Conditions: Small Cell Lung Cancer
Keywords: Extensive-Stage Small Cell Lung Cancer (ED SCLC) Cancer Platinum-Based Chemotherapy Rovalpituzumab tesirine first-line chemotherapy Small Cell Lung Cancer (SCLC) Delta-like protein 3 (DLL3)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 748
Healthy volunteers: no

Brief summary:
This is a Phase 3, randomized, double-blind, placebo-controlled, multinational, and multicenter study to evaluate the efficacy of rovalpituzumab tesirine as maintenance therapy following first-line platinum-based chemotherapy.

Detailed description:

Arms:
arm 1: Rovalpituzumab tesirine/dexamethasone every 6 weeks (q6 wk); omitting every third cycle arm 2: Placebo q6 wk; omitting every third cycle

Interventions: intervention 1: Placebo for dexamethasone intervention 2: Placebo for rovalpituzumab tesirine intervention 3: Rovalpituzumab tesirine intervention 4: Dexamethasone
Intervention descriptions: intervention 1: Placebo for dexamethasone PO twice daily on Day -1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle. intervention 2: Placebo for rovalpituzumab tesirine administered intravenously Day 1 of each 6-week cycle, omitting every third cycle intervention 3: Rovalpituzumab tesirine 0.3 mg/kg administered intravenously Day 1 of each 6-week cycle, omitting every third cycle intervention 4: Dexamethasone 8 mg administered orally (PO) twice daily on Day -1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle.

Protocol document:
ICF_002.pdf: 
Cover page of Informed Consent for Study 
M16-298 Date: 23 October 2018 
Title of Study 
A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study 
of Rovalpituzumab Tesirine as Maintenance Therapy Following 
First-Line Platinum-Based Chemotherapy in Subjects with 
Extensive Stage Small Cell Lung Cancer (MERU) 
Protocol Number 
M16-298 
Clinicaltrials.gov 
NCT03033511 
Study Sponsor 
AbbVie 
Phone: (800) 633-9110 
Email: abbvieclinicaltrials@abbvie.com 



























































Prot_000.pdf: 
Rovalpituzumab Tesirine
M16-298 Protocol Amendment 4
EudraCT 2016-003503-64
1
1.0
Title Page
Clinical Study Protocol M16-298
A Randomized, Double-Blind, Placebo-Controlled 
Phase 3 Study of Rovalpituzumab Tesirine as 
Maintenance Therapy Following First-Line
Platinum-Based Chemotherapy in Subjects with 
Extensive Stage Small Cell Lung Cancer (MERU)
Incorporating Amendments 1, 2, 3 and 4
AbbVie Investigational 
  Product:
Rovalpituzumab tesirine (Rova-T)
Date:
05 March 2019
Development Phase:
3
Study Design:
A Randomized, Double-Blind, Placebo-Controlled Phase 3 
Study of Rovalpituzumab Tesirine as Maintenance Therapy 
Following First-Line Platinum-Based Chemotherapy in 
Subjects with Extensive Stage Small Cell Lung Cancer 
(MERU)
EudraCT Number:
2016-003503-64
Investigators:
Investigator information is on file at AbbVie.
Sponsor:
AbbVie Inc.*
Sponsor/Emergency 
  Contact:
Senior Medical Director
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
USA
Phone:
Cell Phone:
Fax:
Email:
* 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.
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.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT03033511


Rovalpituzumab Tesirine
M16-298 Protocol Amendment 4
EudraCT 2016-003503-64
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date 
Original
13 October 2016
Amendment 1
03 February 2017
Amendment 2
20 April 2017
Amendment 3
09 May 2017
The purpose of this amendment is to:
●
Modified Section 1.0 Sponsor/Emergency Contact
Rationale:  Modification of the emergency contact for the study.
●
Update Section 1.2, Synopsis, Section 4.0, Study Objectives, Section 5.3.3.2, 
Section 5.3.3.3, Section 5.3.3.4, Section 8.1.4 Primary Efficacy Endpoints, 
Section 8.1.5 Secondary Efficacy Endpoints, Section 8.1.6 Exploratory 
Efficacy Endpoints to clarify the DLL3high population, secondary endpoints 
updated to include, OS, PFS and PRO endpoints to be tested in all randomized 
patient population and prioritize these ahead of other efficacy endpoints such 
as ORR, CBR and DOR.  Exploratory endpoints were added.
Rationale:  This clarifies the population for primary endpoints (unchanged 
from prior protocol version) and allows evaluation of Rova-T efficacy on OS, 
PFS, and PRO in all enrolled patient population in secondary endpoint.  ORR, 
CBR etc., are clinically less relevant than PFS, OS and PRO and thus, will be 
tested as exploratory endpoints.  
●
Modified Section 1.2, Synopsis Study sites and Section 5.1 Overall Study 
Design to Approximately 300 from 275.
Rationale:  The number of study sites has increased since the last amendment.
●
Update Section 1.2 Synopsis, Section 5.2.1, Inclusion criteria 1 to add the 
option of the subject's legally accepted representative as a person that can sign 
consent on the subject's behalf.
Rationale:  To align with the approved informed consent language.


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●
Updated Section 1.2 Synopsis, Section 5.2.1, Inclusion criteria 3 to say 
'Histologically or cytologically confirmed ED SCLC (extensive stage disease 
at initial diagnosis) with ongoing clinical benefit (SD, PR, or CR per RECIST 
v1.1) following completion of 4 cycles of first-line platinum-based therapy 
(cisplatin or carboplatin in combination with etoposide or irinotecan).'
Rationale:  Clarify that intended patient population is ED SCLC as per 
staging performed at the initial diagnosis and not any other time point.
●
Updated Section 1.2 Synopsis, Section 5.2.1, Inclusion criteria 5 to say 
'Subject is eligible to be randomized at least 3 but no more than 9 weeks from 
Day 1 of the fourth cycle of first-line platinum-based chemotherapy.'
Rationale:  Clarify intended window between front-line therapy and 
randomization.
●
Updated Section 1.2 Synopsis, Section 5.2.1, Inclusion criteria 9f to add 
'modified' to say 'Calculated creatinine clearance ≥ 30 mL/min by the modified 
Cockroft-Gault formula (Refer to Appendix E).'
Rationale:  Clarify required method for assessment of calculated creatinine 
clearance.
●
Updated Section 1.2 Synopsis, Section 5.2.2, Exclusion criteria 1 to remove 
'the disease under study' and replace it with 'SCLC.'
Rationale:  Further clarify that subjects who received prior treatment for LD-
SCLC are excluded
●
Updated Section 1.2 Synopsis, Section 5.2.2, Exclusion criteria 2 to add 
'palliative radiotherapy to a radiographically documented non-progressing 
lesion for symptom control.'
Rationale:  Clarify that palliative radiotherapy is allowed for non-progressing 
lesions.
●
Updated Section 1.2 Synopsis, Section 5.2.2, Exclusion criteria 4 to change the 
reference from Appendix E to Appendix F.
Rationale:  Correcting a typo from the previous amendment.
●
Updated Section 1.2 Synopsis Statistical Methods section, Section 8.1
Statistical and Analytical Plans, Section 8.4, Section 8.5 and Section 8.6 to 


Rovalpituzumab Tesirine
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remove the efficacy interim analysis after observing 75% of the final OS 
events and to add a futility analysis at 50% of the final OS events.
Rationale: Enable earlier stopping of the trial in the event of futility and 
improve statistical properties at final OS.  
●
LD SCLC defined in List of Abbreviations as Limited-stage disease small cell 
lung cancer
Rationale:  Definition added to clarify the different disease states for SCLC.
●
Modified Section 3.3 Rovalpituzumab Tesirine to provide updated data.
Rationale:  Latest data added from ongoing Rova-T studies.
●
Modified Section 3.5 Benefits and Risks to update safety language.  
Rationale: To provide updated safety information
●
Modified Section 5.1 Overall Study Design, Footnote number 3 under Figure 1
to include the following updated language- 'Subject is eligible to be 
randomized at least 3 but no more than 9 weeks from Day 1 of the fourth cycle 
of first-line platinum-based chemotherapy.'
Rationale:  To be consistent with the update to Inclusion Criteria 5.
●
Modified Section 5.2 Selection of Study Population to include the LD and ED 
SCLC definition.
Rationale:  Modified to include the definition per IASLC/VA for LD and ED 
SCLC.
●
Modified Section 5.2.3.1 Prior therapy to be consistent with changes to 
Inclusion Criteria 3 and 5.
Rationale:  To be consistent with the update to Inclusion Criteria 3 and 5.
●
Modified Section 5.2.3.2 Concomitant Therapy to add additional safety 
guidelines regarding sun exposure. 
Rationale:  To provide updated guidelines regarding sun exposure and to 
maintain consistent with the Toxicity Management language in Section 6.1.8.2.
●
Modified Section 5.3.1.1 Study Procedures, Vital signs, to address weight 
increases of 5% or greater and add 'actual' prior to 'weight.'  
Rationale:  To ensure accurate determination of dose in the event of blinded 
investigational product-related weight gain due to fluid retention


Rovalpituzumab Tesirine
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●
Modified Section 5.3.1.1 Study Procedures, Echocardiogram, the following 
language has been changed:  'Echocardiograms will be performed per 
Appendix C, Study Activities to rule out pericardial effusion (or assess, if 
present), as well as assess cardiac function (left ventricular ejection fraction, 
LVEF).' 
Rationale:  Clarifying the purpose of on-study Echocardiograms.
●
Modified Section 5.3.1.1 Study Procedures, Disease/Response Assessment 
(Radiographic Imaging), language has been added to advise sites on the need 
to discuss with TA MD regarding the gaps between tumor assessments and 
doses in certain cases of dose delays. 
Rationale:  Modified to address the planning of CTs in cases of treatment 
delays.
●
Modified Section 5.3.1.1 Study Procedures, MRI/CT of the Brain and Footnote 
t under Appendix C to clarify that the MRI/CT of the brain is required at 
screening and when clinically indicated thereafter. 
Rationale:  Modified to clarify when MRI/CT of the brain is required on study.
●
Modified Section 5.3.1.1 Study Procedures, Fluid Retention Questionnaire 
(Including Subject Daily Weight), the following language has been added:  
'The site will advise subjects to contact the site in cases where sudden weight 
gain (5% or greater) is observed for possible assessment in the clinic.'
Rationale:  Modified to clarify the definition of weight gain that requires 
additional assessment by the site.
●
Modified Section 5.3.1.1 Study Procedures, End of Treatment (EOT) Visit, the 
following language has been added:  'The EOT procedures should be done 
within 7 days of documented decision to discontinue treatment and prior to 
subjects beginning any new anti-cancer therapy if possible.'
Rationale:  Modified to fix conflicted language in the protocol.
●
Modified Section 5.3.3.2 Primary Variables to add '…determined by a Central 
Radiographic Assessment Committee (CRAC) per RECIST v. 1.1 and overall 
survival (OS) in DLL3high population.'
Rationale:  To clarify the version of RECIST used for this study and to clarify 
that the DLL3high subjects are analyzed.


Rovalpituzumab Tesirine
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●
Modified Section 5.5.1 Treatment Administration to add 'placebo' after 
'dexamethasone' in the last sentence of the first paragraph
Rationale:  Modified to be consistent with the rest of the paragraph.
●
Modified Section 5.5.2.1 Packing and Labeling, Rovalpituzumab Tesirine and 
Placebo to include updated Hazardous Drug packing and shipping standards.
Rationale:  Added to clarify packaging and shipping requirements as per 
applicable regulations.
●
Modified Section 5.5.2.2 Storage and Disposition of Blinded Investigational 
Product(s) and Section 5.5.2.3 Preparation/Reconstitution of Dosage Form(s) 
to note specific instructions for reconstituted and diluted IP will be found in an 
outside document.
Rationale:  Site awareness for a separate document that contains additional 
information on IP storage and disposition.
●
Modified Section 5.5.4.1 Dosing to add fluid retention weight gain guidance. 
Rationale:  To instruct sites on cases of weight gain due to fluid retention.
●
Modified Table 5 to include: 
Grade 2 pneumonitis
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Grade ≥ 3 pneumonitis
Discontinue Rova-T
N/A
●
Addition of footnote b.
Rationale:  Update dose modification guidelines to align with safety profile 
for Rova-T as described in the IB v.7.
●
Modified Section 5.5.5.2 Blinding of Data for Independent Data Monitoring 
Committee (IDMC) to update the change from an interim analysis to a futility 
analysis.
Rationale:  To align with the updated statistical plan.
●
Modified Section 5.5.7 Drug Accountability to update classification of Rova-T 
as a dangerous good/hazardous material. 
Rationale:  Added to clarify classification as well as packaging and shipping 
requirements as per applicable regulations.


Rovalpituzumab Tesirine
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●
Modified Section 6.1.1.3 to update guidance on capturing disease progression 
and fatal events for AEs and SAEs in the CRF.
Rationale:  To clarify on AE/SAE reporting regarding events due to disease 
progression.
●
Modified Section 6.1.4 Deaths to add language about capturing these events in 
the CRF.
Rationale:  To provide guidance on capturing deaths during AE/SAE 
reporting period in EDC.
●
Modified Section 6.1.5 Adverse Event Collection Period, to say 'All adverse 
events reported from the time of blinded investigational product administration 
until 70 days following the last dose of blinded investigational product will be 
collected, whether solicited or spontaneously reported by the subject.'
Rationale:  To clarify AE collection period from last dose of blinded IP.
●
Modified Section 6.1.6 Adverse Event Reporting to update the emergency 
contact for the study and add updated language regarding SUSARs and 
guidelines for the Reference Safety Information (RSI).
Rationale:  Modification of the emergency contact for the study and current 
information regarding SUSAR reporting.
●
Modified Section 6.1.8 Toxicity Management to add additional safety 
guidance on serosal effusions, skin reactions, edema, and pneumonitis.  
Rationale:  Provide additional guidance to investigators and subjects for 
awareness and guidance to align with IBv7.
●
Updated Section 7.0 Protocol Deviations-Primary and Alternate contact 
information.
Rationale:  To provide sites with current AbbVie contact information.
●
Modified Section 8.1.3 Efficacy Endpoints and Analyses to delete the first 
sentence.
Rationale: Align with updated analysis plan as outlined above.
●
Updated Section 8.1.7 to Patient Reported Outcomes (PRO) and add the 
following language, 'Physical functioning scale score in EORTC QLQ-C30 is 
the key secondary endpoint.'  
Rationale:  Align with updated analysis plan as outlined above.


Rovalpituzumab Tesirine
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●
Changed Section Planned Sensitivity and Subgroup Analysis to 8.1.8 and 
delete the first, third and last sentence of the section.
Rationale:  Align with updated analysis plan as outlined above.
●
Changed Section Pharmacokinetic and Exposure-Response Analyses to 8.1.9.  
Modified Synopsis Section 1.2 Criteria for Evaluation, Pharmacokinetic, 
Section 5.3.5 Pharmacokinetic Variables and Section 8.1.9 Pharmacokinetic 
and Exposure-Response Analyses to change 'plasma' to 'serum.'
Rationale:  To update numbering in the section of the protocol and align with 
the lab manual.
●
Modified Section 8.3 Type I Error Adjustment Procedure for Multiple Testing 
to include the DLL3high set, update the null hypotheses and level of 
significance.  Figure 3 was also added.  This is outlined above in the Synopsis 
section.
Rationale:  Align with updated analysis plan as outlined above.
●
Modified Section 10.1 Source Documents to clarify that the Investigator 
Awareness date of a SAE should be noted in the source, not the EDC.
Rationale:  This data point cannot be captured in the EDC.
●
Added the following addition to References, '19. AbbVie.  Rovalpituzumab 
Tesirine Dear Rova-T Investigator Letter.  05 December 2018.'
Rationale:  Added reference due to new safety data.
●
Modified Appendix B:  List of Protocol Signatories
Rationale:  Updated new team members since last amendment.
●
Modified Appendix C:  Echocardiogram.  Now a required assessment listed 
under Screening.
Rationale:  To provide a bigger window for sites to complete the assessment.
●
Modified Footnote b under Appendix C to say, 'End of Treatment Visit 
procedures should be done within 7 days of documentation of the decision to 
discontinue treatment and prior to subjects beginning any new anti-cancer 
therapy if possible.'
Rationale:  Updated to be consistent with EOT treatment language.


Rovalpituzumab Tesirine
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EudraCT 2016-003503-64
9
●
Modified Footnote e under Appendix C to add the following language, 
'Cycle 1 Day 1 procedures, with the exception of weight.'
Rationale:  Updated to clarify when weight should be done to be used for 
dosing decisions.
●
Modified Footnote n under Appendix C to clarify when Echocardiograms are 
required throughout the study and in relation to pericardial effusion 
assessments.
Rationale:  To allow for a larger window for the assessment to be completed.
●
Modified Footnote q under Appendix C to advise sites on the need to contact 
TA MD for the gaps in tumor assessments.
Rationale:  Updated to indicate when the TA MD should be consulted.
●
Make administrative changes of typographical errors, minor language and 
word revision as needed throughout the document.
Rationale:  Clarifies and ensures consistency throughout.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix K.


Rovalpituzumab Tesirine
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-298
Name of Study Drug:  rovalpituzumab tesirine 
(Rova-T)
Phase of Development:  3
Name of Active Ingredient:  rovalpituzumab 
tesirine
Date of Protocol Synopsis:  05 March 2019
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rovalpituzumab 
Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with 
Extensive Stage Small Cell Lung Cancer (MERU)
Objectives:
Primary
•
To evaluate if rovalpituzumab tesirine improves progression-free survival, assessed by a Central 
Radiographic Assessment Committee (CRAC) according to RECIST v1.1, and overall survival 
in subjects with extensive-stage small cell lung cancer (ED SCLC) tumors with a high level of 
DLL3 expression (DLL3high) who have ongoing clinical benefit (SD, PR, or CR) following 
first-line platinum-based chemotherapy (cisplatin or carboplatin plus irinotecan or etoposide) 
compared to placebo.
Secondary
•
To evaluate if rovalpituzumab tesirine improves progression-free survival by CRAC and overall 
survival in all randomized subjects compared to placebo. 
•
To assess change in patient reported outcomes (PRO) with physical functioning as measured by 
the EORTC QLQ-C30 questionnaire in all randomized subjects compared to placebo.
Exploratory
•
To evaluate rovalpituzumab tesirine anti-tumor activity by determining objective response rate 
(ORR), clinical benefit rate (CBR), and duration of responses (DOR) by CRAC and Investigator 
assessment in DLL3high and in all randomized subjects.
•
To evaluate if rovalpituzumab tesirine improves progression-free survival by Investigator 
assessment compared to placebo in DLL3high and in all randomized subjects.
•
To assess change from baseline in all patient reported outcomes (PRO) domains (except physical 
functioning) measured by EORTC QLQ-C30/LC13 and EQ-5D-5L.
•
To characterize the pharmacokinetics and incidence of anti-therapeutic antibodies (ATAs) 
against rovalpituzumab tesirine.
•
To evaluate pharmacodynamic and predictive biomarkers in blood and tumor for association 
with sensitivity, efficacy and safety.
•
To explore DLL3 expression in circulating tumor cells (CTCs) for association with efficacy.
Investigators:  Multicenter, International
Study Sites:  Approximately 300
Study Population:  Subjects with extensive-stage Small Cell Lung Cancer (ED SCLC) with ongoing 
clinical benefit (SD, PR, or CR per RECIST v1.1) following completion of 4 cycles of first-line 
platinum-based chemotherapy (cisplatin or carboplatin in combination with etoposide or irinotecan).


