for exploratory analyses of CTC-associated biomarkers such as DLL3, implemented only at specific sites based on feasibility.
53) CTC collection to occur pre-dose on Day 1 of Cycles 1 and 5.
54) Genotyping includes blood and/or tumor sample for possible assessment of genes for genetic lesions and/or polymorphisms which may influence the safety or efficacy 
response to the study drugs. Such genes may include but are not necessarily limited to 
55) Serosal Fluid 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, 
pericardiocentsis, or paracentesis), for possible PK, PD, and/or biomarker testing.
56) ctDNA collection to occur pre-dose on Day 1 of Cycle 1and EOT.


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Final Protocol
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13.1.3 Schedule of Assessments Cohort 3
Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
Washout 
Period Safety 
Assessment2
EOT3 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk5 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 84
(±2 d)
Day 154
(±2 d)
Location
Clinic Visit
X
X
X
X
X
X7
X
X
Telephone Follow-Up
X6
X7
Investigator  present
X
X
X
X
X
X
Screening, 
Baseline, and 
Safety 
Assessments
Informed Consent
X8
X9
Demographics
X
X
Inclusion/Exclusion Criteria10
X
Medical and Surgical History11
X
Malignancy History12
X
Prior Anticancer Treatments13
X
Physical examination
X
X
X
X
X14
X
Vital Signs15
X
X
X
X
X14
X
Height
X
Complete Blood Count with 
differential17
X
X
X
X
X14
X
Serum Chemistries18
X
X
X
X
X14
X
Coagulation Tests19
X
X
X
Urinalysis20
X
X
X
X
X
Endocrinology Tests21
X
X
X
Hepatitis B and C tests22
X
Pregnancy Test23
X
X
X
Electrocardiogram (ECG)
X
X24
X
Echocardiogram
X25
X
Performance Status (ECOG)
X
X
X14
X
Study 
Assessments
Fluid Retention Questionnaire26
X
X
X
X
Adverse Events
X27
X
X
X
X
X16
X
X


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Final Protocol
Version 3
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Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
Washout 
Period Safety 
Assessment2
EOT3 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk5 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 84
(±2 d)
Day 154
(±2 d)
Concomitant Medications28
X29
X
X
X
X
X16
X
CT Scan30
X
X31
X
X
MRI Brain32
X
X33
X
X
Paraneoplastic Assessment
X
Disease Assessment
X
Treatment
Dexamethasone 
X
X
X
Rovalpituzumab tesirine (0.3 
mg/kg)
X34
Nivolumab (1 mg/kg)
X35, 36
Nivolumab (480 mg)
X37, 38
Ipilimumab (3 mg/kg)
X39,40
Response 
Assessment
Survival Status
X
Response Assessment
X31
X
X
PK and PD
Pharmacokinetics
X41
X42
X42
X42
X41
Rovalpituzumab tesirine anti-
therapeutic antibodies (ATA)
X43
X
Nivolumab ATA
X44
X
Ipilimumab ATA
X45
X
Tumor Tissue46
X
X
X47
X47
Blood 
 
X
X
X
Blood Soluble Markers49
X
X
X
X
Flow cytometry50
X
X
X
Peripheral blood RNA51
X
X
X
Circulating Tumor Cells52
X53
X
Genotyping54
X
Serosal Fluid55
X
X
X
X