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Number of Subjects to be Enrolled:  Up to approximately 740 SCLC subjects, to obtain approximately 
480 subjects with DLL3high expression in tumor (DLL3high).  DLL3high is defined as ≥ 75% tumor cells 
staining positive according to the VENTANA DLL3 (SP347) IHC Assay.
Methodology:  
This is a Phase 3, randomized, double-blinded, placebo-controlled, multinational, and multicenter study.
ED SCLC subjects who meet all the inclusion criteria and none of the exclusion criteria, and demonstrate 
ongoing clinical benefit (SD, PR, or CR) at the completion of 4 cycles of first-line platinum-based 
chemotherapy (such benefit must be ongoing at the last re-staging assessment prior to randomization), 
will be randomly assigned in a 1:1 ratio to receive 0.3 mg/kg rovalpituzumab tesirine or placebo, and will 
receive their assigned therapy on Day 1 of each 6-week cycle, omitting every third cycle.  Upon 
completion of first-line chemotherapy, eligible subjects must be offered prophylactic cranial irradiation 
(PCI), if offering this procedure is not contradictory to country or institutional guidelines.  Subjects 
receiving PCI must complete it prior to randomization into the study.  Subjects will also receive 8 mg 
orally (PO) of dexamethasone or placebo twice daily on Day –1, Day 1, and Day 2 of each 6-week cycle, 
omitting every third cycle.  Randomization will be stratified by RECIST v1.1 response after completion 
of first-line platinum-based chemotherapy at screening assessment (SD vs. PR/CR), DLL3 expression, 
(Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or above), history of central nervous system 
(CNS) metastases (Yes vs. No), and for subjects with no history of CNS metastases, PCI vs. no PCI.
Survival Follow-up will continue until the endpoint of death, the subject becomes lost to follow-up or 
withdraws consent, or termination of the study by AbbVie, whichever occurs first.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
1.
Subject or the subject's legally acceptable representative must voluntarily sign and date an informed 
consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), 
prior to the initiation of any screening or study-specific procedures and should be willing and able to 
comply with parameters as outlined in the protocol.
2.
Subject must be ≥ 18 years of age.
3.
Histologically or cytologically confirmed ED SCLC (extensive stage disease at initial diagnosis), 
with ongoing clinical benefit (SD, PR, or CR per RECIST v1.1) following completion of 4 cycles of 
first-line platinum-based therapy (cisplatin or carboplatin in combination with etoposide or 
irinotecan).
4.
Subjects with a history of CNS metastases prior to the initiation of first-line platinum-based 
chemotherapy must have received definitive local treatment and have documentation of stable or 
improved CNS disease status based on brain imaging within 28 days prior to randomization, off or on 
a stable dose of corticosteroids. 
5.
Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the 
fourth cycle of first-line platinum-based chemotherapy 
6.
Availability of archived or representative tumor material for assessment of DLL3 expression. 
7.
Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.  
8.
Recovery to ≤ Grade 1 of any clinically significant toxicity (excluding alopecia) prior to 
randomization.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
9.
Subject must have adequate bone marrow, renal and hepatic function as follows:
a.
Absolute neutrophil count (ANC) ≥ 1,000/μL
b.
Platelet count ≥ 75,000/μL
c.
Hemoglobin ≥ 8.0 g/dL
d.
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with 
Gilbert's disease
e.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN 
(≤5× ULN if evidence of hepatic involvement by malignant disease)
f.
Calculated creatinine clearance ≥ 30 mL/min by the modified Cockroft-Gault formula (Refer to 
Appendix E).
g.
Albumin ≥ 3g/dL
10. If female, subject must be either postmenopausal as 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
•
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
OR a Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method 
of birth control, starting at randomization through at least 6 months after the last dose of blinded 
investigational product.
If the male subject is sexually active, he must agree, from randomization through at least 6 months 
after the last dose of blinded investigational product, to practice the protocol specified contraception.
11. Females of childbearing potential must have a negative serum pregnancy test result at Screening, and 
a negative urine pregnancy test at randomization.
Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as 
defined in the protocol) at Screening do not require pregnancy testing.
Main Exclusion:  
1.
Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint inhibitors, other 
monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, T-cell or other cell-based 
or biologic therapies, or any other anti-cancer therapy than that described in Inclusion Criteria 3 – 5 
for SCLC.
2.
Any disease-directed radiotherapy (except, PCI, palliative radiotherapy to a radiographically 
documented non-progressing lesion for symptom control, or pre-planned radiotherapy for CNS 
metastases present prior to start of first-line therapy and non-progressing) after last dose of first-line 
chemotherapy.
3.
Any significant medical condition including any suggested by screening laboratory findings that in 
the opinion of the Investigator or Sponsor may place the subject at undue risk from the study.


Rovalpituzumab Tesirine
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):  
4.
Documented history of a cerebral vascular event, unstable angina, myocardial infarction, or cardiac 
symptoms consistent with New York Heart Association (NYHA) Class III – IV heart failure (refer to 
Appendix F) within 6 months prior to randomization.
5.
Documented history of capillary leak syndrome.
6.
Grade 2 or higher pleural or pericardial effusion within 4 weeks of randomization or earlier history of 
recurrent Grade 2 or higher effusions with ongoing requirement for pericardiocentesis or 
thoracentesis.
7.
Serious infection within 2 weeks prior to randomization, including any Grade 3 or higher (per NCI 
CTCAE version 4.0) viral, bacterial, or fungal infection.
8.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study 
or for approximately 6 months after the last dose of blinded investigational product.
9.
Male subject who is considering fathering a child or donating sperm during the study or for 
approximately 6 months after the last dose of blinded investigational product.
10. Systemic therapy with corticosteroids at > 10 mg/day prednisone or equivalent within 1 week prior to 
randomization.
11. Subject has a history of active malignancies other than SCLC within the past 2 years prior to study 
entry, with the exception of in situ cancer which was curatively treated.
12. Any prior exposure to a pyrrolobenzodiazepine (PBD-based)-or indolinobenzodiazepine-based drug, 
prior participation in a rovalpituzumab tesirine clinical trial, or known hypersensitivity or other 
contraindications to rovalpituzumab tesirine or excipient contained in the drug formulation.
13. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
Investigational Products:
Rovalpituzumab tesirine or Placebo
Dexamethasone or Placebo
Doses:
Rovalpituzumab tesirine/Placebo:  0.3 mg/kg, Day 1 of each 6-week 
cycle, omitting every third cycle.
Dexamethasone/Placebo 8 mg orally (PO) twice daily on Day –1, Day 1 
(the day of dosing), and Day 2 of each 6 week cycle, omitting every 
third cycle.
Mode of Administration:
Rovalpituzumab tesirine/Placebo:  Intravenous
Dexamethasone/Placebo:  Oral
Duration of Treatment:  Subjects will receive rovalpituzumab tesirine/placebo in combination with 
dexamethasone/placebo on Day 1 of a 6-week cycle, omitting every third cycle until disease progression.
Criteria for Evaluation:
Efficacy: Efficacy assessments will consist of evaluations for tumor progression using Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 and will be based on a Central Radiographic 
Assessment Committee (CRAC) review of medical images, as outlined in the Schedule of Assessments.  
Additionally, efficacy will be assessed by overall survival.  
Pharmacokinetic:  Serum concentrations of rovalpituzumab tesirine ADC and the presence of anti-
therapeutic antibodies (ATA) will be determined.


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Criteria for Evaluation (Continued):
Biomarkers:  Pharmacodynamic and predictive biomarker assessments will include analyses of tumor 
material and circulating tumor cells for DLL3 expression, blood samples for inflammatory, tumor, and 
soluble markers.  Samples may also be used for other nucleic acid or protein based exploratory 
biomarkers to understand the sensitivity or resistance to rovalpituzumab tesirine and biology of SCLC.
Safety:  Safety assessments include physical exam, vital signs, body weight, ECOG score, clinical 
adverse events, laboratory tests (hematology, serum chemistries, urinalysis, and coagulation), ECGs, 
echocardiogram, fluid retention questionnaire, radiographic images review for fluid retention, and 
monitoring of concomitant medications.
Patient Reported Outcome (PRO): 
Changes in the patient reported outcomes (PROs) EORTC QLQ-C30, EORTC QLQ-LC13, and 
EQ-5D-5L from baseline will be assessed.
Statistical Methods:
Efficacy:  
Progression-free survival (PFS) per CRAC and overall survival (OS) in patients with DLL3high ED SCLC 
are the two primary efficacy endpoints.  To meet global regulatory requirements, a multiple testing 
strategy will be implemented to control the family-wise type I error (alpha) for comparisons of 
rovalpituzumab tesirine arm versus placebo arm with respect to progression-free survival (PFS) per 
CRAC in DLL3high patients, overall survival (OS) in DLL3high patients, PFS per CRAC in randomized 
patients, OS in randomized patients, and physical functioning scale score (EORTC QLQ-C30) in the 
randomized set.
The following null hypotheses are considered:
Two hypotheses in H01 are H01a and H01b.
H01a:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in DLL3high set. 
H01b:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in DLL3high set. 
H02:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in randomized set. 
H03:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in randomized set. 
H04:  Rovalpituzumab tesirine arm is not superior to placebo arm in physical functioning scale score 
(EORTC QLQ-C30) in randomized set. 
The null hypotheses will be tested in a fixed sequence of {H01a, H01b, H02, H03, and H04} in order.  To 
maintain the family-wise type I error for the study, the null hypotheses in H01 (H01a and H01b) will be first 
tested with an alpha-split approach.  The one-sided alpha of 0.25% and 2.25% will be assigned for PFS 
and OS hypothesis in H01, respectively.  Out of one-sided alpha of 2.25% allocated to OS hypothesis
(H01b), the one-sided alpha of 10–6 will be spent for the early look at the OS data for futility analysis.  If 
the hypothesis for PFS in H01 (H01a) is rejected the one-sided alpha of 0.25% will be recycled to the OS 
hypothesis in H01 (H01b).  Hence, the hypothesis for OS in H01 (H01b) will be tested either at a one-sided 
2.4999% or one-sided 2.2499% level of significance depending on the PFS hypothesis in H01 a is rejected 
or not. 
If either PFS or OS endpoint reaches statistical significance, the study is considered positive.  No further 
tests will be performed if the OS endpoint in DLL3high population (H01b) does not reach statistical 
significance.


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Statistical Methods (Continued):
The hypothesis in H02 will be tested if the hypothesis in H01b is rejected. If the hypothesis in H02 is 
rejected, then, either (i) H03 and H04 will be tested sequentially if the PFS endpoint in DLL3high subjects 
(H01a) is also rejected or (ii) only H04 will be tested if the PFS endpoint in DLL3high subjects (H01a) is not 
rejected.
Futility Analysis:
Unblinded interim data will be analyzed and reviewed by the IDMC.  A futility analysis will be 
conducted when approximately 160 deaths in subjects with DLL3high ED SCLC (approximately 50% of 
the planned deaths) are observed.  The trial may be stopped for futility if the estimated Overall Survival 
Cox HR of Rova-T to Placebo at this analysis exceeds 0.9.  The one-sided alpha of 10–6 will be spent for 
the early look at the efficacy data for futility analysis.
Sample Size:
There are two primary efficacy endpoints for this study:  Progression-free survival (PFS) based on the 
CRAC and overall survival (OS) in subjects with DLL3high ED SCLC.  To maintain the overall 1-sided 
type I error at a 2.5% for this study, the type I error will be split, assigning 0.25% to progression-free 
survival and the remaining 2.25% to overall survival.  However, the OS endpoint will be tested at a 
one-sided 2.2499% significance level as a one-sided alpha of 10–6 will be spent for the early look at the
OS data for futility analysis. 
The sample size of the study is primarily determined by the analysis of OS.  It is assumed, taking into 
account the expected patient population for the study, that median overall survival in the placebo and 
rovalpituzumab tesirine arm will be around 9 months and 13 months, respectively.  The increase of 
median OS in rovalpituzumab tesirine arm corresponds to a hazard ratio of 0.69, i.e., a reduction in the 
hazard of death by 31%.  With all these assumptions, a total of 319 deaths among subjects with DLL3high
are needed to achieve a 90% power based on a log-rank test at a one-sided significance level of 0.022499.  
Assuming a 19-month accrual period and the last enrolled subject followed for 12 months, at least 
480 subjects with DLL3high are expected to be randomized (240 subjects in each arm).  A total of 
740 subjects regardless of DLL3 expression level (including 480 subjects with DLL3high) will enroll in 
the study, assuming an approximate prevalence of 65% for subjects with DLL3high.  For one-sided 
significance level of 0.022499, it is projected that an observed hazard ratio of 0.799 or less, 
corresponding to a 2.3 months or greater improvement in median OS, would result in a statistically 
significant improvement in the primary analysis of OS.
The primary endpoints of OS and PFS in DLL3high patients will be analyzed at the same time after 
observing at-least 319 OS event.  It is expected at approximately 420 PFS events will be observed at the 
time of the primary analysis.
It is assumed, taking into account the expected patient population for the study, that median progression-
free survival for the placebo and rovalpituzumab tesirine arm will be approximately 3 months and 
4.5 months, respectively.  The increase of median progression-free survival in rovalpituzumab tesirine 
arm corresponds to a hazard ratio of 0.667.  With all these assumptions, a total of 420 PFS events 
assessed by the CRAC for the subjects with DLL3high are needed to achieve a 91% power based on a log-
rank test at a one-sided significance level of 0.0025.  It is projected that an observed hazard ratio of 0.760 
or less, corresponding to approximately 1 month or greater improvement in median PFS, would result in 
a statistically significant improvement in the PFS.


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Statistical Methods (Continued):
Pharmacokinetic:  
Individual concentrations of rovalpituzumab tesirine ADC will be tabulated and summarized for subjects 
treated with the active regimen and summary statistics provided.  The incidence of ATA will be 
summarized.
Biomarkers:
Biomarkers will be measured at baseline and post-treatment and analyses performed to identify markers 
associated with rovalpituzumab tesirine response, pharmacodynamics, PK, or safety.
Safety:  
The safety of rovalpituzumab tesirine will be assessed by evaluating the study drug exposure, adverse 
events, all deaths, as well as changes in laboratory determinations and vital sign parameters.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADC
Antibody-drug conjugate
AE
Adverse event
ALT
Alanine aminotransferase
ANA
Anti-nuclear antibodies
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ASCL1
Achaete-scute homolog 1 
ASRO
American Society for Radiation Oncology
AST
Aspartate aminotransferase 
AT
Aminotransferase 
ATA
Anti-therapeutic antibody
ATC
Anatomical therapeutic chemical (codes)
β-hCG
Beta-human chorionic gonadotropin
BUN
Blood urea nitrogen
CBR
Clinical benefit rate
CDSM
Clinical Drug Supply Management
CFR
Code of Federal Regulations
CNS
Central nervous system
CR
Complete response
CRAC
Central Radiographic Assessment Committee 
CRP
C-reactive protein
CSC
Cancer stem cell
CT
Computerized tomography
CTC
Circulating tumor cell
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating Tumor DNA
CYP3A4
Cytochrome P450 3A4
DILI
Drug-induced liver injury
DLL3
Delta-like protein 3
DLL3high
DLL3 high expression in tumor defined as ≥ 75% tumor cells staining 
positive according to the VENTANA DLL3 (SP347) IHC Assay


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DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
Electronic data capture
ED SCLC
Extensive-stage disease small cell lung cancer
EFNS
European Federation of Neurological Societies
EGF
Epidermal growth factor
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of Treatment
EQ-5D-5L
EuroQoL Five Dimensions Questionnaire
ESMO
European Society for Medical Oncology 
ESR
Erythrocyte sedimentation rate
EU
European Union 
FDA
US Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
Gy
Gray
HDPE
High-density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
HR
Hazard ratio
ICF
Informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IL
Interleukin
IMP
Investigational Medicinal Product
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive response technology
IUD
Intrauterine device
IV
Intravenous(ly)


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JSMO
Japanese Society of Medical Oncology
LCNEC
Large cell neuroendocrine cancer
LDH
Lactate dehydrogenase
LD SCLC
Limited-stage disease small cell lung cancer
LFT
Liver function test
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
nAb
Neutralizing antibodies
NASH
Non-alcoholic steatohepatitis
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NEUROD1
Neurogenic differentiation 1
NSAID
Non-steroidal anti-inflammatory drug
NSE
Neuron-specific enolase
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
PBD
Pyrrolobenzodiazepine
PCI
Prophylactic cranial irradiation
PD
Progressive disease
PDX
Patient-derived xenografts
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetics
PO
Per os (by mouth)
PR
Partial response
PRO
Patient reported outcome
PT
Prothrombin time
PTFU
Post-treatment follow up
q6wk
Every 6 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RF
Rheumatoid factor


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Rova-T
Rovalpituzumab tesirine
RPTD
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SC-DR002
DNA cross-linking agent also known as D6.5
SC16
Humanized DLL3-specific IgG1 antibody
SCLC
Small cell lung cancer
SD
Stable disease
SIADH
Syndrome of Inappropriate Anti-Diuretic Hormone
SMPC
Summary of product characteristics
SPF
Sun protection factor
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TIC
Tumor-initiating cells
TNM
Tumor, node, metastases
TTP
Time to progression
ULN
Upper limit of normal
VA
Veterans Administration
VEGF
Vascular endothelial growth factor
WHODRUG
World Health Organization Drug (Dictionary)
WOCBP
Women of childbearing potential


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis ...................................................................................................10
1.3
List of Abbreviations and Definition of Terms........................................17
2.0
Table of Contents...................................................................21
3.0
Introduction ...........................................................................26
3.1
Small Cell Lung Cancer...........................................................................26
3.2
Delta-Like Protein 3.................................................................................26
3.3
Rovalpituzumab Tesirine.........................................................................27
3.4
Differences Statement..............................................................................29
3.5
Benefits and Risks....................................................................................29
4.0
Study Objectives....................................................................30
5.0
Investigational Plan...............................................................32
5.1
Overall Study Design and Plan:  Description ..........................................32
5.2
Selection of Study Population..................................................................33
5.2.1
Inclusion Criteria .....................................................................................34
5.2.2
Exclusion Criteria ....................................................................................36
5.2.3
Prior and Concomitant Therapy...............................................................38
5.2.3.1
Prior Therapy ...........................................................................................38
5.2.3.2
Concomitant Therapy...............................................................................39
5.2.3.2.1
Allowed Concomitant Therapy................................................................39
5.2.3.3
Prohibited Therapy...................................................................................41
5.2.4
Contraception Recommendations ............................................................41
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic and 
Safety Assessments/Variables..................................................................42
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................42
5.3.1.1
Study Procedures .....................................................................................43
5.3.1.2
Collection and Handling of Biomarker and Optional Exploratory 
Research Samples ....................................................................................55
5.3.2
Drug Concentration Measurements .........................................................58
5.3.2.1
Collection of Samples for Analysis .........................................................58


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5.3.2.2
Handling/Processing of Samples .............................................................58
5.3.2.3
Disposition of Samples ............................................................................58
5.3.2.4
Measurement Methods.............................................................................59
5.3.3
Efficacy Variables....................................................................................59
5.3.3.1
Definition of Disease Progression............................................................59
5.3.3.2
Primary Variables ....................................................................................59
5.3.3.3
Secondary Variables ................................................................................60
5.3.3.4
Exploratory Variables ..............................................................................60
5.3.4
Safety Variables.......................................................................................60
5.3.5
Pharmacokinetic Variables ......................................................................61
5.3.6
Biomarker and/or Optional Exploratory Research Variables ..................61
5.4
Removal of Subjects from Therapy or Assessment.................................62
5.4.1
Discontinuation of Individual Subjects....................................................63
5.4.2
Discontinuation of Entire Study...............................................................64
5.5
Treatments................................................................................................64
5.5.1
Treatments Administered.........................................................................64
5.5.2
Identity of Investigational Product(s) ......................................................65
5.5.2.1
Packaging and Labeling...........................................................................65
5.5.2.2
Storage and Disposition of Blinded Investigational Product(s)...............66
5.5.2.3
Preparation/Reconstitution of Dosage Form(s)........................................67
5.5.3
Method of Assigning Subjects to Treatment Arms..................................67
5.5.4
Selection and Timing of Dose for Each Subject......................................68
5.5.4.1
Dosing......................................................................................................68
5.5.4.2
Dose Modifications..................................................................................68
5.5.4.2.1
Dose Treatment Delays due to Toxicity or Progression ..........................68
5.5.4.2.2
Dose Reduction Guidelines......................................................................69
5.5.5
Blinding....................................................................................................72
5.5.5.1
Blinding of Investigational Product.........................................................72
5.5.5.2
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ....................................................................................................72
5.5.6
Treatment Compliance.............................................................................72
5.5.7
Drug Accountability.................................................................................73
5.6
Discussion and Justification of Study Design..........................................74