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Clinical Protocol M16-300
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Final Protocol
Version 3
Page 102 of 125
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Category
Description
Pre-
Screening
Screening
Day 
before 
dosing1
Treatment (Each Cycle*)
Washout 
Period Safety 
Assessment2
EOT3 
Within 
≤7 days of 
last dose
LTFU 
q6-12wk5 
(±1 week)
Day –14 
to -1
Day –1
Day 1 
(±2 d)
Day 21
Day 84
(±2 d)
Day 154
(±2 d)
Cell Free Circulating Tumor DNA 
(ctDNA) 56
X
X
Table Notes
*       Cycles 1 – 5 are 3 weeks. Cycles 6 and beyond are 4 weeks.
1)
Only applies to Cycle 1 and Cycle 3 when rovalpituzumab tesirine is administered.
2)
Washout Period will occur after Cycle 5 Day 1 and will consist of both telephone follow-up calls and in clinic visits (Section 6.4.5).
3)
EOT occurs within 7 days of documentation of the decision to discontinue treatment.
4)
Visits on Days 8 and 15 should be done during Cycles 1 and 3 only (may be omitted during cycles that do not include rovalpituzumab tesirine).
5)
LTFU includes the 100 day follow up for safety; LTFU also occurs q6wk (±1 week) until 6 months, then q12wk (±1 week) until disease progression, initiation of new 
anticancer therapy, or withdrawal/termination from the study. 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. After disease progression, 
subjects who are not retreated will be followed (Section 6.6).
6)
This may be a telephone follow-up or performed in clinic.
7)
The Safety Visit in clinic should occur 2 weeks (±3 days) and 6 weeks (±3 days) after Cycle 5 Day 1. The telephone follow-up calls should occur 4 weeks (±3 days) after 
Cycle 5 Day 1.
8)
Prescreening ICF only.
9)
Informed consent for the main portion of this study will be obtained prior to the performance of any study procedures and may occur within 30 days prior to the Day 1 Visit. 
All other screening procedures must occur within 14 days prior to Day 1.
10) Confirmation of study eligibility per inclusion/exclusion criteria.
11) Medical and Surgical History includes descriptions of conditions or procedures, and dates of onset - offset.
12) Malignancy History includes tumor type, stage, sites of metastases, mutational status.
13) Prior Anticancer Treatments include names of specific treatments, dates of administration, response to therapy, and DOR, if known.
14) To be performed at in clinic visit only.
15) All vitals should be measured after subject has been sitting/resting for at least 5 minutes. Vital signs include temperature, blood pressure, pulse, respiration rate, and weight. 
Vital signs should be collected at least 30 minutes (but no longer than 4 hours) pre-infusion and then 30 minutes (±10 minutes), 2 hours (±15 minutes), and 4 hours 
(±30 minutes) post-infusion for Cycles 1 and 3 only. Weight needs to be collected only once prior to infusion and does not need to be collected within 30 minutes prior to 
infusion. All other cycles, vitals should be collected at least 30 minutes (but no longer than 4 hours) pre-infusion.


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Final Protocol
Version 3
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16) To be performed during both telephone follow-up and in clinic visit.
17) CBC includes white blood cell count with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), red blood cell (RBC) count, platelet count, 
hemoglobin, and hematocrit.
18) Chemistries include electrolytes (sodium, potassium, chloride, and carbon dioxide), creatinine, BUN, eGFR, magnesium, calcium, phosphorus, glucose, albumin, total protein, 
amylase, lipase, and liver function tests (total and direct bilirubin, ALT, AST, alkaline phosphatase, LDH).
19) Coagulation tests include PT, PTT or aPTT, and INR.
20) Urinalysis includes dipstick results for color, appearance, specific gravity, pH, glucose, bilirubin, ketones, occult blood, and protein; as well as spot urine protein and 
creatinine.
21) Endocrinology Tests include ACTH, thyroid stimulating hormone (TSH), and free thyroxine (T4).
22) 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 Hepatitis B and/or C.
23) Screening pregnancy test consists of serum testing for β-hCG in women of childbearing potential (Section 5.10 for definition). Urine pregnancy test will be performed at Day 
1 of all cycles prior to dosing. Repeat testing may be done per the investigator.
24) ECGs consist of 12-lead studies taken in triplicate, performed within a 5 minute window after at least 10 minutes of quiet rest in a supine position. ECGs will be performed 
prior to infusion (prior to blood sample collection for pharmacokinetics) and 30 minutes ± 10 minutes post-infusion, when applicable.
25) Echocardiogram includes assessment of LVEF and pericardial effusion, if present; performed only on Cycles 1 and 3 when rovalpituzumab tesirine is administered. ECHO 
may be performed up to 72 hours prior to Rova-T administration.
26) Fluid Retention Questionnaire includes diary of daily weights and queries for worsening/ new edema or dyspnea; Fluid Retention Questionnaire will be administered on 
Cycles 1, 2, 3, 4 and EOT visit if occurs prior to Cycle 5. Subjects should record daily weight from Day 1 through the end of Cycle 4.
27) Procedure-related AEs (only).
28) Concomitant Medications include names of all concomitant therapies, including dates of administration, dose regimen, route of administration, and purpose.
29) Procedure related concomitant medications (only).
30) CT imaging of the chest, abdomen, and pelvis, and neck (if indicated), for assessment via RECIST v1.1.
31) On applicable cycles, disease assessment will occur at least 3 days but no greater than 7 days prior to day of dosing. See Section 6.4.6 for imaging schedule per cohort.
32) CT of the brain with IV contrast may be substituted at the discretion of the investigator.
33) MRI brain is only required after screening if clinically indicated (e.g. if CNS progression is documented).
34) Cycles 1 and 3 only.
35) Nivolumab (1 mg/kg) will be administered after rovalpitzumab tesirine on applicable cycles.
36) Cycles 2 – 5 only.
37) Nivolumab 480 mg (monotherapy) to be started 8 weeks after Cycle 5 Day 1.
38) Cycles 6 and beyond.