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5.6.1
Discussion of Study Design and Choice of Control Groups....................74
5.6.2
Appropriateness of Measurements...........................................................74
5.6.3
Suitability of Subject Population .............................................................75
5.6.4
Selection of Doses in the Study ...............................................................75
6.0
Complaints .............................................................................75
6.1
Medical Complaints.................................................................................76
6.1.1
Definitions................................................................................................76
6.1.1.1
Adverse Event..........................................................................................76
6.1.1.2
Serious Adverse Events ...........................................................................77
6.1.1.3
Adverse Events Expected Due to SCLC or Progression of SCLC ..........78
6.1.2
Adverse Event Severity............................................................................79
6.1.3
Relationship to Study Drug......................................................................79
6.1.4
Deaths ......................................................................................................80
6.1.5
Adverse Event Collection Period.............................................................81
6.1.6
Adverse Event Reporting.........................................................................82
6.1.7
Pregnancy.................................................................................................84
6.1.8
Toxicity Management ..............................................................................84
6.1.8.1
Management of Serosal Effusions/Serositis ............................................85
6.1.8.2
Management of Skin Reactions ...............................................................85
6.1.8.3
Management of Potential Drug-Induced Liver Injury .............................87
6.1.8.4
Monitoring and Management of Edema ..................................................89
6.1.8.5
Pneumonitis..............................................................................................91
6.2
Product Complaint ...................................................................................92
6.2.1
Definition .................................................................................................92
6.2.2
Reporting..................................................................................................92
7.0
Protocol Deviations................................................................93
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................94
8.1
Statistical and Analytical Plans................................................................94
8.1.1
Disposition of Study Subjects..................................................................95
8.1.2
Demographics and Baseline Characteristics............................................95
8.1.3
Efficacy Endpoints and Analyses ............................................................95
8.1.4
Primary Efficacy Endpoints.....................................................................96


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8.1.5
Secondary Efficacy Endpoints.................................................................97
8.1.6
Exploratory Efficacy Endpoints...............................................................97
8.1.7
Patient Reported Outcomes (PRO) ..........................................................98
8.1.8
Planned Sensitivity and Subgroup Analyses............................................99
8.1.9
Pharmacokinetic and Exposure-Response Analyses ...............................99
8.2
Safety Analyses......................................................................................100
8.2.1
Treatment-Emergent Adverse Events (TEAEs).....................................100
8.2.2
Clinical Laboratory Evaluation..............................................................101
8.2.3
Vital Signs..............................................................................................101
8.2.4
ECOG Performance Status ....................................................................101
8.2.5
Electrocardiogram..................................................................................101
8.2.6
Concomitant Medications ......................................................................101
8.3
Type I Error Adjustment Procedure for Multiple Testing .....................101
8.4
Determination of Sample Size ...............................................................105
8.5
Futility Analysis.....................................................................................106
8.6
Accrual/Study Duration Considerations ................................................106
8.7
Randomization Methods ........................................................................107
9.0
Ethics.....................................................................................107
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................107
9.2
Ethical Conduct of the Study.................................................................108
9.3
Subject Information and Consent...........................................................108
9.3.1
Informed Consent Form and Explanatory Material ...............................109
9.3.2
Revision of the Consent Form and Explanatory Material .....................109
10.0
Source Documents and Case Report Form 
Completion ...........................................................................110
10.1
Source Documents .................................................................................110
10.2
Case Report Forms.................................................................................110
11.0
Data Quality Assurance ......................................................112
12.0
Use of Information...............................................................112
13.0
Completion of the Study .....................................................113
14.0
Investigator's Agreement....................................................114
15.0
Reference List ......................................................................115


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List of Tables
Table 1.
Examples of Strong CYP3A4 Inhibitors..................................................41
Table 2.
Clinical Laboratory Tests.........................................................................49
Table 3.
Identity of Investigational Products.........................................................65
Table 4.
Dose Reductions for Blinded Investigational Product (IP)......................70
Table 5.
Dose Reductions and Discontinuation for Unacceptable Toxicities........71
Table 6.
Recommended Management of Photosensitivity.....................................87
List of Figures
Figure 1.
Study Schema...........................................................................................33
Figure 2.
Adverse Event Collection ........................................................................81
Figure 3.
Diagram of Hierarchical Testing of Primary and Secondary 
Endpoints ...............................................................................................104
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................117
Appendix B.
List of Protocol Signatories....................................................................119
Appendix C.
Study Activities......................................................................................120
Appendix D.
Performance Status Scales Conversion..................................................127
Appendix E.
Calculated Creatinine Clearance Using Modified Cockcroft-Gault 
Equation .................................................................................................128
Appendix F.
New York Heart Association Classification..........................................129
Appendix G.
Response Evaluation Criteria for Solid Tumors (RECIST) v 1.1 
for Tumor Response...............................................................................130
Appendix H.
CTCAE v 4.0 Grading of Relevant AEs................................................137
Appendix I.
Fluid Retention Questionnaire ...............................................................142
Appendix J.
Adverse Events Expected Due to SCLC or Progression of SCLC ........144
Appendix K.
Protocol Amendment:  List of Changes.................................................146


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3.0
Introduction
3.1
Small Cell Lung Cancer 
Small cell lung cancer (SCLC) is an important unmet medical need, representing 15 –
20% of the 220,000 annual new cases of lung cancer.1,2  SCLC arises from epithelial cells 
with neuroendocrine differentiation.  Historically, SCLC has been staged using the 
Veterans Administration (VA) staging system as 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.  
Systemic chemotherapy remains the cornerstone of therapy for all stages of SCLC.  
Standard initial chemotherapy for all patients with a suitable performance status consists 
of a platinum salt (carboplatin or cisplatin) in combination with a second agent, usually 
etoposide or irinotecan.  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, 
responses are typically not durable and recurrence rates are high in the limited stage 
disease and nearly universal in the extensive stage disease, leading to median survivals of 
14 – 20 months and 9 – 11 months, respectively.3
Extensive stage disease subjects achieving SD or better during first-line platinum-based 
therapy have median progression-free survival (PFS) of approximately 2.1 – 2.3 months 
and median OS of approximately 6.9 – 8.9 months from the completion of first-line 
therapy.4,5  Exploration of clinical benefit maintenance strategies in extensive disease 
SCLC with the goal of prolonging PFS and OS after completion of first-line standard 
therapies is therefore warranted.
3.2
Delta-Like Protein 3 
Delta-like protein 3 (DLL3) is an atypical, inhibitory ligand of the Notch receptor family, 
discovered by AbbVie Stemcentrx scientists as a novel therapeutic target in SCLC and 


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other high-grade neuroendocrine carcinomas.  It was identified by whole transcriptome 
sequencing of tumor initiating cells (TICs) isolated from SCLC and large cell 
neuroendocrine cancer (LCNEC) patient-derived xenografts (PDXs), and found to be 
expressed in the majority of SCLC and LCNEC tumors, but with no detectable protein 
expression in normal tissues or non-neuroendocrine tumor types.6  DLL3 has been 
implicated in the regulation of cell fate decisions during development, and likely acts as 
an oncogene in high-grade neuroendocrine tumors where it is a downstream 
transcriptional target of the achaete-scute homolog 1 (ASCL1) transcription factor in 
SCLC tumor cells, and acts to inhibit the Notch receptor pathway, thereby facilitating 
neuroendocrine tumorigenesis.6-8
3.3
Rovalpituzumab Tesirine
Rovalpituzumab tesirine (SC16LD6.5) is a DLL3-targeted antibody-drug conjugate 
(ADC) consisting of the humanized DLL3-specific IgG1 monoclonal antibody SC16; the 
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. 
In the Phase 1 first in human study of rovalpituzumab tesirine (Study SCRX16-001), the 
best overall response (confirmed) for all SCLC subjects (dose escalation, retreatment, and 
maintenance cohorts) was retrospectively assessed by the Independent Review Committee 
(IRC) by RECIST v1.1 criteria.  The ORR (confirmed) was 16% (95% CI:  7.35, 27.42), 
with 12% achieving PR.  The clinical benefit rate (CBR) was 59% (95% CI:  44.93, 
71.40).  The median duration of response by the IRC was 1.7 months (95% CI:  0.03, 
3.06).  The median progression-free survival by the IRC was 3.0 months (95% CI:  2.56, 
3.84), with a probability of progression-free survival at 12 weeks of 52% (95% CI:  39, 
63).  The median overall survival was 4.3 months (95% CI:  3.22, 5.65).  The probability 
of overall survival at 12 weeks was 69% (95% CI:  52, 81).  In DLL3-positive (≥ 1% 


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tumor cells staining positive for DLL3 with murine anti-DLL3 antibody assay) subjects, 
the ORR was 23% (95% CI:  10.42, 40.14), and the CBR was 77% (95% CI:  59.86, 
89.58).  A slightly higher ORR (27%) and CBR (87%) were observed in DLL3-high 
(≥50% tumor cells staining positive for DLL3 with murine anti-DLL3 antibody assay) 
subjects.
In the Phase 2 Study SCRX001-002 (TRINITY) in patients with SCLC recurrent after at 
least two systemic chemotherapy regimens, rovalpituzumab tesirine dosed at 0.3 mg/kg 
every 6 weeks for two cycles (with an option for additional two cycles upon progression 
occurring ≥ 12 weeks after the second dose) resulted in the following: 
●
In DLL3high (Ӌ 75% tumor cells staining positive for DLL3 with VENTANA 
Rabbit IHC (SP347) DLL3 assay) subjects, ORR of 14% per IRC assessment, 
median OS of 5.7 months and median PFS of 3.8 months
●
In DLL3high subjects, the clinical benefit rate was 74% with a median duration 
of clinical benefit of 3.0 months per IRC assessment
Additionally, DLL3 positive (≥ 25% tumor cells staining positive for DLL3 with 
VENTANA Rabbit IHC (SP347) DLL3 assay) and DLL3high groups had comparable 
response rates given highly overlapping populations where approximately 85% of DLL3 
positive subjects were also DLL3high.
In December 2018, enrollment in Study M16-289 TAHOE ("A Randomized, Open-Label, 
Multicenter, Phase 3 Study of Rovalpituzumab Tesirine Compared with Topotecan for 
Subjects with Advanced or Metastatic DLL3high Small Cell Lung Cancer (SCLC) who 
have First Disease Progression During or Following Front-Line Platinum-Based 
Chemotherapy") was discontinued at the recommendation of the Independent Data 
Monitoring Committee (IDMC) after review of available efficacy data which 
demonstrated shorter overall survival in the rovalpituzumab tesirine arm compared with 
the topotecan control arm.  At the time enrollment was halted, 444 DLL3high (≥ 75% 
tumor cells staining positive for DLL3 with VENTANA Rabbit IHC (SP347) DLL3 
assay) subjects had enrolled on the trial.  The IDMC recommended that investigators and 


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subjects make individual decisions as to whether or not to continue treatment based on 
patient level response.  The results of the TAHOE study did not adversely impact the 
safety profile for rovalpituzumab tesirine.19
3.4
Differences Statement
This is the first randomized, double-blind, multicenter, Phase 3 study comparing 
rovalpituzumab tesirine versus placebo as maintenance therapy following first-line 
platinum-based therapy in subjects with extensive-stage SCLC.
3.5
Benefits and Risks
Although response rates to first-line platinum-based chemotherapy in ED SCLC are high, 
SCLC nearly invariably recurs, which may be attributed to the relative resistance of 
cancer stem cells (CSCs)/TICs to conventional chemotherapy.  Rovalpituzumab tesirine 
has been found to reduce the frequency of TICs in low passage SCLC patient-derived 
xenograft models significantly more than platinum-based SOC therapy.6  By targeting this 
resistant, residual cell population, rovalpituzumab tesirine has a unique mechanistic 
rationale for benefit in post-chemotherapy maintenance setting.  Rovalpituzumab tesirine 
had shown promising clinical activity in subjects with recurrent/relapsed SCLC 
(Section 3.3), and it is likely that the observed benefit will translate into maintenance 
setting.  This study will assess the efficacy, tolerability, and safety of rovalpituzumab in 
subjects with extensive-stage SCLC who have ongoing clinical benefit (SD, PR, or CR) 
following first-line platinum-based chemotherapy (cisplatin or carboplatin in combination 
with etoposide or irinotecan). 
As of 30 June 2018, 1246 subjects have received study medication in the rovalpituzumab 
tesirine clinical program; an estimated 1039 subjects (with SCLC or other DLL3-
expressing solid tumors) have received at least 1 dose of rovalpituzumab tesirine at doses 
ranging from 0.05 mg/kg to 0.8 mg/kg on a q3w schedule and 0.3 mg/kg to 0.4 mg/kg on 
a q6w schedule.


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Among subjects with SCLC treated with rovalpituzumab tesirine 0.3 mg/kg q6w, 96.8% 
of subjects reported at least 1 adverse event.  The most frequently reported adverse events 
among subjects with SCLC treated with rovalpituzumab tesirine 0.3 mg/kg q6w were 
decreased appetite (28.0%), photosensitivity reaction (27.7%), oedema peripheral 
(27.2%), dyspnoea (26.6%), and nausea (25.6%).  Important identified risks following 
treatment with rovalpituzumab tesirine include:  pleural effusions (33.9%), pericardial 
effusions (16.7%), generalized edema (2.7%) and photosensitivity reactions (27.7%).  
Important potential risks following treatment with rovalpituzumab tesirine include 
pneumonitis (1%).  The following adverse events of special interest have also been 
identified:  cutaneous reactions (48.7%), thrombocytopenia and hemorrhage events 
(28%), edema (33.8%), hypoalbuminemia (16.2%), hepatotoxicity (19.3%), 
nephrotoxicity (5.9%), anemia (19.7%), neutropenia (9.2%) and infusion related reaction 
(0.2%).  In addition, preclinical toxicology studies conducted in the rat and the 
cynomolgus monkey have identified bone marrow, lung, and kidney as potential sources 
of clinical adverse events (AEs) (AbbVie Investigator Brochure v7).  Accordingly, safety 
assessments will include regular assessments at protocol-specified time points of routine 
physical examination, laboratory and imaging tests including CT/MRI assessments and 
echocardiograms, a fluid retention questionnaire, and daily weights (Section 5.3.1.1).  The 
timing and frequency of these assessments are designed so that potential rovalpituzumab 
tesirine-related toxicities are identified prior to additional drug doses, limiting the risk of 
toxicity exacerbation.  The dose delay/reduction/discontinuation protocol guidelines 
provide additional level of risk mitigation for subjects enrolled in this study. 
It is thus considered that the study has acceptable benefit/risk profile for subjects with ED 
SCLC and stable disease or better following completion of four cycles of platinum-based 
standard front line treatment, taking into account short progression-free and overall 
survival of these subjects.4
4.0
Study Objectives
The primary objective of this study is to evaluate if rovalpituzumab tesirine improves 
progression-free survival, assessed by CRAC, and overall survival in subjects with 


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extensive-stage SCLC tumors with a high level of DLL3 expression (DLL3high) who have 
ongoing clinical benefit (SD, PR, or CR) following the completion of 4 cycles of 
first-line, platinum-based chemotherapy (cisplatin or carboplatin plus irinotecan or 
etoposide) compared to placebo.
The secondary objectives are:
●
To evaluate if rovalpituzumab tesirine improves progression-free survival by 
CRAC and overall survival in all randomized subjects compared to placebo.
●
To assess change in patient reported outcomes (PRO) with physical 
functioning as measured by the EORTC QLQ-C30questionnaire in all 
randomized subjects compared to placebo.
The exploratory objectives are: 
●
To evaluate rovalpituzumab tesirine anti-tumor activity by determining 
objective response rate (ORR), clinical benefit rate (CBR), and duration of 
responses (DOR) by CRAC and investigator assessment in DLL3high and in all 
randomized subjects. 
●
To evaluate if rovalpituzumab tesirine improves progression-free survival by 
investigator assessment compared to placebo in DLL3high and in all 
randomized subjects. 
●
To assess change from baseline in all patient reported outcomes (PRO) 
domains (except physical functioning) measured by EORTC QLQ-C30/LC13 
and EQ-5D-5L.
●
To characterize the pharmacokinetics and incidence of anti-therapeutic 
antibodies (ATAs) against rovalpituzumab tesirine.
●
To evaluate pharmacodynamic and predictive biomarkers in blood and tumor 
for association with sensitivity, efficacy and safety.
●
To explore the DLL3 expression in circulating tumor cells (CTCs) for 
association with efficacy.


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5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
The study is designed to enroll approximately 740 SCLC subjects to obtain approximately 
480 subjects with DLL3high expression in tumor (DLL3high) and to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  DLL3high is defined as ≥75% tumor cells staining positive 
according to the VENTANA DLL3 (SP347) IHC Assay.
This is a Phase 3, randomized, double-blinded, placebo-controlled, multinational, and 
multicenter study.  Approximately 300 clinical sites will participate.
Eligible subjects will be randomly assigned in a 1:1 ratio to receive 0.3 mg/kg 
rovalpituzumab tesirine or placebo, and will receive their assigned therapy on Day 1 of 
each 6-week cycle, omitting every third cycle.  Subjects will also receive 8 mg orally (PO) 
of dexamethasone or placebo twice daily on Day –1, Day 1 (the day of dosing), and Day 2 
of each 6-week cycle, omitting every third cycle.  Subjects will be stratified by 
RECIST v1.1 response after completion of first-line platinum-based chemotherapy at 
screening assessment (SD vs. PR/CR), DLL3 expression (Unknown vs. 0% to < 25% vs. 
25% to < 75% vs. 75% or above), history of central nervous system (CNS) metastases 
(Yes vs. No), and for subjects with no history of CNS metastases, PCI vs. no PCI.  
Survival Follow-up will continue until the endpoint of death, the subject becomes lost to 
follow-up or withdraws consent, or termination of the study by AbbVie, whichever occurs 
first.
A schematic of the study is provided in Figure 1, Study Schema.


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Figure 1.
Study Schema
Arrowheads = blinded investigational product administration; CR = complete response; OS = overall survival; 
PR = partial response; PTFU = post-treatment follow-up; SD = stable disease
1.
Upon completion of first-line platinum-based chemotherapy, eligible subjects must be offered prophylactic cranial 
irradiation (PCI), if offering this procedure is not contradictory to country or institutional guidelines.  Subjects 
receiving PCI must complete it prior to randomization into the study.
2.
Collection of tumor material for DLL3 testing will be provided any time after the signing of the informed consent 
and prior to randomization.
3.
Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the fourth cycle of first-line 
platinum-based chemotherapy.
On study disease assessments, for the purposes of efficacy assessments will be performed 
by a Central Radiographic Assessment Committee (CRAC) blinded to study treatment 
information and independent of Investigators and personnel who are involved in 
conducting the study (Section 5.3.1.1).
5.2
Selection of Study Population
Current standard of care after first-line platinum-based chemotherapy consists primarily 
of observation until disease progression, at which time second line chemotherapy, such as 
with topotecan, may be instituted.  No therapy is approved for use or routinely used as 
maintenance or consolidation after first-line platinum-based chemotherapy in extensive 
stage SCLC.  Rovalpituzumab tesirine may be beneficial in this setting, but no prior 
studies have formally explored its potential.  Therefore, this study will involve a 
comparison of rovalpituzumab tesirine against placebo.