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Final Protocol
Version 3
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39) Ipilimumab will be administered after rovalpitzumab tesirine and nivolumab on applicable cycles.
40) Cycles 2 – 5 only.
41) See Appendix 13.2 for rovalpituzumab tesirine, nivolumab, and ipilimumab PK time points.
42) Rovalpituzumab tesirine single PK will be collected at Cycle 1: Day 2, Day 8, Day 15, Cycle 3: Day 2, Day 8, and Day 15.
43) Prior to infusion on Cycles 1, 3, 5 only.
44) Prior to infusion for all cycles.
45) Prior to infusion on Cycles 1 – 6 only.
46) Tumor Tissue consists of procurement of archived, representative tumor tissue, or an optional fresh tumor biopsy, if accessible for DLL3 and PD-L1 testing. Any remaining   
tissue may be utilized for additional biomarker research and exploratory studies including, but not necessarily limited to, assessment of tissue for nucleic acid or protein based 
biomarkers to understand drug sensitivity and resistance, biology of SCLC, and to develop new diagnostic tests. With consent from the subject, tumor tissue may be obtained 
prior to the screening period (during the prescreening portion of the study) and tested for DLL3 and PD-L1 expression. Up to the first 12 subjects enrolled into each cohort 
must be DLL3 positive.  For any subjects who did not complete a prescreening visit, this will be done at screening.
47) Optional collection of tumor tissue at progression.
48)
49) Blood soluble markers sample will be tested for various soluble markers that may include but are not limited to chemokines or cytokines, soluble DLL3, and soluble tumor-
specific biomarkers such as 
  Samples will be collected pre-dose on designated visits again during retreatment cycles at pre-dose of C1D1, C2D1, 
C3D1.
50) Flow cytometry consists of the collection of blood for characterization of immune cell subsets.  Samples will be collected during screening, predose of C1D1, C2D1, C3D1 
and C4D1.
51) Peripheral blood RNA consists of whole blood RNA for assessment of analytes that may reflect the PD effects of rovalpituzumab tesirine, nivolumab and/or ipilimumab, 
including 
.  Samples will be collected pre-dose at designated visits.
52) CTC collection includes a sample for exploratory analyses of CTC-associated biomarkers such as DLL3, implemented only at specific sites based on feasibility.
53) CTC collection to occur pre-dose on Day 1 of Cycles 1 and 5.
54) Genotyping includes blood and/or tumor sample for possible assessment of genes for genetic lesions and/or polymorphisms which may influence the safety or efficacy 
response to the study drugs.  Such genes may include but are not necessarily limited to 
55) Serosal Fluid 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, 
pericardiocentsis, or paracentesis), for possible PK, PD, and/or biomarker testing.
56) ctDNA collection to occur pre-dose on Day 1 of Cycle 1and EOT.


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Final Protocol
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13.2
Schedule Peridosing Assessments
Description
Day -1
Predose 
Day 1
Dosing
Day 1
Day 2
Day 8
Day 15
Prior to 
Infusion
0
+30 min 
(±10 min)
+2 hour 
(±15 min)
+4 hour 
(±30 min)
+ 24 hours   
(±2 hours)
± 2 days
± 2 days
Dexamethasone Peridosing1
X
X
X
Rovalpituzumab Tesirine Administration
X
Vital Signs2
X
X
X
X
X
X
ECG3
X
X
Pharmacokinetic sample of Rovalpituzumab 
tesirine4
X
X
X
X
X
X
X
Pharmacokinetic sample of Nivolumab5
X
Pharmacokinetic sample of Ipilimumab6
X
1)
Dexamethasone peridosing as instructed in Section 6.4.1 for Cycles 1 and 3 only (when rovalpituzumab tesirine is administered).
2)
Vital signs as per Appendix 13.1.
3)
ECG as per Appendix 13.1.
4)
PK sample of rovalpituzumab tesirine to be collected at the following cycles (See Section 6.4.2 and 6.4.3):
!
Cycle 1: Day 1, Day 2, Day 8, Day 15
!
Cycle 3: Day 1, Day 2, Day 8, Day 15
!
Cycle 5: Day 1 predose only 
5)
PK sample of nivolumab to be collected predose beginning at Cycle 1 Day 1 and beyond.
6)
PK sample of ipilimumab to be collected predose on Day 1 of Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, and Cycle 6 (Cohorts 2 and 3 only)