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For the purposes of study eligibility, limited stage disease SCLC (LD-SCLC) is defined as
a disease confined to the hemithorax of origin, with or without the involvement of 
regional lymph nodes, including ipsilateral and contralateral hilar, ipsilateral and 
contralateral mediastinal, and ipsilateral supraclavicular nodes.  Extensive stage disease 
SCLC (ED-SCLC) is defined as all other SCLC.
Subjects must meet all of the inclusion and none of the exclusion 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 a Good Clinical Practice (GCP) audit and/or regulatory authority 
inspection.
5.2.1
Inclusion Criteria
1.
Subject or the subject's legally acceptable representative must voluntarily sign and 
date an informed consent, approved by an Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or 
study-specific procedures and should be willing and able to comply with 
parameters as outlined in the protocol.
2.
Subject must be ≥ 18 years of age.
3.
Histologically or cytologically confirmed ED SCLC (extensive stage disease at 
initial diagnosis), with ongoing clinical benefit (SD, PR, or CR per RECIST v.1.1) 
following completion of 4 cycles of first-line platinum-based therapy (cisplatin or 
carboplatin in combination with etoposide or irinotecan).
4.
Subjects with a history of CNS metastases prior to the initiation of first-line 
platinum-based therapy must have received definitive local treatment and have 
documentation of stable or improved CNS disease status based on brain imaging 
within 28 days prior to randomization, off or on a stable dose of corticosteroids.
5.
Subject is eligible to be randomized at least 3 but no more than 9 weeks from 
Day 1 of the fourth cycle of first-line platinum-based chemotherapy.


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6.
Availability of archived or representative tumor material for assessment of DLL3 
expression. 
7.
Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 (Refer 
to Appendix D).
8.
Recovery to ≤ Grade 1 of any clinically significant toxicity (excluding alopecia) 
prior to randomization.
9.
Subject must have adequate bone marrow, renal and hepatic function as follows:
a.
Absolute neutrophil count (ANC) ≥ 1,000/μL
b. Platelet count ≥ 75,000/μL
c.
Hemoglobin ≥ 8.0 g/dL
d. Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for 
subjects with Gilbert's disease
e.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤3 × ULN (≤ 5 × ULN if evidence of hepatic involvement by malignant 
disease)
f.
Calculated creatinine clearance ≥ 30 mL/min by the modified Cockroft-Gault 
formula (Refer to Appendix E)
g. Albumin ≥ 3 g/dL
10.
If female, subject must be either postmenopausal as 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
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).


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OR a Woman of Childbearing Potential (WOCBP) practicing at least one protocol 
specified method of birth control (Section 5.2.4), starting at randomization through 
at least 6 months after the last dose of blinded investigational product.
If the male subject is sexually active, he must agree, from randomization through at 
least 6 months after the last dose of blinded investigational product, to practice the 
protocol specified contraception (Section 5.2.4).
11.
Females of childbearing potential must have a negative serum pregnancy test result 
at Screening, and a negative urine pregnancy test at randomization.
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in Section 5.2.4) at Screening do not require pregnancy 
testing.
Rationale for Inclusion Criteria
1
In accordance with Harmonized Good Clinical Practice (GCP)
2 – 7
To select and/or collect data on the subject population
8 – 9
For the safety of the subjects
10 – 11
The impact of rovalpituzumab tesirine on pregnancy in humans is 
unknown
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint 
inhibitors, other monoclonal antibodies, antibody-drug conjugates, 
radioimmunoconjugates, T-cell or other cell-based or biologic therapies, or any 
other anti-cancer therapy than that described in Inclusion Criteria 3 – 5 for SCLC.


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2.
Any disease-directed radiotherapy (except PCI, palliative radiotherapy to a 
radiographically documented non-progressing lesion for symptom control, or pre-
planned radiotherapy for CNS metastases present prior to start of first-line therapy 
and non-progressing) after last dose of first-line chemotherapy.
3.
Any significant medical condition including any suggested by screening laboratory 
findings that in the opinion of the Investigator or Sponsor may place the subject at 
undue risk from the study.
4.
Documented history of a cerebral vascular event, unstable angina, myocardial 
infarction, or cardiac symptoms consistent with New York Heart Association 
(NYHA) Class III – IV heart failure (refer to Appendix F) within 6 months prior to 
randomization.
5.
Documented history of capillary leak syndrome.
6.
Grade 2 or higher pleural or pericardial effusion within 4 weeks of randomization 
or earlier history of recurrent Grade 2 or higher effusions with ongoing requirement 
for pericardiocentesis or thoracentesis.
7.
Serious infection within 2 weeks prior to randomization, including any Grade 3 or 
higher (per NCI CTCAE version 4.0)11 viral, bacterial, or fungal infection.
8.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or for approximately 6 months after the last dose of blinded 
investigational product.
9.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 6 months after the last dose of blinded investigational 
product.
10.
Systemic therapy with corticosteroids at > 10 mg/day prednisone or equivalent 
within 1 week prior to randomization.
11.
Subject has a history of active malignancies other than SCLC within the past 
2 years prior to study entry, with the exception of in situ cancer which was 
curatively treated.


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12.
Any prior exposure to a pyrrolobenzodiazepine (PBD-based) or 
indolinobenzodiazepine-based drug, prior participation in a rovalpituzumab tesirine 
clinical trial, or known hypersensitivity or other contraindications to 
rovalpituzumab tesirine or excipient contained in the drug formulation.
13.
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells.
Rationale for Exclusion Criteria
1, 10 – 13
To select the appropriate subject population
2 – 7
For the safety of the subjects
8 – 9
The impact of rovalpituzumab tesirine on pregnancy in humans is 
unknown
5.2.3
Prior and Concomitant Therapy
Any concomitant medication or vaccine (including over-the-counter or prescription 
medicines, vitamins and/or herbal supplements) that the subject is receiving at the time of 
study drug administration or receives during the study through the safety reporting period 
(Section 6.1.5), 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 protocol-related AE should be recorded from the 
time of informed consent.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapies.
5.2.3.1
Prior Therapy
Subjects will have received first-line platinum-based chemotherapy consisting of 4 cycles 
of treatment with combination of either cisplatin or carboplatin with etoposide or 


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irinotecan; administration of Day 1 of the last cycle of first-line chemotherapy must be at 
least 3 weeks but no more than 9 weeks prior to randomization.  Subjects previously 
treated for LD-SCLC are not eligible. 
Subjects with central nervous system (CNS) metastases present prior to the initiation of 
first-line chemotherapy will have completed definitive local treatment (e.g., surgery or 
radiotherapy).  Upon completion of first-line chemotherapy, subjects without a history of 
CNS metastases must have been offered prophylactic cranial irradiation (PCI), if offering 
this procedure is not contradictory to country or institutional guidelines.  Subjects 
receiving PCI must complete it prior to randomization into the study.  PCI regimen must 
be consistent with those endorsed by the National Comprehensive Cancer Network 
(NCCN) or European Society for Medical Oncology (ESMO).
5.2.3.2
Concomitant Therapy
All subjects enrolled will receive premedication consisting of dexamethasone/placebo.  
Refer to Section 5.5.1, Treatments Administered for details.
There are no other required concomitant therapies.  However, due to the potential for 
rovalpituzumab tesirine-related skin photosensitivity, patients should be advised to avoid 
direct and indirect sun exposure as much as possible from Cycle 1 Day 1 until 30 days 
after the final dose.  When sun exposure is unavoidable, patients should wear protective 
clothing and sunglasses, and use a broad-spectrum sunscreen and lip balm (SPF 30 or 
greater).  Thirty-one to ninety days after last dose of Rova-T/placebo, the patient may 
resume outdoor activities with appropriate sun protection including broad brimmed hat, 
protective clothing and sunscreen SPF 30 or higher.
5.2.3.2.1
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 


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(e.g., bisphosphonates, denosumab) 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 ≤ 10 mg/day.  The use 
of intermittent high-dose corticosteroid treatment to prevent or manage infusion reactions, 
serosal effusions (see Section 6.1.8.1), 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 randomization, and 
documentation must exclude active infection.  After exclusion of active infection, 
otherwise eligible subjects should complete or continue suppressive anti-infectives as 
prescribed.
If a subject requires palliative radiation during the study (e.g., symptomatic worsening of 
a bone lesion) diagnostic imaging has to be performed to assess for radiographic 
progression prior to radiation, and documentation of non-progressive status by 
radiography will be captured in the eCRF.  Any cancer-directed therapy a subject receives 
due to disease improvement should be discussed with the TA MD in advance, if possible.
In the event of isolated CNS-only progression during study treatment, blinded 
investigational product may be withheld while local treatment is administered 
(e.g., radiotherapy) in accordance with institutional practice.  Blinded investigational 
product may be restarted 1 week after the completion of local CNS disease-directed 
therapy.


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5.2.3.3
Prohibited Therapy
Subjects may not receive other investigational drugs, immunosuppressive medications, 
radiotherapy, or systemic anti-neoplastic therapy during the study, other than as allowed 
in Section 5.2.3.2 and Section 5.2.3.2.1.  Additionally, strong inhibitors of cytochrome 
P450 3A4 (CYP3A4) should be avoided (refer to Table 1).
Table 1.
Examples of Strong CYP3A4 Inhibitors
Enzyme/Transporter
Strong Inhibitor Examples10
CYP3A4
boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir and ritonavir, diltiazem, elvitegravir 
and ritonavir, idelalisib, indinavir and ritonavir, 
itraconazole, ketoconazole, lopinavir and ritonavir, 
nefazodone, nelfinavir paritaprevir and ritonavir 
and (ombitasvir and/or dasabuvir), posaconazole, 
ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, troleandomycin, 
voriconazole
(CYP) Cytochrome P450. 
Note:
This is not an exhaustive list; so if in question, please refer to the appropriate product label.
5.2.4
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 
(WOCBP), practicing at least one of the following methods of birth control, on 
randomization (or earlier) through at least 6 months after the last dose of blinded 
investigational product.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to randomization.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
randomization.


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●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence).
Male subjects who are sexually active with a WOCBP, even if the male subject has 
undergone successful vasectomy, must agree from randomization through at least 
6 months after the last dose of blinded investigational product 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 randomization through at least 6 months 
after the last dose of blinded investigational product.
5.3
Efficacy, Pharmacokinetic, Biomarker, Pharmacogenetic 
and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C, Study Activities.


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5.3.1.1
Study Procedures
Unless otherwise stated, the baseline measurement for any given variable will be defined 
as the last value obtained for the variable prior to the first dose of blinded investigational 
product. 
Screening procedures must be performed within 21 days prior to randomization, with the 
exception of radiographic assessments (CT scan or MRI including the head, chest, and 
abdomen) which may be performed within 28 days prior to randomization.  The collection 
of tumor material for DLL3 testing will be provided any time after the signing of the 
informed consent and prior to randomization.  Randomization may occur within 3 days 
prior to C1D1.
Subsequent study procedures should be performed within 3 days prior to the scheduled 
treatment visits, within a ±3 day window during the non-treatment visits, and within a 
±1 week window during the post-treatment follow up, and survival follow up phase unless 
otherwise indicated.
The results of all screening and evaluations at the time of randomization must be within 
clinically acceptable limits, upon review by the investigator, before a subject can be 
randomized.  Subjects will not be randomized in the study if laboratory or other screening 
results are unacceptable.  Subjects are allowed to rescreen and have laboratory samples 
redrawn to meet eligibility within the same 21 day screening window.  Subjects who meet 
the inclusion criteria and do not meet any of the exclusion criteria may be randomized.
Informed Consent
Signed informed consent will be obtained from the subject before any study-specific 
procedures are undertaken or before any prohibited medications are withheld from the 
subject in order to participate in this study.  Informed consent may be obtained before the 
21-day screening window.  For the optional tumor biopsy procedure at time of disease 
progression an optional tumor material biopsy procedure informed consent should be 


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completed.  Details about how informed consent will be obtained and documented are 
provided in Section 9.3.
Subjects will be considered screen failures if the informed consent has been signed and a 
study-specific procedure has been performed (e.g., central laboratories drawn), but subject 
does not randomize into the study.  The reason for screen failure will be documented in 
the source and will be captured in the eCRF.
Tumor Material at Screening
For all subjects, archived or fresh tumor material must be submitted to the AbbVie 
designated central IHC laboratory for determination of DLL3 expression prior to 
randomization, as per Appendix C, Study Activities.
Tumor material testing for DLL3 status may occur at any time after initial diagnosis for 
subjects who provide consent.  These subjects must be registered in IRT.  Eligibility will 
depend on the fulfillment of all other inclusion and exclusion criteria and the trial status 
(whether the study is still open for accrual).
For purposes of the study, "unknown" status is possible if all available samples were 
tested and failed due to unforeseen technical or logistical reasons; subject with no tumor 
sample will not be eligible for the trial or subject with sample not fulfilling sponsor's 
specifications (different method of tissue fixation, known necrotic, too few cells etc.) will 
not be eligible.
Medical and Surgical History (Including Malignancy History); Adverse Event and 
Prior/Concomitant Medication Assessment
The following will be collected during the Screening Visit:
●
Medical history, including demographics and documentation of any clinically 
significant medical condition and/or surgical history
●
History of tobacco and alcohol use:


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○
current smoker [subject who has > 100 smoking events in their lifetime 
and has smoked within the last 12 months] 
○
past smoker [subject who has > 100 smoking events in their lifetime and 
has not smoked in past 12 months]
○
never smoked [subject with ≤ 100 smoking events in lifetime]
●
Detailed oncology history including:
○
Histology
○
Date of initial cancer diagnosis
○
TNM Stage at diagnosis, if available
○
Veterans Administration (VA) Stage at diagnosis 
○
Sites of metastases
●
Absence of active CNS metastases will be confirmed by MRI or CT of 
the brain
○
Mutational status, if performed or applicable
○
Any surgical procedures
○
Treatments administered (including dates and type of modality)
●
Detailed prior and concomitant medication usage including dates of usage and 
dosing information for all medications and supplements taken
Any changes observed from the Screening assessments (prior to dosing) will be recorded 
in the subject's medical history.  At each visit, including the End of Treatment Visit, the 
subject's medical history will be reviewed and any changes from baseline will be recorded 
on the adverse event eCRF.
All medication (prescription or over-the-counter, including vitamins and/or herbal 
supplements) will be recorded from the first study drug administration through the 
70 days following the last dose of blinded investigational product.


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Physical Examination
A physical examination will be performed per Appendix C, Study Activities.  If the 
Screening assessment is performed within 21 days of C1D1, it is not required to be 
repeated on C1D1 unless clinically indicated.  Clinically significant changes from 
baseline will be documented in the source documentation and eCRFs as adverse events.
Height will be measured at the Screening visit only.  For height assessments, the subject 
should not wear shoes.
Investigators will assess subjects for pleural and pericardial effusion prior to dosing of 
blinded investigational product on Day 1 of each cycle.
Physical exam will include cardiac, pulmonary (including cardiopulmonary exam for 
serosal effusions), evaluation of extremities for peripheral edema, neurological (sensory, 
motor, cranial nerves), head and neck, lymphatic, hepatobiliary, gastrointestinal, 
genitourinary, and skin evaluation per local standard of care.
Vital Signs
Vital signs will be performed per Appendix C, Study Activities.  Vital signs include actual 
weight, sitting blood pressure, heart rate and body temperature.  If possible, blood 
pressure and heart rate measurements should not immediately follow scheduled blood 
collections.
Actual weight will be collected in the clinic prior to dosing at each cycle and the recorded 
weight will be utilized for dosing calculations.  For weight assessments, the subject 
should not wear shoes.  In the event of a 5% or greater increase in weight within 
2 consecutive visits or compared to baseline which ever has the shorter interval, a prompt 
workup for fluid retention (e.g., edema, effusions, etc.) should be conducted.  If weight 
gain is due to proven or suspected fluid retention related to study drug, and dosing is not 
prohibited per Section 5.5.4, dose should be calculated based on actual weight before the 
event of fluid retention.


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Vital signs should be collected prior to the infusion. 
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed per Appendix C, Study Activities.  ECGs 
consist of a single 12-lead study performed within a 5-minute window after at least 
5 minutes of quiet rest in a supine position.  Additional ECG monitoring may occur as 
clinically indicated during the study.
A qualified physician will determine whether any findings outside of normal 
physiological variation are clinically significant (in consultation with a cardiologist if 
necessary).  The physician will document whether findings are clinically significant (CS) 
or not clinically significant (NCS) on the tracing and sign and date the tracing.  The 
original annotated ECG tracing containing the physician's assessment will be retained in 
the subject's records at the study site.
Echocardiogram
Echocardiograms will be performed per Appendix C, Study Activities to rule out 
pericardial effusion (or assess, if present), as well as assess cardiac function (left 
ventricular ejection fraction, LVEF).  
ECOG Performance Status
The ECOG performance status will be documented according to Appendix C, Study 
Activities.  Refer to Appendix D, Performance Status Scales Conversion for details.
If the Screening assessment is performed within 21 days of C1D1, it is not required to be 
repeated on C1D1 unless clinically indicated.
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 6.1.6).
For female subjects of childbearing potential, the laboratory will perform pregnancy 
testing according to Appendix C, Study Activities.  A serum pregnancy test will be 
performed at Screening and the results must be available prior to the administration of the 
first dose of blinded 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, the Non-Treatment cycle, End of Treatment Visit, and PTFU until 6 months 
after the last dose of blinded investigational product.
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined in Section 5.2.4) 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.
Clinical Laboratory Tests 
Samples for chemistry, hematology, coagulation, and urinalysis will be collected per 
Appendix C, Study Activities.  Specific laboratory assessments are outlined in Table 2, 
Clinical Laboratory Tests.
If the Screening assessment is performed within 7 days of C1D1, it is not required to be 
repeated on C1D1 unless clinically indicated.  Starting at Cycle 2, lab assessments may be 
performed 3 days prior to Day 1 visits.  All laboratory samples will be assessed using a 
certified central laboratory and these data will be used for all data analysis.  The central 
laboratory will provide instructions regarding the collection, processing, and shipping of 
samples.  All laboratory samples will be shipped to the central laboratory.  A qualified 
(e.g., certification or accreditation) local laboratory may be used to perform laboratory 
analyses for treatment decisions as per standard of care.


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Qualified medical staff at the site will review, initial and date all local and central 
laboratory results.  Any laboratory value outside the reference range that is considered 
clinically significant by the Investigator will be followed as appropriate.  Clinically 
significant laboratory values will be recorded as adverse events if they meet the criteria as 
specified in Section 6.1.1.
Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis (Dipstick)
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils 
Bands (if indicated)
Lymphocytes
Monocytes
Basophils (if indicated)
Eosinophils (if indicated) 
Platelet count (estimate not
acceptable)
Mean corpuscular volume
Mean corpuscular hemoglobin 
concentration
RBC distribution width
Blood urea nitrogen (BUN)
Serum creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Total protein
Glucose
Albumin
Magnesium
Chloride
Amylase
Lipase
Lactate dehydrogenase (LDH)
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocyte esterase
Serum Pregnancy Test
Beta-Human Chorionic 
Gonadotropin (β-hCG) (if
applicable)
Follicle-stimulating hormone 
(FSH) (if applicable)
Coagulation
Activated Partial
Thromboplastin Time
(aPTT)
Prothrombin time (PT)
International Normalized Ratio
(INR)
Disease/Response Assessment (Radiographic Imaging)
Treatment response will be assessed by radiographic tumor evaluation per RECIST v1.1 
at protocol-specified time points as outlined in the Appendix C, Study Activities.  
Diagnostic quality, spiral CT scan with contrast is recommended for all anatomic areas 
except brain (MRI is recommended for brain imaging); other CT methods or MRI for 


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respective anatomic areas may be used if performed consistently throughout the study for 
each individual subject and only under the circumstances described in Appendix G.  Scans 
of the chest and abdomen must be obtained; scans of the neck and pelvis must also be 
obtained if there is documented or suspected involvement in these regions.  Screening 
radiographic assessment must include brain MRI/CT.  Diagnostic/baseline pre-first-line 
scans through screening scans will be reviewed by the investigator to determine disease 
response status per RECIST v1.1 for eligibility and stratification.  On study disease 
response will be determined by the Investigator at each assessment according to 
RECIST v1.1 (Appendix G, Response Evaluation Criteria for Solid Tumors 
(RECIST) v 1.1)12 and independently reviewed by Central Radiographic Assessment 
Committee (described below).  Disease/Response Assessment may be performed within 
7 days prior to the Day 1 visit.
Effusion (pleural, pericardial, etc.) assessments will be performed by a radiologist at each 
on-study radiographic assessment and any new findings communicated to the Investigator 
prior to the next dose of blinded investigational product.  Effusions should contribute to 
disease status assessment per RECIST v 1.1 only if confirmed malignant by cytology or 
otherwise clearly disease-related; if disease progression is suspected solely based on the 
appearance of new or increase of existing effusions, confirmation of malignant nature of 
such effusions is strongly recommended due to known adverse event profile of 
rovalpituzumab tesirine.  If collected, effusion fluid must be tested for cytology if disease 
progression due to appearance/worsening of effusion is suspected.
Isolated CNS-only progression will not require removal of the subject from therapy.  
Refer to Section 5.2.3.2.1, Allowed Concomitant Therapy for details associated with CNS 
only progression.
The EOT assessment may be omitted if the previous assessment was performed within the 
preceding 6 weeks. 
Scheduled tumor assessments should not be affected by delays in therapy and/or drug 
holidays.  Subjects will continue to be monitored by the same diagnostic method 


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throughout the study every 6 weeks after randomization, unless evidence of tumor 
progression warrants otherwise.  In some cases, mandatory dose delays due to toxicity 
will lead to a gap between tumor assessment and dosing.  In cases where this gap exceeds 
1 week, the TAMD should be contacted for guidance.
Subjects who discontinue treatment for reasons other than radiographic disease 
progression will continue to be followed every 6 weeks from randomization to determine 
the extent of tumor burden, until disease progression occurs.
MRI/CT of the Brain
MRI of the brain will be performed at protocol-specified time points as outlined in 
Appendix C, Study Activities.  Brain MRI may be substituted by CT with intravenous 
contrast at the discretion of the Investigator.  MRI/CT of the brain is required at screening 
and when clinically indicated (e.g., if CNS progression is suspected) thereafter.
Central Radiographic Assessment Committee (CRAC) 
In addition to being reviewed by the investigator and/or site staff, radiological scans will 
be assessed by a Central Radiographic Assessment Committee (CRAC), as outlined in the 
Appendix C, Study Activities.  Sites will collect the appropriate scans and ship by courier 
or submit electronically to the central facility at each subject's disease assessment.  If, in 
addition to protocol-specified disease assessment modalities other modalities were used to 
assess disease (e.g., FDG-PET, X-ray), imaging should also be transferred to the central 
facility.
The EOT assessment may be omitted if the previous assessment was performed within the 
preceding 6 weeks. 
Subject treatment management will be based on review by the local investigator and/or 
site staff.  The investigator should treat according to clinical judgment and the CRAC will 
make the definitive decision on tumor response or progression in regards to the PFS 
endpoint.


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Randomization and Subject Number Assignment
An Interactive Response Technology system (IRT) will be utilized to register subjects.  
Subjects who complete all Screening procedures and meet the eligibility criteria will 
proceed to randomization.  Refer to Section 5.5.3 for details associated with subject 
assignment to treatment arms.
Health Resource Utilization
Health Resource Utilization will be documented at each clinic visit per Appendix C, 
Study Activities.  Information regarding hospitalizations, emergency room visits, and 
physician office visits will be collected since the last study visit.
Patient Reported Outcomes (PRO)
Health-related quality of life and symptom assessments will be performed per 
Appendix C, Study Assessments using the EORTC QLQ-C30, the EORTC QLQ-LC13, 
and the European Quality of Life-5 Dimensions (EQ-5D-5L).  The European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30)13 is used as general cancer-specific instrument.  The 
EORTC QLQ-C30 has 30 items and 5 functional domain scales:  Physical, Role, 
Emotional, Social, and Cognitive; two items evaluate global quality of life.  The EORTC 
QLQ-C30 core questionnaire can be supplemented by the additional lung module EORTC 
QLQ-LC13, resulting in a 43-item disease and cancer site-specific quality of life and 
symptom questionnaire.  The EORTC QLQ-LC13 module items evaluate symptoms such 
as cough, haemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling 
hands or feet, hair loss, and pain.  The EuroQol 5 Dimensions 5 Level (EQ-5D-5L) is a 
generic preference instrument that has been validated in numerous populations.  The 
EQ-5D-5L is composed of 5 questions and a visual analog scale (VAS) assessing overall 
health that can be converted into a single health status or "utility" score for use in an 
economic evaluation to adjust life-years gained by the subject's health-related quality of 
life.


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Fluid Retention Questionnaire (Including Subject Daily Weight)
Throughout the treatment period as outlined in the Appendix C, Study Activities, subjects 
will be asked about the development of any new or worsening peripheral edema or 
dyspnea (Appendix I, Fluid Retention Questionnaire).  The assessments on Days 8, 15, 
29, and 36 may take place by phone, with the site contacting the subject and reviewing the 
questionnaire. 
Starting on Day 1 through the EOT visit, subjects will maintain a diary of daily weights 
(captured on the Fluid Retention Questionnaire).  Subjects should be instructed to use a 
consistent device throughout the study.  The site will advise subjects to contact the site in 
cases where sudden weight gain (5% or greater) is observed for possible assessment in the 
clinic.
Non-Treatment Cycle Visit
In order to establish 12 weeks of non-treatment after two dosing cycles, every third cycle 
of treatment should be omitted and a clinic visit conducted, as outlined in Appendix C, 
Study Activities.  The visit should be performed after the Disease Response/Assessment 
has been conducted and reviewed by the Investigator. The subject should continue to 
complete the Fluid Retention Questionnaire, including conducting daily weight 
assessments, and the site should contact the subject weekly during this 42 day non-
treatment cycle to review the questionnaire and assess for any adverse events or changes 
in concomitant medications.  The following cycle of treatment may be resumed 
42 days ± 3d if the subject has not met any reason for study treatment discontinuation as 
outlined in Section 5.4.
End of Treatment (EOT) Visit 
The visit at which an investigator identifies disease progression or a subject meets other 
criteria for study treatment discontinuation will be considered the End of Treatment Visit.  
The EOT procedures should be done within 7 days of documented decision to discontinue 
treatment and prior to subjects beginning any new anti-cancer therapy if possible.  The 


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EOT visit is the last visit during the treatment phase before subjects begin the Post 
Treatment Follow Up and/or Survival Follow Up phase.  The reason(s) for the 
discontinuation from study treatment will be recorded and assessments will be performed 
per Appendix C, Study Activities.  
Disease/Response Assessment, CT/MRI of the brain (if applicable), and submission of 
scans to the CRAC, may be omitted if performed within the last 6 weeks. 
Post-Treatment Follow Up 
For all subjects who discontinue study treatment for reasons other than disease 
progression, the first follow-up visit will occur at 6 weeks (± 1 week) after the last 
Disease Response/Assessment, then every 6 weeks (± 1 week) until disease progression or 
initiation of new anti-cancer therapy, whichever occurs first.  Refer to Appendix C, Study 
Activities for details of required assessments.
At disease progression, an optional collection of fresh tumor material may be conducted 
(Section 5.3.1.2, Collection and Handling of Biomarker and Optional Exploratory 
Research has details regarding Tumor Material at Time of Disease Progression).
Survival Follow Up (OS)
After disease progression or if subjects stop treatment and decline further study 
radiographic assessments prior to the endpoint of disease progression, subjects will be 
followed for subsequent anti-cancer therapies (dates and responses), as well as survival 
status, every 6 weeks* (± 1 week) until the endpoint of death, the subject becomes lost to 
follow-up or withdraws consent, or termination of the study by AbbVie, whichever occurs 
first (*or as requested by AbbVie to support data analysis).  If the subject withdraws from 
study follow-up, the study staff may use a public information source (such as county 
records) to obtain information about survival status only, as appropriate per local 
regulations.  Refer to Appendix C, Study Activities for details of required assessments.


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5.3.1.2
Collection and Handling of Biomarker and Optional 
Exploratory Research Samples
Biomarker Samples
Blood, tumor material, and serosal fluid will be collected as noted in Appendix C, Study 
Activities and may be utilized to evaluate known and/or novel markers (nucleic acids, 
peptides/proteins and/or metabolites) of disease status, related conditions or to evaluate 
the association with pharmacokinetics, safety or efficacy.  Samples will also be utilized 
for the development of Companion Diagnostics in conjunction with rovalpituzumab 
tesirine clinical development.  The biomarker rationale is discussed in the Biomarker 
Research Variables Section (Section 5.3.6).
All biomarker samples should be labeled and shipped as outlined in the study-specific 
laboratory manual.
AbbVie (or people or companies working with AbbVie) will store the samples in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be 
retained while research on rovalpituzumab tesirine (or drugs of this class) or this disease 
and related conditions continues, but for no longer than 20 years after study completion, 
or per local requirement.
Tumor Material at Screening
For all subjects, tumor material representative of the qualifying malignancy must be 
submitted to a central laboratory for determination of DLL3 expression.  An archived 
tumor specimen or fresh tumor material (obtained via on-study biopsy procedure if 
archival tumor specimen is unavailable) may be used for DLL3 expression evaluation by 
methods such as but not necessarily limited to immunohistochemistry (IHC).  Additional 
analyses, such as routine hematoxylin and eosin for morphology, IHC for confirmation of
diagnosis (e.g., for synaptophysin, chromogranin-A, or CD56), or scoring of immune 
infiltrates (e.g., IHC for CD3+, CD4+, CD8+, and Foxp3+ cells) may be performed.  


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Material may also be utilized for exploratory biomarkers research of drug sensitivity, 
resistance, or disease biology.
Blood (Plasma) for Inflammatory Markers and Circulating Tumor DNA (ctDNA)
At the indicated times noted in Appendix C, Study Activities, blood will be collected, 
processed to plasma for testing of inflammatory markers including erythrocyte 
sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies (ANA), 
rheumatoid factor (RF), and ctDNA.  On Day 1 (–3 day window is permitted) of each 
cycle, the collection will be pre-infusion.  A sample will also be collected at the EOT or at 
the time of disease progression. 
Blood (Serum) for Tumor and Soluble Markers
At the indicated times noted in Appendix C, Study Activities, blood will be collected, 
processed as serum for possible testing of tumor-specific biomarkers that may reflect 
disease burden such as but not necessarily limited to neuron-specific enolase (NSE) and 
biomarkers that may be related to the pharmacodynamics effects of rovalpituzumab 
tesirine such as but not necessarily limited to soluble DLL3, circulating chemokines, or 
cytokines such as vascular endothelial growth factor (VEGF), epidermal growth factor 
(EGF), interleukin (IL)-6, or IL-8.  Other biomarkers based on emerging science may also 
be assessed.  On Day 1 (–3 day window is permitted) of each cycle, the collection will be 
pre-infusion.  A sample will also be collected at the EOT or at the time of disease 
progression.
Blood for Circulating Tumor Cells
At the indicated times noted in Appendix C, Study Activities, blood samples will be 
collected for assessment and characterization of circulating tumor cells (CTCs) as a 
possible reflection of disease burden and DLL3 expression to study association with 
efficacy.  Whole blood sample will be collected for CTC analysis at pre-dose on Cycle 1
Day 1 (–3 days window is permitted) and EOT only at specific sites based on feasibility.


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Serosal Fluid
Any pericardial, pleural, and/or ascitic fluid collected as part of routine care (e.g., as part 
of a therapeutic thoracentesis, pericardiocentesis, or paracentesis) will be procured for 
possible PK, pharmacodynamic, and/or biomarker testing.  See the laboratory manual for 
additional details.
Pharmacogenetic Samples
A whole blood sample for DNA isolation will be collected on Cycle 1 Day 1 (pre-
infusion) and End of Treatment Visit from each subject.  Pharmacogenetic collection 
should occur unless precluded by local or national regulations or policies.
Samples will be shipped frozen to AbbVie or a designated laboratory for DNA extraction 
and long-term storage.  Instructions for the preparation and shipment of the 
pharmacogenetic exploratory research samples will be provided in a laboratory manual.
Optional Exploratory Research Samples
Subjects will have the option to provide samples for exploratory research.  Subjects may 
still participate in the main study even if they decide not to participate in this optional 
exploratory research.
AbbVie (or people or companies working with AbbVie) will store the exploratory 
research samples in a secure storage space with adequate measures to protect 
confidentiality.  The samples will be retained while research on rovalpituzumab tesirine 
(or drugs of this class) or this disease and related conditions continues, but for no longer 
than 20 years after study completion.  The procedure for obtaining and documenting 
informed consent for exploratory research samples is discussed in Section 9.3.
Tumor Material at the Time of Disease Progression
An optional tumor material collection by biopsy procedure may be obtained at the time of 
disease progression, from subjects who consent to undergo biopsy procedure to better 


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understand mechanisms of resistance and expression of DLL3.  Other nucleic acid or 
protein based biomarkers related to the response to rovalpituzumab tesirine and SCLC 
biology may be assessed.
Samples will be shipped to AbbVie or a designated laboratory for long-term storage.  
Instructions for the preparation and shipment of the biomarker exploratory research 
samples will be provided in a laboratory manual.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Approximately 6 mL of blood will be collected by venipuncture for pharmacokinetic 
(PK), Anti-therapeutic antibody (ATA), and neutralizing antibodies (nAb) testing as 
indicated in Appendix C, Study Activities.  Two samples will be collected at each 
treatment cycle.  The pre-infusion sample will be collected prior to dosing on Day 1
(–3 days window is allowed) and the second sample will be collected within 60 minutes 
post-infusion.  Only one collection will be required at the Non-Treatment Cycle visit and 
EOT visit.  Blood will be processed to serum and three aliquots generated, each 
containing approximately 0.8 mL of serum.
The date and time of each sample collected will be recorded to the nearest minute.
5.3.2.2
Handling/Processing of Samples
Specific instructions for collection of blood/serum samples and subsequent preparation 
and storage of the samples for the assays will be provided by the central laboratory, 
AbbVie, or its designee.
5.3.2.3
Disposition of Samples
The frozen serum samples for the rovalpituzumab tesirine ADC, rovalpituzumab tesirine 
ADC ATA, and neutralizing antibodies (nAb) assays will be packed in dry ice sufficient 
to last during transportation and shipped from the study site to the central laboratory. 


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An inventory of the included samples will accompany the package and an electronic copy 
of the manifests (including subject number, study day, the time of sample collection and 
barcode) will be sent to the contact person at gprd_lupet@abbvie.com.
5.3.2.4
Measurement Methods
Serum concentrations of rovalpituzumab tesirine ADC and relative titers of 
rovalpituzumab tesirine ADC ATA will be determined using validated methods.  Any 
additional related analytes may be analyzed using non-validated methods.  Serum samples 
collected for the PK, ATA and nAb analysis may be used for future assay development or 
validation activities.  Rovalpituzumab tesirine ADC nAb samples upon request may be 
used for the analysis of neutralizing anti-drug antibodies in a validated assay. 
5.3.3
Efficacy Variables
5.3.3.1
Definition of Disease Progression
Disease progression will be defined as radiographic progression of disease by RECIST 
version 1.1.  Refer to Appendix G, Response Evaluation Criteria for Solid Tumors 
(RECIST) version 1.1 for Tumor Response.12  Effusions (pleural, pericardial, etc.) will 
contribute to disease response assessment only if confirmed malignant by cytology or 
otherwise clearly disease-related; if disease progression is suspected solely based on the 
appearance of new or increase of existing effusions, confirmation of malignant nature of 
such effusions is strongly recommended prior to making the decision on treatment 
discontinuation due to known adverse event profile of rovalpituzumab tesirine.  If 
collected, effusion fluid must be tested centrally and/or locally for cytology if disease 
progression due to appearance/worsening of effusion is suspected.
5.3.3.2
Primary Variables
The primary endpoints are progression-free survival (PFS) determined by a Central 
Radiographic Assessment Committee (CRAC) per RECIST v. 1.1 and overall survival 
(OS) in DLL3high population.


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5.3.3.3
Secondary Variables
The secondary variables are progression-free survival (PFS) determined by a Central 
Radiographic Assessment Committee (CRAC) per RECIST v. 1.1 and overall survival 
(OS) in randomized set population.  Change in patient reported outcome (PRO) with
physical functioning as measured by European Organization for Research and Treatment 
of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) in randomized set 
population is also a secondary endpoint in this study.
5.3.3.4
Exploratory Variables
The exploratory variables are progression-free survival (PFS) based on investigator 
assessment, objective response rate (ORR) per the CRAC and investigator assessment, 
respectively, clinical benefit rate (CBR) per the CRAC and investigator assessment, 
respectively, and the duration of response (DOR) per the CRAC and investigator 
assessment, respectively.  Response assessment will be based on RECIST v1.1.  Changes 
in patient reported outcomes (PROs) as measured by EQ-5D-5L and all other PRO 
domains (except for physical functioning) as measured by European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) 
and Lung Cancer Module (QLQ-LC13) are also exploratory endpoints in this study.
5.3.4
Safety Variables
AbbVie will assess adverse events, laboratory data, ECGs and vital signs throughout the 
study.  Adverse events intensity and laboratory evaluation changes will be assessed by 
utilizing NCI CTCAE Version 4.0.11
During the conduct of the study, the AbbVie medical and safety team will be monitoring 
blinded, subject laboratory results and serious adverse event data as they are reported.
Safety endpoints will be summarized using data from the Safety set.  Safety analyses will 
involve examination of the incidence, severity, and type of treatment-emergent adverse 
events (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.


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5.3.5
Pharmacokinetic Variables
Serum concentrations of rovalpituzumab tesirine ADC as well as the timing and incidence 
of ATAs will be tabulated and summarized.
5.3.6
Biomarker and/or Optional Exploratory Research Variables
Biomarker Research Variables
Blood, serosal fluid, and tumor material samples will be collected to conduct analyses to 
investigate biomarkers.  The types of biomarkers to be analyzed may include, but are not 
limited to, nucleic acids, proteins, lipids or metabolites.  
Tumor specimen and CTCs will be tested for DLL3 expression and analyses will be 
performed to correlate the expression levels to rovalpituzumab tesirine response.
Enumeration of CTCs, soluble DLL3 in plasma, or markers that are related to the disease 
or to drug response will be measured at baseline and post-treatment.  The information 
learned from analyzing these samples may be used to investigate factors influencing 
response to treatment, pharmacodynamics, PK, safety, scientific questions related to 
SCLC, and/or in the development of new therapies and diagnostic tests.  The results of 
biomarker testing may not be included with the study summary.
Whole blood for pharmacogenetic analysis may include but not be limited to DLL3, 
ASCL1, or NEUROD1.
Exploratory Research Variables
Optional samples may be collected to conduct exploratory investigations into known and 
novel biomarkers.  The types of biomarkers to be analyzed may include, but are not 
limited to, nucleic acids, proteins, lipids or metabolites.  The samples may be analyzed as 
part of a multi-study assessment of factors influencing the subjects' response to the 
blinded investigational product (or drugs of the same or similar class) or the development 
and progression of the subjects' disease or related conditions.  The samples may also be 


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used to develop new diagnostic tests, therapies, research methods or technologies.  The 
results from these analyses are exploratory in nature and may not be included with the 
study report.
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 of samples, the subject may request for 
samples to be withdrawn.  Once AbbVie receives the request, remaining samples will be 
destroyed.  If the subject changes his/her consent, and the samples have already been 
tested, those results will still remain part of the overall research data.
5.4
Removal of Subjects from Therapy or Assessment
Each subject has the right to withdraw from study treatment at any time.  In addition, the 
Investigator may discontinue a subject from the study treatment at any time for any reason 
if the Investigator considers it necessary.  Each subject will be withdrawn from the study 
or study treatment (as applicable) per Section 5.4.1 if any of the following occur:
●
The subject has radiographic progression according to RECIST v1.1 (with the 
exception of CNS-only progression).
●
The subject requires cancer-directed radiotherapy or surgery related to clinical 
disease progression, or alternate anti-cancer agents during the study period.  
(Refer to Section 5.2.3.2.1, Allowed Concomitant Therapy for exceptions from 
this criterion).  
●
The subject experiences treatment toxicity which, in the Investigator's opinion, 
prohibits further therapy or the Investigator believes it is otherwise in the best
interest of the subject.
●
Subject is pregnant or begins breastfeeding during the treatment portion of the 
study.
●
The subject decides to withdraw consent for any reason.
●
Any other medical reason that AbbVie or the study Investigator deems 
appropriate.
●
Significant non-compliance to the protocol.