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Clinical Protocol M16-300
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Final Protocol
Version 3
                        Page 106 of 125                                                                 Confidential
13.3
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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Final Protocol
Version 3
                        Page 107 of 125                                                                 Confidential
13.4
New York Heart Association (NYHA) Classification
Class I
Subjects with no limitation of activities; they suffer no symptoms 
from ordinary activities.
Class II
Subjects with slight, mild limitation of activity; they are 
comfortable with rest or with mild exertion.
Class III
Subjects with marked limitation of activity; they are comfortable 
only at rest.
Class IV
Subjects 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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Final Protocol
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                        Page 108 of 125                                                                 Confidential
13.5
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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Final Protocol
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13.6
CTCAE v4.03 Grading of Some AEs Relevant to Rovalpituzumab Tesirine
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
–
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.


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Final Protocol
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Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
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.
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).


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Final Protocol
Version 3
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Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
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. Available from:  http://evs nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.


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Rovalpituzumab tesirine (SC16LD6.5)
Final Protocol
Version 3
Page 112 of 125
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13.7
Guidance for Management of Immune-Mediated Adverse Events
These general guidelines constitute guidance to the investigator and may be supplemented by 
discussions with the medical monitor representing the sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. The frequency and severity of the related adverse events 
covered by these algorithms will depend on the immuno-oncology agent or regimen being used.
















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Clinical Protocol M16-300
Rovalpituzumab tesirine (SC16LD6.5)
Final Protocol
Version 3
Page 120 of 125
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13.8
Paraneoplastic Assessment
[EXAMPLE: see Study Binder for actual document]
Paraneoplastic Assessment for Study M16-300 
Subject ID: ____________________
Does this subject have a history of any of the 
following?
Date of Onset
DD/MMM/YYYY
Ongoing?
Clinically 
Significant?
Hypercalcemia
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Lambert-Eaton Myasthenic 
Syndrome (LEMS)
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Syndrome of Inappropriate 
Antidiuretic Hormone Secretion 
(SIADH)
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Cerebellar Ataxia
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Sensory Neuropathy
☐Ye s ☐No
/    /
☐Yes
☐No
☐Yes
☐No
Limbic Encephalitis
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Encephalomyelitis
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Autonomic Neuropathy
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Opsomyoclonus
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Retinopathy
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Other: 
☐Yes
☐No
/    /
☐Yes
☐No
☐Yes
☐No
Investigator Signature: _________________________________
Date: _______________


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Clinical Protocol M16-300
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Final Protocol
Version 3
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13.9
Fluid Retention Questionnaire
[EXAMPLE: see Study Binder for actual document]
Fluid Retention Questionnaire for Study M16-300
Subject ID: ____________________
Over the past 7 days, or since the last time this questionnaire was asked:
1.
What has your daily weight been? 
!
Please weigh yourself at the same time each day and record the date and your weight 
for that day below.
!
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
☐No
3.
Have you noticed any new or worsening shortness of breath during the days above? 
☐Yes
☐No
4.
Please sign below to confirm that you have completed this questionnaire.
____________________________________________
Date: ___________________






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Clinical Protocol M16-300
Rovalpituzumab tesirine (SC16LD6.5)
Final Protocol
Version 3
Page 124 of 125
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13.11
Investigator Signature Page
Investigator Statement and Signature
I have read the attached protocol entitled, A Phase 1/2 Study on the Safety of Rovalpituzumab 
Tesirine Administered in Combination with Nivolumab or Nivolumab and Ipilimumab for 
Adults with Extensive-Stage Small Cell Lung Cancer.
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.
Protocol M16-300 Version 3
Dated:  01-DEC-2017
Investigator Signature
Date
Investigator Name, Printed


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Clinical Protocol M16-300
Rovalpituzumab tesirine (SC16LD6.5)
Final Protocol
Version 3
Page 125 of 125
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13.12 Document History
Version
Date
1
01-DEC-2016
2
16-DEC-2016
3
01-DEC-2017