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Discontinued subjects will not be replaced.
5.4.1
Discontinuation of Individual Subjects
When subject discontinuation from study treatment (without reaching a protocol-defined 
endpoint) is planned, the Investigator is to notify the AbbVie Therapeutic Area Medical 
Director (TA MD) or the clinical team representative (Section 7.0) via telephone as soon 
as possible (provided, in each case, subject care and safety are not compromised).  If not 
notified prior to discontinuation, the AbbVie TA MD may contact the site to discuss the 
reason for withdrawal from the study.
The visit at which an investigator identifies disease progression or a subject meets other 
criteria for study treatment discontinuation will be considered the End of Treatment Visit.  
The reason(s) for the discontinuation from study treatment will be recorded and 
assessments will be performed per Appendix C, Study Activities.  It is preferable that End 
of Treatment Visit procedures be conducted prior to the initiation of another anti-cancer 
therapy.  However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the Investigator feels are necessary to treat the 
subject's condition.
If a subject is discontinued with an ongoing adverse event or an unresolved clinically 
significant laboratory result, the site will attempt to provide follow-up until a satisfactory 
clinical resolution of the laboratory results or adverse event is achieved.
Subjects no longer undergoing clinical assessments will have survival information 
collected at every 6 weeks (± 1 week) until the endpoint of death, the subject becomes lost 
to follow-up or withdraws consent, or termination of the study by AbbVie, whichever 
occurs first.
In the event that a positive result is obtained on a pregnancy test for a subject during the 
study, the administration of blinded investigational product to that subject must be 


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discontinued immediately.  The site must report the positive pregnancy test result by 
completing the appropriate eCRF within 24 hours of becoming aware of the pregnancy.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will notify the 
investigator and provide written instructions for study termination.
5.5
Treatments
5.5.1
Treatments Administered
Rovalpituzumab tesirine, the investigational agent under study in this protocol, is an 
ADC.  All subjects randomized will receive premedication consisting of 
dexamethasone/placebo orally (PO) at 8 mg twice daily on Day –1, Day 1 (the day of 
dosing), and Day 2 of each cycle in which rovalpituzumab tesirine/placebo is 
administered.  Dexamethasone/placebo dosing should occur such that there are 
approximately 12-hours (i.e., 10 – 14 hours) between AM and PM doses.  The first dose 
of the dexamethasone/placebo on the day of dosing should be at least 30 minutes but no 
more than 4 hours prior to the rovalpituzumab tesirine/placebo infusion.  If the dose of 
dexamethasone/placebo is vomited within 15 minutes of taking the medication, the 
subject should retake the medication.
In the event that a subject arrives for rovalpituzumab tesirine/placebo administration on 
Day 1, but has not taken any or all required dexamethasone/placebo doses on Day –1 
and/or Day 1, rovalpituzumab tesirine/placebo administration may not proceed, and 
rovalpituzumab tesirine/placebo will be held until the required dexamethasone/placebo 
dosing has occurred.


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5.5.2
Identity of Investigational Product(s)
Table 3.
Identity of Investigational Products
Investigational 
Product
Rovalpituzumab 
Tesirine
Placebo for 
Rovalpituzumab 
Tesirine
Dexamethasone*
Placebo for 
Dexamethasone
Dosage Form
Powder for 
solution for 
infusion in vials
Powder for 
solution for 
infusion in vials
Capsules
Placebo capsules
Strength
10 mg/ml when 
reconstituted with 
3.2 ml of sterile 
water for injection
N/A
8 mg
N/A
Route of 
Administration
Intravenous
Intravenous
Oral
Oral
*
Commercially-available Dexamethasone tablets are over-encapsulated to maintain study blinding.
AbbVie will supply rovalpituzumab tesirine/placebo and dexamethasone/placebo.
Each site will be responsible for maintaining drug accountability records, including 
product description, manufacturer, and lot numbers for all investigational products 
dispensed by the site.
5.5.2.1
Packaging and Labeling
Rovalpituzumab Tesirine and Placebo
Vials of rovalpituzumab tesirine/placebo will be packaged in cartons.  Each vial and 
carton will be labeled per country requirements.  Labels must remain affixed to the vial 
and carton.  Rova-T drug product is classified as a Dangerous Goods/Hazardous Material 
and is packaged and shipped by AbbVie according to US Department of Transportation 
(DOT) and International Air Transport Association (IATA) certified regulations.


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Dexamethasone and Placebo
Dexamethasone/placebo will be packaged in high-density polyethylene (HDPE) bottles 
according to the study needs.  The bottles will be labeled per country requirements.  
Labels must remain affixed to the containers.
5.5.2.2
Storage and Disposition of Blinded Investigational 
Product(s)
For all storage areas and refrigerators, temperature logs will be maintained to document 
proper storage conditions.  The temperature must be recorded on the temperature logs to 
verify proper function on each business day.  Temperature excursions must be reported to 
AbbVie immediately.
Sites should use the AbbVie Temperature Excursion Management System (ATEMS) 
module via IRT, if available, or fax copies of the temperature log indicating the extent of 
the excursion (time, duration of the temperature excursion, min/max values and study 
drugs affected) to AbbVie Clinical Drug Supply Management (CDSM) including the 
Storage Temperature Excursion Reporting Form.
In case of a temperature excursion, study medication should be quarantined and not 
dispensed until AbbVie CDSM or ATEMS deems the medication as acceptable.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to the destruction facility.
Rovalpituzumab Tesirine/Placebo
Rovalpituzumab tesirine/placebo must be stored refrigerated at 2° to 8°C (36° to 46°F), 
protected from light, and must not be frozen.  Specific storage conditions for reconstituted 
and diluted rovalpituzumab tesirine/placebo will be provided in a separate document 
outside of this protocol.


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Dexamethasone/Placebo
Dexamethasone/placebo should be stored at 15° to 25°C (59° to 77°F) and protected from 
light.  For Australia, dexamethasone/placebo should be stored below 25°C and protected 
from light.
5.5.2.3
Preparation/Reconstitution of Dosage Form(s)
Both rovalpituzumab tesirine and matching placebo will be supplied as a lyophilized 
powder in a vial.  Each vial of rovalpituzumab tesirine or placebo will be reconstituted 
with 3.2 mL of sterile water for injection.  When reconstituted, vial of rovalpituzumab 
tesirine will contain 10 mg/mL (30 mg total per vial).  The rovalpituzumab tesirine drug 
product is dosed based on actual body weight.  The contents of two or more vials of 
reconstituted drug product may be required to accomplish the desired dose.  The total 
volume administered treatment arm will be dependent upon the assigned dose.  The 
rovalpituzumab tesirine drug product and placebo solution(s) will be administered via 
intravenous (IV) infusion.  Rovalpituzumab tesirine drug product and placebo solution(s) 
will be added to 50 mL or 100 mL of 0.9% normal saline with an infusion over 
30 minutes (20 – 45 minute infusion window).  The rate should be adjusted based on 
patient tolerability.  Specific dose preparation and documentation details will be provided 
to the site pharmacy in a separate document.  A complete description of the chemistry and 
formulation may be found in the Investigator's Brochure.14
5.5.3
Method of Assigning Subjects to Treatment Arms
All subjects in the study will be randomized using an IRT system.  Before the study is 
initiated, directions for the IRT will be provided to each site.  The site will contact the IRT 
to obtain a Screening (subject) number once the subject has signed the informed consent 
and a study-specific procedure has been performed (i.e., central laboratory samples 
drawn).  Once the screening number is assigned, if the subject is not randomized into the 
study, the reason for screen failure will be documented in the source document and in the 
eCRF.  For others, the site will access the system and a unique randomization number will 
be provided.


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The IRT will randomize subjects in a 1:1 ratio, with one-half of the subjects being 
randomized to the rovalpituzumab tesirine treatment arm and the other one-half to the 
placebo arm.  The stratification factors used for the randomization should be the last 
values on or prior to the date of randomization.
5.5.4
Selection and Timing of Dose for Each Subject
5.5.4.1
Dosing
Dosing is based on actual body weight of the subject to the nearest kilogram, assessed in 
the clinic prior to dosing at each cycle, and administered according to the calculated dose.  
In cases of weight gain due to fluid retention, dosing should be based on most recent pre-
fluid retention actual weight.
Subjects must meet all of the following criteria on each dosing day before receiving 
blinded investigational product:
●
Absolute neutrophil count (ANC) ≥ 1,000/μL
●
Platelet count ≥75,000/μL
●
Resolution of blinded investigational product-related AEs, including findings 
indicative of pleural or pericardial effusions, and clinically-significant 
laboratory abnormalities to Grade 0 or 1 (excluding ANC and alopecia), or to 
baseline grade.  
5.5.4.2
Dose Modifications
5.5.4.2.1
Dose Treatment Delays due to Toxicity or Progression
Subjects who experience blinded investigational product-related toxicity during a cycle 
must have recovered as specified above before the next cycle may proceed.  Any dose 
modifications except those indicated as mandatory below (including dose delay, 
reduction, resumption, and discontinuation) are to be performed at the discretion of the 
Investigator.  Further guidelines suggesting dose modifications based on prior studies of 
rovalpituzumab tesirine are provided in Section 5.5.4.2.2, Dose Reduction Guidelines.


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In cases of treatment delays of > 28 days, the TA MD should be contacted regarding the 
subject's continuation of treatment.
In the event of isolated CNS-only progression during study treatment, blinded 
investigational product will be withheld while local treatment is administered 
(e.g., radiotherapy) in accordance with institutional practice.  Blinded investigational 
product may be restarted 1 week after the completion of local CNS disease-directed 
therapy.  If more than 6 weeks have elapsed since the previous radiographic tumor 
assessment, the subject must undergo a radiographic tumor assessment to evaluate extra-
cranial disease status prior to resuming blinded treatment.  If additional sites of PD are 
present, the subject will be required to discontinue blinded investigational product.
5.5.4.2.2
Dose Reduction Guidelines
Blinded investigational product dose reductions and discontinuation of blinded 
investigational product for specific toxicities should occur as outlined in Table 4, Dose 
Reductions for Blinded Investigational Product (IP) and Table 5, Dose Reductions and 
Discontinuation for Unacceptable Toxicities.  Dose reductions for unacceptable toxicities 
described in Table 5 are mandatory.  Reduced dose levels are described in (Table 4).  
Generally, if unacceptable toxicity recurs after two dose reductions, treatment will be 
discontinued (for further details, refer to Table 5).  If the blinded investigational product 
dose is reduced, no re-escalation will be allowed.  If different unacceptable toxicities 
occur in sequential treatment cycles (e.g., Grade 3 LFT after the first dose and Grade 3 
thrombocytopenia lasting more than 7 days after the second dose), dose reduction will 
proceed to the next lower dose level.  If different unacceptable toxicities occur within 
one cycle, maximum specified dose reduction will be implemented.  Dose reductions and 
discontinuation are not planned for dexamethasone/placebo.  If full dose of 
dexamethasone/placebo cannot be administered due to an AE, the blinded infusion should 
be delayed until dexamethasone/placebo can be administered.
Exceptions to the dose modification guidelines should be discussed with the TA MD prior 
to implementation.


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Details of toxicity management are further outlined in Section 6.1.8, Toxicity 
Management.
Table 4.
Dose Reductions for Blinded Investigational Product (IP)
Starting Dose
First Dose Reduction
(Reduce Dose)
Second Dose Reduction
(Reduce Dose)
0.3 mg/kg
0.2 mg/kg
0.1 mg/kg


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Table 5.
Dose Reductions and Discontinuation for Unacceptable Toxicities
Toxicitya
First Occurrence
Second Occurrence
Grade 3 thrombocytopenia lasting more than 
7 days
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 4 thrombocytopenia/Grade 3 
thrombocytopenia with bleeding/Need for 
platelet transfusion
Reduce dose to 0.1.mg/kg
Discontinue Blinded IP
Grade 4 neutropenia lasting more than 7 days
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 3 febrile neutropenia
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 4 febrile neutropenia
Reduce dose to 0.1.mg/kg
Discontinue Blinded IP
Grade 3 Liver Function Tests (LFTs)
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 4 LFTs or Grade 3 LFTs with 
concomitant Bilirubin Grade 2 or higherb
Reduce dose to 0.1.mg/kg
Discontinue Blinded IP
Potential DILI (Drug-induced liver injury)
See Section 6.1.8.3
See Section 6.1.8.3
Grade 3 or 4 hypoalbuminemia
Reduce dose to 0.1 mg/kg
Discontinue Blinded IP
Any other Grade 3 or 4 laboratory 
abnormality considered clinically significant 
and treatment-related
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
Grade 2 serosal effusions or edema
Reduce to 0.2 mg/kg
Reduce to 0.1 mg/kg
Grade 3 serosal effusions or edema or 
Grade 2 capillary leak syndrome
Reduce dose to 0.1.mg/kg
Discontinue Blinded IP
Grade 4 serosal effusions or edema or 
Grade ≥ 3 capillary leak syndrome
Discontinue Blinded IP
N/A
Grade 3 photosensitivity reaction
Reduce dose to 0.2 mg/kg
See Section 6.1.8.2
Reduce dose to 0.1 mg/kg
See Section 6.1.8.2
Grade 4 photosensitivity reaction
Discontinue Blinded IP
N/A
Grade 2 pneumonitis
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Grade ≥ 3 pneumonitis
Discontinue Rova-T
N/A
Any other Grade 3 or Grade 4 non-laboratory 
treatment-related toxicity with the exception 
of fatigue, asthenia, nausea, or other 
manageable constitutional symptom
Reduce dose to 0.2 mg/kg
Reduce dose to 0.1 mg/kg
a.
Refer to Appendix H, CTCAE v 4.0 Grading of Relevant AEs for definitions of NCI-CTCAE severity grades and 
for definition of serosal effusions and edema.
b.
If potential DILI is suspected please follow guidelines of Section 6.1.8.3.


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5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
AbbVie, the Investigator, the study site personnel, and subject will remain blinded to each 
subject's treatment with rovalpituzumab tesirine or placebo and dexamethasone or placebo
and throughout the course of the study.  
The IRT system will provide access to blinded subject treatment information during the 
study.  AbbVie must then be notified within 24 hours of the blind being broken.  The date 
and reason that the blind was broken must be recorded in the source documentation and 
eCRF, as applicable.
5.5.5.2
Blinding of Data for Independent Data Monitoring 
Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will be formed and constituted 
according to appropriate regulatory guidelines.  The IDMC will review the unblinded data 
from the study with respect to subject accrual, pretreatment characteristics of accrued 
subjects, the frequency and severity of toxicities and morbidity, and provide 
recommendations according to the charter.  Detailed information regarding the 
composition of the committee and procedures including frequency of meetings and scope 
of reviews will be documented in a separate charter.  For the futility analysis, OS, other 
efficacy and safety data will be analyzed and reviewed by the IDMC for recommendation.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense blinded investigational product only to subjects randomized in the 
study in accordance with the protocol.  The blinded investigational product must not be 
used for reasons other than that described in the protocol.
Blinded investigational product administration must be performed by study site staff and 
documented in source documents and the eCRF. 


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5.5.7
Drug Accountability
The site will record the dose of rovalpituzimab tesirine/placebo and 
dexamethasone/placebo given to each subject in the source documents and on the eCRF.  
Upon receipt of a shipment of rovalpituzimab tesirine/placebo and 
dexamethasone/placebo, the representative at each site will (1) open and inspect the 
shipment; (2) verify that the rovalpituzimab tesirine/placebo has been received intact, in 
the correct amounts and at the correct address; (3) sign and date the Proof of Receipt 
(POR) or similar documentation accompanying the shipment; (4) register the shipment as 
received via the IRT.  All blinded investigational products must be retained in the 
designated secure area under proper storage conditions.  This will be documented by 
signing and dating the Proof of Receipt (POR) or similar document or via direct recording 
in the IRT.
An overall accountability of the blinded investigational product will be performed and 
verified by the site monitor throughout the study and at the study site closeout visit.  An 
accurate running inventory of rovalpituzimab tesirine/placebo and dexamethasone/placebo 
will be maintained utilizing the IRT drug accountability module and, if required, 
according to your institutional policy and will include the lot number, POR number(s), the 
bottle/kit numbers, and the date blinded investigational product was dispensed for each 
subject.
Upon completion or termination of the study, all original bottles/cartons containing 
unused rovalpituzimab tesirine/placebo and dexamethasone/placebo (empty containers 
will be defaced and discarded on site) will be returned to the Destruction Facility 
according to AbbVie's instructions, or if pre-arranged between the sponsor and site, 
destruction of used and unused bottles will be performed at the site.  Rova-T is classified 
as a Dangerous Good/Hazardous Material according to US Department of Transportation 
(DOT) and International Air Transport Association (IATA).  Dangerous 
Goods/Hazardous Materials must be packaged and shipped according to applicable 
regulations.


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The study Investigator or his/her designated representative agrees not to supply study 
medication to any persons not enrolled in the study or not named as a sub-investigator 
listed on the FDA 1572 or Investigator Information and Agreement (IIA) form.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
Phase 1 data described in Section 3.0 and proposed mechanism of action suggest that 
rovalpituzumab tesirine may improve outcome of SCLC patients by extending clinical 
benefit following first-line platinum-based chemotherapy.  This randomized, double-
blind, placebo controlled phase 3 study will evaluate the effect of rovalpituzumab tesirine 
as maintenance therapy following first-line platinum-based chemotherapy of extensive 
stage SCLC.  Primary endpoints of PFS and OS are well established in solid tumor trials 
and in SCLC specifically.
A randomized, double-blind, placebo controlled study such as described here is optimal 
for assessing the treatment effect of rovalpituzumab tesirine versus current standard, best 
supportive care to a current standard treatment (placebo is required to allow for blinding).
5.6.2
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.  Adverse events and, when 
applicable, clinical laboratory data will be graded using NCI CTCAE, version 4.0.11
Response will be assessed according to RECIST v1.1,12 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 
blinded investigational product.  Pharmacokinetic assessments for drug activity are also 
common in clinical studies.


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5.6.3
Suitability of Subject Population
Although response rates to first-line chemotherapy remain high with platinum-based 
regimens, time to disease recurrence is short in extensive-stage SCLC.  Rovalpituzumab 
tesirine has demonstrated anti-tumor activity in relapsed/refractory SCLC population.  
Exploring rovalpituzumab tesirine in ED SCLC subjects with stable disease or objective 
response following first-line chemotherapy is acceptable considering observed 
activity/toxicity profile of rovalpituzumab tesirine, and that the standard approach in this 
setting is no treatment until progression.
5.6.4
Selection of Doses in the Study
In a recent Phase 1 study (SCRX16-001) with rovalpituzumab tesirine, the maximum 
tolerated dose (MTD) was established at 0.4 mg/kg every 3 weeks based on the incidence 
of Cycle 1 toxicities, while the recommended Phase 2 dose (RPTD) in SCLC was chosen 
as 0.3 mg/kg every 6 weeks for a total of two doses with the allowance to retreat at the 
same dose level and schedule upon progression.  The RPTD is based on the toxicity and
efficacy profile during multiple cycles dosing (AbbVie Stemcentrx data on file).  This 
experience included multiple doses of rovalpituzumab tesirine at a) 0.2 mg/kg every 
6 weeks, b) 0.3 mg/kg every 6 weeks or c) 0.3 mg/kg every 6 weeks for a total of 
two doses and then at 0.1 mg/kg every 6 weeks thereafter.  Based on the totality of the 
experience with rovalpituzumab tesirine and taking into consideration its pharmacokinetic 
characteristics, dosing of 0.3 mg/kg q6wk for 2 cycles, omitting every third cycle will be 
used in this study.  This study will not exceed a maximum dose of 1.5 mg/kg at each dose.
6.0
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.


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The investigational product in this study is defined as rovalpituzumab tesirine or placebo 
and dexamethasone or placebo.  Complaints associated with any component of this 
investigational product must be reported to the Sponsor (Section 6.2.2).  For AEs, please 
refer to Sections 6.1.1 through 6.1.6.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event 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 blinded investigational product, and any action(s) taken.  For serious 
adverse events considered as having "no reasonable possibility" of being associated with 
blinded investigational product, the investigator will provide an Other cause of the event.  
For adverse events to be considered intermittent, the events must be of similar nature and 
severity.  Adverse events, whether in response to a query, observed by site personnel, or 
reported spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (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 adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (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 adverse event.  


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Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meets protocol specific criteria (see Section 6.1.8 regarding toxicity 
management) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event 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 adverse event.
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 70 days have elapsed following 
discontinuation of study drug administration will be considered as treatment-emergent 
adverse events.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie 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 or admission to an 


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outpatient facility or hospitalization for respite care.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a study subject.  Disability 
is not intended to include experiences of relatively minor 
medical significance such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or stillbirth 
is considered an important medical event.  Examples of such 
events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.1.3
Adverse Events Expected Due to SCLC or Progression of 
SCLC
Adverse events that may be expected from primary SCLC lesions, compression of 
adjacent thoracic structures or distant metastases are presented in Appendix J, Adverse 
Events Expected Due to SCLC or Progression of SCLC of the protocol.
These adverse events may occur alone or in various combinations and are considered 
expected adverse events in SCLC subjects.


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Although exempted from expedited reporting to Health Authorities and Institutional 
Review Boards (IRBs) as individual cases, these SAEs must be reported to the Sponsor 
within 24 hours of the site being made aware of the SAE.  
AEs or SAEs should not be reported as "Disease progression," even if fatal, as PD is an 
efficacy endpoint for the study.  Rather, report the specific disease (clinical) manifestation 
of the progression (eg, 'malignant pleural effusion,' 'spinal bone metastases,' 
'lymphadenopathy,' 'brain metastases') or if not possible, report "malignant neoplasm 
progression" as the AE or SAE as appropriate.
6.1.2
Adverse Event Severity
The investigator will rate the severity of each adverse event according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
Version 4.0).11  If a reported adverse event increases in severity, the initial adverse event 
should be given an outcome date and a new adverse event reported on a different date 
from the end date of the previous adverse event to reflect the change in severity.  For all 
reported serious adverse events that increase in severity, the supplemental eCRFs also 
need to be updated to reflect the change in severity.
When CTCAE criteria cannot be used, the event should be graded as defined below:
Grade 1
The adverse event is transient and easily tolerated by the subject (mild).
Grade 2
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities (moderate).
Grade 3/4
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening (severe). 
Grade 5
The adverse event resulted in death of the subject (severe).
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of blinded investigational products:


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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 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, an Other cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Deaths
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
Deaths that occur during the protocol specified AE reporting period (Section 6.1.6) that 
are more likely related to disease progression will therefore be considered as an expected 
SAE and will not be subject to expedited reporting.  These events should be recorded on 
the AE eCRF as described in Section 6.1.1.3.  After the AE reporting period, deaths 
attributed to progression of disease under study should not be recorded on the AE eCRF.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the AE eCRF.  Generally, only one such event should be reported.  The term 
"sudden death" should only be used for the occurrence of an abrupt and unexpected death 


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due to presumed cardiac causes in a patient with or without pre-existing heart disease, 
within 1 hour of the onset of acute symptoms or, in the case of an unwitnessed death, 
within 24 hours after the patient was last seen alive and stable.  If the cause of death is 
unknown and cannot be ascertained at the time of reporting, "unexplained death" should 
be recorded on the AE eCRF.  If the cause of death later becomes available (e.g., after 
autopsy), "unexplained death" should be replaced by the established cause of death.
6.1.5
Adverse Event Collection Period
All adverse events reported from the time of blinded investigational product 
administration until 70 days following the last dose of blinded investigational product will 
be collected, whether solicited or spontaneously reported by the subject.  In addition, 
protocol-related serious adverse events and non-serious 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.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
*
Only if considered by the Investigator to be causally related to study-required procedures.


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6.1.6
Adverse Event Reporting
In the event of a serious adverse event, whether associated with blinded investigational 
product or not, the Investigator will notify Clinical Pharmacovigilance within 24 hours of 
the site being made aware of the serious adverse event by entering the serious adverse 
event data into the electronic data capture (EDC) system.  Serious adverse events that 
occur prior to the site having access to the RAVE® system, or if RAVE is not operable, 
should be documented on the SAE Non-CRF forms and emailed (preferred route) or faxed 
to Clinical Pharmacovigilance within 24 hours of the site being made aware of the serious 
adverse event.
Email:  
FAX to:  
For safety concerns, contact the Oncology Safety Management Team at:
Oncology Safety Team
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Office:
Email:


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For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
Senior Medical Director
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
USA
Telephone Contact Information:
Office:
Mobile:
Email:
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:  
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines and Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow-up reports, the RSI in 
place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to 
assess expectedness.
In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.


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6.1.7
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 24 hours of the 
investigative site becoming aware of the pregnancy.  Subjects who become pregnant 
during the study must be discontinued (Section 5.4).
All subjects should be informed that contraceptive measures (refer to Section 5.2.4, 
Contraception Recommendations and Pregnancy Testing for the details on contraception) 
should be taken throughout the study and for at least 6 months after the last dose of study 
drug.  Male subjects should be informed that contraceptive measures should be taken by 
their female partner.  
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  In the event of a pregnancy occurring in the partner of an 
enrolled subject, written informed consent for release of medical information from the 
partner must be obtained prior to the collection of any pregnancy-specific information, 
and the pregnancy will be followed to outcome.
Pregnancy in a study subject is not considered an adverse event.  The medical outcome for 
either mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion is considered a serious adverse event and must be reported to AbbVie within 
24 hours of the site becoming aware of the event.
6.1.8
Toxicity Management
Subjects will be monitored continuously for toxicity while on study treatment.  Toxicity 
will be assessed using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) Version 4.0.11  If a subject has an AE possibly related to 
blinded investigational product administration, then dose interruptions/holds with possible 
modifications as described below may be implemented.  Adjustments to these guidelines 
may occur based on the clinical judgment of the investigator with notification to the TA 
MD.  Dose modifications for toxicities as described in Section 5.5.4.2.2 are mandatory.


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6.1.8.1
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., cardiac 
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, or disease progression, should be ruled out.  When 
appropriate, a unifying diagnosis should be reported, e.g., "heart failure," not the signs and 
symptoms "pleural effusion" and "edema limbs."  Effusion events were reported during 
treatment and may occur up to several months after last Rova-T dose.  As a result, 
subjects should be advised of signs and symptoms of fluid retention and contact treating 
physician if they arise during this time.
When considered clinically significant (e.g., Grade 2 or higher and considered related to 
blinded investigational product):
●
Systemic corticosteroids, when initiated promptly, have been reported to be 
beneficial in some prior cases.  The Investigator should consider a tapering 
regimen, such as dexamethasone up to 8 mg orally twice a day for 5 days, 
followed by 4 mg orally twice a day for 5 days, then 2 mg orally twice a day 
for 5 days.  Alternatively, nonsteroidal therapies for serositis may be 
considered, such as non-steroidal anti-inflammatory drugs (NSAIDs, 
e.g., ibuprofen 400 – 600 mg orally three to four times daily) or colchicine 
(e.g., 0.6 mg orally two to three times daily) given for 1 – 2 weeks.
●
Until clinical experience suggests otherwise, guidance for dose delay and/or 
reduction, as well as criteria for ongoing dosing, should follow Section 5.5.4.2.
6.1.8.2
Management of Skin Reactions
All cutaneous reactions which develop during treatment warrant prompt evaluation.  Skin 
toxicity with rovalpituzumab tesirine may consist of photosensitivity but possibly other 
reactions such as palmar-plantar erythrodysesthesia or erythema multiforme.  As such, 


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development of a cutaneous reaction during treatment warrants prompt evaluation by the 
Investigator or designee.
Photosensitivity reactions may occur hours to days after sun exposure.  Patients should be 
advised to avoid direct and indirect sun exposure as much as possible from Cycle 1 Day 1 
until 30 days after the final dose.  When sun exposure is unavoidable, patients should 
wear protective clothing and sunglasses, and use a broad-spectrum sunscreen and lip balm 
(SPF 30 or greater).  Thirty-one to ninety days after last dose of Rova-T/placebo, the 
patient may resume outdoor activities with appropriate sun protection including broad 
brimmed hat, protective clothing and sunscreen SPF 30 or higher.  Subjects with a grade 3 
photosensitivity reaction should dose reduce Rova-T/placebo to 0.2 mg/kg after the first 
occurrence and following a second grade 3 photosensitivity reaction, reduce Rova-
T/placebo to 0.1 mg/kg.  Subjects with a grade 4 photosensitivity reaction must 
permanently discontinue Rova-T/placebo.
If clinically consistent with photosensitivity, the AE should be reported as such (using 
medically accurate and descriptive AE terminology), and managed as described in 
Table 6. 
Photo-documentation of skin toxicity should be available upon request by the TA MD.  
The investigative site will take measures to protect the identity of the patient.  These 
measures include taking the photograph very close to the affected skin region to exclude 
facial features, or if facial features cannot be excluded due to the location of the skin 
reaction, covering identifying features (such as the eyes) with a black rectangle.
Formal evaluation by a dermatologist, including possible skin biopsy to rule out 
alternative etiologies such as erythema multiforme, which may warrant discontinuation of 
blinded investigational product, and to facilitate the most appropriate terminology for AE 
reporting.
All events of cutaneous toxicity should be monitored until resolution or return to baseline.  
Recommendations for management of photosensitivity reactions are outlined in Table 6.


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Table 6.
Recommended Management of Photosensitivity
CTCAE v4.0
Treatment Recommendations
Dose Modifications
Grade 1
Painless erythema and 
erythema covering < 10% BSA
Low-potency topical steroid (face) 
High-potency topical steroid 
(body)
–
Grade 2
Tender erythema covering 10 –
30% BSA
Low-potency topical steroid (face) 
High-potency topical steroid 
(body)
Nonsteroidal anti-inflammatory 
agents orally as needed
–
Grade 3
Erythema covering > 30% 
BSA and erythema with 
blistering; photosensitivity; 
oral corticosteroid therapy 
indicated; pain control 
indicated (e.g., narcotics or 
NSAIDs)
Low-potency topical steroid (face) 
High-potency topical steroid 
(body)
Prednisone 0.5 mg/kg × 7 days
Reduce dose
Grade 4
Life-threatening consequences; 
urgent intervention indicated
Low-potency topical steroid (face) 
High-potency topical steroid 
(body)
Prednisone 0.5 mg/kg × 7 days 
Hospitalization
Discontinue
In order to simplify the collection of detailed Safety Data associated with dermatological 
issues, prior to the verification of a specific diagnosis the general term of "Skin Toxicity" 
should be recorded on the Adverse Event eCRF and the corresponding details should be 
captured on the Skin Toxicity Supplemental eCRF (as outlined in the form).  Once a final 
dermatological diagnosis is verified, the AE eCRF should be updated to reflect the 
specific diagnosis.
6.1.8.3
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.


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A potential DILI is defined as:
●
ALT or AST elevation > 3 times (3×) upper limit of normal (ULN) and
●
Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) and
●
No other immediately apparent possible causes of aminotransferase (AT) 
elevation and hyperbilirubinemia including but not limited to viral hepatitis, 
pre-existing chronic or acute liver disease or tumor(s), or the administration of 
other drug(s) known to be hepatotoxic
In general, an increase of AT to > 3 × ULN should be followed by repeat testing within 48 
– 72 hours of all four of the usual measures (ALT, AST, alkaline phosphatase, and total 
bilirubin) to confirm the abnormalities and to determine if they are increasing or 
decreasing.  An 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 available to the 
Investigator immediately.  All data must be recorded in the CRF.  If symptoms persist or 
repeat testing shows AT > 3 × ULN for subjects with normal baseline measures or 2-fold 
increases above baseline values for subjects with elevated values before drug exposure, 
close observation should be initiated.  If close monitoring is not possible, blinded 
investigational product 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


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●
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
Blinded investigational product will be discontinued if potential DILI is suspected and:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks
●
ALT or AST > 3 × ULN and (TBL > 2× ULN or INR > 1.5)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia
All subjects showing possible DILI should be followed until all abnormalities return to 
normal or to the baseline state. 
Any hepatic related adverse event should be recorded and the Hepatic Adverse Event 
eCRF triggered from the Adverse Event page.
6.1.8.4
Monitoring and Management of Edema
The majority of the edema events with rovalpituzumab tesirine have been reported as low 
grade 1 or 2 (mild or moderate); however, a small number of fatal events of generalized 
edema have been reported with rovalpituzumab tesirine.  Physical exams and monitoring 
of weight gain and signs or symptoms of fluid retention should be conducted during 
treatment.  Edema events were reported during treatment and may occur up to several 
months after last Rova-T dose.  As a result subjects should be advised of signs and 
symptoms of fluid retention as well as monitor their weight and contact treating physician 
if they arise during this time.


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Consistent with institutional guidelines or standard practice, the use of diuretics with or 
without albumin may be considered in subjects with clinically significant edema and 
hypoalbuminemia.  The selection and use of diuretics in subjects should be based on 
individual clinical characteristics and include monitoring of electrolyte status and signs or 
symptoms of intravascular volume depletion such as hypotension and impaired renal 
function. 
Systemic corticosteroids, when initiated promptly, have been reported to be beneficial in 
some prior cases.
Reported Term
Grade 1
Grade 2
Grade 3
Grade 4
Generalized 
edema 
(Anasarca)
Noted on exam; 
1+ pitting edema
Interfering with 
instrumental ADLs; oral 
therapy initiated
Interferes with 
self care ADL; 
intravenous 
therapy indicated; 
skin breakdown
Life-
threatening 
consequences
Definition:  A disorder characterized by fluid accumulation in the tissues of the body including the skin.
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.
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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6.1.8.5
Pneumonitis
Pneumonitis has been infrequently reported with rovalpituzumab tesirine but has resulted 
in fatal outcomes.  Although the causal role of rovalpituzumab tesirine could not be ruled 
out, the reports of pneumonitis had one or more confounders including underlying 
pulmonary disease/cancer, prior thoracic radiation, prior cytotoxic chemotherapy or 
clinical evidence suggestive of an alternative diagnosis including pneumonia. 
Heavily pretreated SCLC patients and patients with a history of pneumonitis may be at 
increased risk, and careful monitoring for signs and symptoms of pneumonitis is 
important.  The risk of pneumonitis is increased with prior radiation to lung.
In general, signs and symptoms coinciding with or preceding pneumonitis may include 
new or worsening cough, chest pain and/or shortness of breath, fever, and radiographic 
changes (reticular markings, ground glass opacities).  Protocol defined disease 
assessments provide the opportunity for on study pulmonary monitoring with "gold 
standard" diagnostic method for detection of pneumonitis.  The protocol allows for 
additional imaging per physician discretion for signs and symptoms of pulmonary 
toxicity.
The diagnosis of drug induced pneumonitis is one of exclusion.  Other etiologies 
including infection, which is a common cause of pulmonary infiltrates with clinical and 
radiographic appearance similar to drug-induced pneumonitis, need to be carefully 
considered and excluded before the diagnosis of drug induced pneumonitis can be 
established. 
If pneumonitis is suspected, close monitoring including additional laboratory and imaging 
investigation per institutional guidelines may be necessary.  Systemic corticosteroids may 
be beneficial for rapidly progressive or more severe pneumonitis.  For events of Grade 1 
pneumonitis close monitoring is recommended; while dose modifications for Grade 2 and 
discontinuation of Rova-T for Grades 3 and 4 are required.  Please see Table 5.


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6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
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.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint eCRF.  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 adverse events 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.


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7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The principal investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the principal investigator is responsible for notifying 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitor(s):
Primary Contact: 
Study Project Manager II
AbbVie Corporation
8401 Trans-Canada Highway
Saint-Laurent, Québec
H4S 1Z1
Canada
Phone:
Fax:
Email:
Alternate Contact:
Study Project Manager I
AbbVie s.r.o.
METRONOM BUSINESS CENTER
Bucharova 2817/13, Stodulky,
158 00 Praha 5
Czech Republic
Phone:
Fax:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
In Japan, the Investigator will record all protocol deviations in the appropriate medical 
records at site.


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8.0
Statistical Methods and Determination of Sample 
Size 
8.1
Statistical and Analytical Plans
This section describes the planned statistical analyses to be performed using data captured 
according to this protocol.  A complete statistical analysis plan (SAP) describing in more 
detail all planned analyses will be finalized prior to database lock.
The primary endpoints of OS and progress free survival (PFS) assessed by a Central 
Radiographic Assessment Committee (CRAC) according to RECIST v1.1 in DLL3high
patients will be analyzed at the same time after observing at least 319 OS events.  It is 
expected at approximately 420 PFS events will be observed at the time of the primary 
analysis.
The following analysis sets are considered:
●
DLL3high Set:  It includes all randomized subjects with DLL3high ED SCLC.  
Subjects will be classified according to the treatment arm to which they are 
randomized regardless the actual treatment received, following intent-to-treat 
principle.  The DLL3high set will be the analysis set for the analysis of the 
primary efficacy endpoints of OS and PFS.  All the exploratory efficacy 
endpoints will be analyzed based on the DLL3high set unless the OS and PFS 
based on the randomized set are statistically significant.
●
Randomized Set:  It includes all randomized subjects, with subjects grouped 
according to the treatment arm to which they are randomized regardless the 
actual treatment received, following intent-to-treat principle.  The randomized 
set will be the analysis set for key secondary efficacy endpoints of OS and 
PFS, and key secondary endpoint of EORTC QLQ-C30 physical functioning 
domain.  All the exploratory efficacy endpoints will be analyzed based on the
randomization set if the OS and PFS based on the randomization set are 
statistically significant.
●
Per Protocol Set:  It includes all subjects in the randomized set without any 
major protocol violations which may affect the evaluation of the primary 


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efficacy endpoint.  Major protocol violations will be defined in the SAP prior 
to the database lock.  Subjects will be classified according to treatment 
assigned at the time of randomization.  The per protocol set will be used for 
supportive analysis of efficacy endpoints.
●
Safety Set:  It includes all subjects who received at least one dose of study 
drug and subjects will be classified according to treatment received.  Thus a 
subject who is randomized to the rovalpituzumab tesirine arm but does not 
receive rovalpituzumab tesirine will be considered in the placebo arm for 
safety analysis.  Dexamethasone treatment will not be taken into consideration 
for subjects' classification in the Safety set.
●
Pharmacokinetic-Evaluable Set:  It consists of all subjects who receive at 
least one dose of study drug, with subjects classified according to the actual 
treatment received.  A baseline measurement and at least one blood sample 
following a dose of study treatment is required for inclusion in this analysis.
8.1.1
Disposition of Study Subjects
The disposition of subjects will be summarized by treatment arm in the randomized set.  
The subject disposition includes the number of subjects for whom study drug was 
permanently discontinued (including the reasons for discontinuation), and the number of 
subjects who discontinued early from the study.
8.1.2
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized in the DLL3high set and 
randomized set.
8.1.3
Efficacy Endpoints and Analyses
Assessment of response and progression will be determined by the CRAC according to 
RECIST v1.1.


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8.1.4
Primary Efficacy Endpoints
Progression-free survival (PFS) and overall survival (OS) in subjects with DLL3high ED 
SCLC are the two primary efficacy endpoints.  
PFS will be defined as the number of months from randomization to disease progression, 
as assessed by the CRAC per RECIST v1.1, or death of any cause, whichever occurs first. 
Disease progression and censoring rules will be based on published conventions.15  If a 
subject neither experienced disease progression nor died, then the data will be censored at 
the last date of post-baseline radiographic assessment.  If a subject with no post-baseline 
assessment did not experience disease progression nor died, then the data will be censored 
at the date of randomization. 
Differences between the treatment arm and the placebo arm in PFS will be assessed by a 
log-rank test stratified by the randomization stratification factors, testing the null 
hypothesis (rovalpituzumab tesirine arm is not superior to placebo arm in PFS).  The 
hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's 
proportional hazards regression model adjusting for the main-effects of the stratification 
factors.  Median PFS and 95% confidence intervals will be estimated using Kaplan-Meier 
survival methodology, with the Kaplan-Meier survival curves presented to provide a 
visual description.  PFS rates at 3, 6, 9, and 12 months after randomization with 95% 
confidence intervals will be reported.  Estimates of the treatment effect will be expressed 
as hazard ratio including 95% confidence intervals estimated through a Cox proportional-
hazards regression model adjusting for the main-effects of the stratification factors.
Overall survival will be defined as the number of months from randomization to death of 
any cause.  OS and censoring rules will be based on published conventions.15  If a subject 
has not died, the data will be censored at the last date documented to be alive. 
Differences between the treatment arm and the placebo arm in OS will be assessed by a 
log-rank test stratified by the randomization stratification factors, testing the null 
hypothesis (rovalpituzumab tesirine arm is not superior to placebo arm in OS).  The 


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hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's 
proportional hazards regression model adjusting for the main-effects of the stratification 
factors.  Median OS and 95% confidence intervals will be estimated using Kaplan-Meier 
survival methodology, with the Kaplan-Meier survival curves presented to provide a 
visual description.  OS rate at 6, 12, 18, and 24 months and corresponding 95% 
confidence intervals will be reported.  Estimates of the treatment effect on will be 
expressed as hazard ratio including 95% confidence intervals estimated through Cox 
proportional-hazards regression models adjusting for the main-effects of the stratification 
factors.
8.1.5
Secondary Efficacy Endpoints
The secondary efficacy endpoints in the randomized set are: 
●
OS  
●
PFS per the CRAC based on RECIST v1.1 
●
EORTC QLQ-C30 physical functioning domain 
Secondary time-to-event endpoints (PFS and OS) will be analyzed using the similar 
statistical methods described for the primary endpoints.  
8.1.6
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints in both DLL3high and randomization set are: 
●
Objective response rate (ORR) per the CRAC based on RECIST v1.1
●
PFS per investigator assessment based on RECIST v1.1
●
ORR per investigator assessment based on RECIST v1.1
●
Clinical benefit rate (CBR) per the CRAC and investigator assessment, 
respectively, based on RECIST v1.1 
●
Duration of response (DOR) per CRAC and investigator assessment, 
respectively 


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●
Change from baseline in all PRO domains (except physical functioning) 
measured by EORTC QLQ-C30/LC13 and EQ-5D-5L
ORR is defined as the proportion of patients with a best overall response (BOR) of 
confirmed complete response (CR) or partial response (PR) by CRAC review according to 
RECIST v1.1.
CBR is defined as the proportion of patients with a BOR of CR or PR, or SD by CRAC 
review according to RECIST v1.1. 
ORR and CBR in treatment arms will be compared using Cochran-Mantel-Haenszel test 
stratified by randomization stratification factors.  Rates and 95% confidence intervals will 
be reported for each treatment arm. 
The duration of overall response for a given subject will be defined as the number of 
months from the day the criteria are met for confirmed complete response (CR) or partial 
response (PR) by CRAC (whichever is recorded first) to the date of progressive disease or 
death, whichever comes first.  If a subject is still responding (i.e., has not progressed nor 
died after CR or PR), then the subject's data will be censored at date of the last 
radiographic assessment by CRAC.  For subjects who never experienced CR or PR, these 
subjects' data will not be included in the duration of response analysis.  Distribution of the 
duration of response will be estimated for each treatment arm using Kaplan-Meier 
methodology.  Median duration of overall response with corresponding 95% CI for each 
treatment arm will be provided.
8.1.7
Patient Reported Outcomes (PRO)
The EORTC QLQ-C30/LC1313 scoring manual will be used to transform the raw scores 
into the domain scores (global heath, functional scales, symptom scales/items).  Physical 
functioning scale score in EORTC QLQ-C30 is the key secondary endpoint.  Change from 
baseline of the items and domains of the QLQ-C30/LC13 will be summarized by 
treatment arm.  The EQ-5D-5L manual and the published weights will be used to convert 
the individual items to the utility scores.  Change from baseline of the EQ-5D-5L utility 


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score and VAS will be summarized by treatment arm.  The treatment group differences 
will be evaluated by analyzing the change from baseline using a one-way analysis of 
variance (ANOVA) model.
8.1.8
Planned Sensitivity and Subgroup Analyses
Efficacy analyses for the primary endpoints (PFS per CRAC and OS) will be performed in 
the per-protocol set.
In the DLL3high and randomized sets, treatment effects for the primary endpoints (PFS per 
CRAC and OS) will be assessed in the following subgroups:
●
RECIST v1.1 response after completion of first-line platinum-based therapy at 
screening assessment (SD vs. PR/CR)
●
DLL3 expression (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or 
above) for the randomized set only
●
History of CNS metastases (Yes vs. No)
●
For subjects with no history of CNS metastases, PCI vs. No PCI
●
Lactate dehydrogenase (LDH), ≤ ULN vs. > ULN
●
Number of metastatic sites, 0 – 1 vs. > 1
●
Age group (age < 40 vs. 40 to < 60 vs. 60 or older)
●
Gender
●
Race
●
ECOG (0 vs. 1)
Differences between rovalpituzumab tesirine arm and the placebo arm for time-to-event 
endpoints will be assessed by an unstratified log-rank test for each subgroup.  Hazard 
ratios of treatment arm over the placebo arm will be calculated by a Cox's model. 
8.1.9
Pharmacokinetic and Exposure-Response Analyses
Serum concentrations of rovalpituzumab tesirine ADC as well as the incidence and timing 
of ATA formation will be tabulated and summary statistics will be computed.  Serum 


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concentration and ATA data from this study may be combined with data from other 
studies and analyzed using population pharmacokinetic methodologies.
The relationship between pharmacokinetics (e.g., exposure) and clinical trial findings 
including, but not limited to demographics, efficacy, and/or safety measures may also be 
explored.  Additional analyses will be performed if useful.  Results of the population 
pharmacokinetic and exposure-response analyses will be provided in a separate report.
8.2
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 treatment-emergent adverse 
events (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 used.  NCI CTCAE version 4.0 will be used in the grading of 
adverse events and laboratory abnormalities that are reported as adverse events.
8.2.1
Treatment-Emergent Adverse Events (TEAEs)
TEAEs reported during the study will be coded using a MedDRA16 dictionary.  Incidence 
of TEAEs will be summarized by treatment arm and the following:
●
System organ class and preferred term
●
System organ class, preferred term, and severity
These summaries will be presented for the following subsets:
●
Serious TEAEs
●
All TEAEs
●
Drug-related TEAEs
For tables reporting AEs by severity, if a subject has multiple occurrences of an AE with 
the same organ class and preferred term, the most severe event will be presented.


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8.2.2
Clinical Laboratory Evaluation
Laboratory parameters will be summarized by treatment arm at each visit.  Each summary 
will include the values of the laboratory parameters and changes from baseline.  Shift 
tables from baseline will be presented for laboratory values in the chemistry and 
hematology panels.  Parameters will be classified according to the laboratory reference 
normal ranges.  A listing will be provided for out-of-normal range as well as clinically 
significant abnormal lab values.
8.2.3
Vital Signs
Vital signs including pulse, blood pressure, temperature, and body weight will be 
summarized by treatment arm and time point.  For each assessment of vital signs, change 
from baseline will be summarized by treatment arm.
8.2.4
ECOG Performance Status
ECOG performance status will be summarized for each visit by treatment arm.  Shifts 
from baseline to the best and worst post-baseline score may be tabulated.
8.2.5
Electrocardiogram
ECG status will be summarized for each scheduled visit by treatment arm.  Shifts from 
baseline may be tabulated.  
8.2.6
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 treatment 
arm.  The table will be sorted by the incidence use of the entire sample.
8.3
Type I Error Adjustment Procedure for Multiple Testing
To meet global regulatory requirements, a multiple testing strategy will be implemented to 
control the family-wise type I error (alpha) to one-sided 0.025 level for comparisons of 


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rovalpituzumab tesirine arm versus placebo arm with respect to progression-free survival 
(PFS) per CRAC in DLL3high set, overall survival (OS) in DLL3high set, PFS per CRAC in 
randomized set, OS in randomized set, and physical functioning scale score (EORTC 
QLQ-C30) in randomized set.
The following null hypotheses are considered:
Two hypotheses in H01 are H01a and H01b.
H01a:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in 
DLL3high set. 
H01b:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in DLL3high set. 
H02:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in randomized set. 
H03: Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in 
randomized set. 
H04:  Rovalpituzumab tesirine arm is not superior to placebo arm in physical functioning 
scale score (EORTC QLQ-C30) in randomized set.
The null hypotheses will be tested in a fixed sequence of {H01a, H01b, H02, H03, and H04} in 
order.  To maintain the family-wise type I error for the study, the null hypotheses in H01
(H01a and H01b) will be first tested with an alpha-split approach.  The one-sided alpha of 
0.25% and 2.25% will be assigned for PFS and OS hypothesis in H01, respectively.  Out of 
one-sided alpha of 2.25% allocated to OS hypothesis (H01b), the one-sided alpha of 10–6
will be spent for the early look at the OS data for futility analysis.  If the hypothesis for 
PFS in H01 (H01a) is rejected the one-sided alpha of 0.25% will be recycled to the OS 
hypothesis in H01 (H01b).  Hence, the hypothesis for OS in H01 (H01b) will be tested either 
at a one-sided 2.4999% or one-sided 2.2499% level of significance depending on the PFS 
hypothesis in H01a is rejected or not. 


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If either PFS or OS endpoint reaches statistical significance, the study is considered 
positive.  No further tests will be performed if the OS endpoint in DLL3high population 
(H01b) does not reach statistical significance. 
The hypothesis in H02 will be tested if the hypothesis in H01b is rejected.  If the hypothesis 
in H02 is rejected, then, either (i) H03 and H04 will be tested sequentially if the PFS 
endpoint in DLL3high subjects (H01a) is also rejected or (ii) only H04 will be tested if the 
PFS endpoint in DLL3high subjects (H01a) is not rejected. 
Diagram of Hierarchical Testing of Primary and Secondary Endpoints is described in 
Figure 3.


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Figure 3.
Diagram of Hierarchical Testing of Primary and Secondary 
Endpoints


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8.4
Determination of Sample Size
There are two primary efficacy endpoints for this study:  Progression-free survival (PFS) 
based on the CRAC and overall survival (OS) in DLL3high ED SCLC patients.  To 
maintain the overall 1-sided type I error at a 2.5% for this study, the type I error will be 
split, assigning 0.25% to progression-free survival and the remaining 2.25% to overall 
survival.  However, the OS endpoint will be tested at a one-sided 2.2499% significance 
level as a one-sided alpha of 10–6 will be spent for the early look at the OS data for futility 
analysis. 
The sample size of the study is primarily determined by the analysis of OS.  It is assumed, 
taking into account the expected patient population for the study, that median overall 
survival in the placebo and rovalpituzumab tesirine arm will be around 9 months and 13 
months, respectively.  The increase of median OS in rovalpituzumab tesirine arm 
corresponds to a hazard ratio of 0.69, i.e., a reduction in the hazard of death by 31%.  
With all these assumptions, a total of 319 deaths among subjects with DLL3high are needed 
to achieve a 90% power based on a log-rank test at a one-sided significance level of 
0.022499.  Assuming a 19-month accrual period and the last enrolled subject followed for 
12 months, at least 480 subjects with DLL3high are expected to be randomized 
(240 subjects in each arm).  A total of 740 subjects regardless of DLL3 expression level 
(including 480 subjects with DLL3high) will enroll in the study, assuming an approximate 
prevalence of 65% for subjects with DLL3high.  For one-sided significance level of 
0.022499, it is projected that an observed hazard ratio of 0.799 or less, corresponding to a 
2.3 months or greater improvement in median OS, would result in a statistically 
significant improvement in the primary analysis of OS.
The primary endpoints of OS and PFS in DLL3high patients will be analyzed at the same 
time after observing at-least 319 OS event. It is expected at approximately 420 PFS 
events will be observed at the time of the primary analysis.
It is assumed, taking into account the expected patient population for the study, that 
median progression-free survival for the placebo and rovalpituzumab tesirine arm will be 


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approximately 3 months and 4.5 months, respectively.  The increase of median 
progression-free survival in rovalpituzumab tesirine arm corresponds to a hazard ratio of 
0.667.  With all these assumptions, a total of approximately 420 PFS events assessed by 
the CRAC for the subjects with DLL3high are needed to achieve a 91% power based on a 
log-rank test at a one-sided significance level of 0.0025.  It is projected that an observed 
hazard ratio of 0.760 or less, corresponding to approximately 1 month or greater 
improvement in median PFS, would result in a statistically significant improvement in the 
PFS.
8.5
Futility Analysis
A futility analysis will be conducted when approximately 160 deaths in subjects with 
DLL3high ED SCLC (approximately 50% of the planned deaths) are observed.  The trial 
may be stopped for futility if the estimated Overall Survival Cox HR of Rova-T to 
Placebo in the DLL3high set at futility analysis exceeds 0.9.  The one-sided alpha of 10–6
will be spent for the early look at the efficacy data for futility analysis.
Unblinded interim data will be analyzed and reviewed by the IDMC.  The trial may be 
considered for early stopping for futility and the Sponsor will be unblinded to the 
aggregated data by randomized treatment arms if the IDMC makes such a 
recommendation after consideration of the OS results and other supportive evidence 
including other relevant efficacy and safety data.
Details for the futility analysis will be provided in the IDMC charter.
8.6
Accrual/Study Duration Considerations
On average, it is expected that accrual rates are 1, 7, 27, 36, and 42 with DLL3high subjects 
per month at study initiation, 3, 6, 9, and 12 month and thereafter, respectively.  The total 
study duration and accrual duration are projected to be 31 months and 19 months with a 
5% rate of loss to follow-up, respectively.  A total of 740 subjects regardless of DLL3 
expression level in tumor are expected to enroll during the accrual period.  It is projected 
that 480 subjects with DLL3high ED SCLC will have enrolled for the primary analysis by 


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the time approximately 420 PFS events per CRAC and at least 319 OS events should be 
observed in DLL3high subjects after approximately 8 - 10 months of follow-up.   
8.7
Randomization Methods
The randomization numbers of the study will assign subjects in a 1:1 ratio to either 
receive 0.3 mg/kg rovalpituzumab tesirine or placebo, on Day 1 of each 6-week cycle, 
omitting every third cycle.  Randomization will be stratified by RECIST v1.1 response 
after completion of first-line platinum-based therapy at screening assessment (SD vs. 
PR/CR), DLL3 expression (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or 
above), history of CNS metastases (Yes vs. No), and for subjects with no history of CNS 
metastases, PCI vs. no PCI.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure,14 the informed consent 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, informed consent 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 (Competent Authority, if 
applicable) 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 and all other applicable regulatory requirements.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 


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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 AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines17,18 applicable regulations and guidelines governing 
clinical study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
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 informed consent form.
Tumor material obtained by biopsy procedure at the time of disease progression (for 
exploratory research) is optional and will only be performed if the subject has voluntarily 
signed and dated an optional tumor material biopsy procedure informed consent, approved 
by an IEC/IRB, after the nature of the testing has been explained and the subject has had 


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an opportunity to ask questions.  If the subject does not consent to the optional informed 
consent, it will not impact the subject's participation in the study.
In the event a subject withdraws consent to participate from the study, stored biomarker 
and tumor specimen for exploratory research 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 and tumor specimen for exploratory research 
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.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating in the study.


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10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.  The Investigator Awareness Date of SAE should be noted 
in the source.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.


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The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) system called Trialmax, provided by the technology vendor CRF Health of 
Plymouth Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR 
Part 11.  The documentation related to the system validation of the ePRO system is 
available through the vendor, CRF Health, while the user acceptance testing of the 
study-specific PRO design will be conducted and maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source, and maintained and 
managed by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 


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following the receipt of the study archive.  Data from the ePRO system will be archived 
on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media.
The (instrument/scale) will be collected electronically via a Tablet/Laptop device into 
which the patient will directly enter the required pieces of information.  The electronic 
device will be programmed to allow data entry for only the visits specified in the protocol 
and will not allow for patients to complete more than one of the same assessment at any 
one visit.  All data entered on the device will be immediately stored to the device itself 
and (manually/automatically) uploaded to a central server administrated by (ePRO 
Vendor).  The Investigator and delegated staff will be able to access all uploaded patient 
entered data via a password protected website, up until the generation, receipt and 
confirmation of the study archive.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be provided to investigators and used in scientific publications or presented at 
medical conventions.  Optional exploratory research information will be published or 
presented only in a way that does not identify any individual subject.


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13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the investigator (Director of the Site in Japan) 
and AbbVie.  The investigator will provide a final report to the IEC/IRB following 
conclusion of the study, and will forward a copy of this report to AbbVie or their 
representative.
The investigator (Director of the Site in Japan) must submit, maintain, and archive any 
records related to the study according to ICH GCP and all other applicable regulatory 
requirements.  If the investigator (Director of the Site in Japan) is not able to retain the 
records, he/she must notify AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit, or the date of the last 
subject's last survival follow-up contact, whichever is later.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for rovalpituzumab 
tesirine and the product labeling for dexamethasone.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of 
Rovalpituzumab Tesirine as Maintenance Therapy Following 
First-Line Platinum-Based Chemotherapy in Subjects with Extensive 
Stage Small Cell Lung Cancer (MERU)
Protocol Date:
05 March 2019
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List 
1.
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.
2.
Siegel R, Naishadham D, Jemal A.  Cancer statistics, 2012.  CA:  a cancer journal 
for clinicians.  2012;62(1):10-29.
3.
Simon M, Argiris A, Murren JR.  Progress in the therapy of small cell lung cancer.  
Crit Rev Oncol Hematol.  2004;49(2):119-33.
4.
Ready N, Pang H, Gu L, A, et al.  Chemotherapy with or without maintenance 
sunitinib for untreated extensive-stage small-cell lung cancer:  a randomized, 
double-blind, placebo-controlled phase II study-CALGB 30504 (Alliance).  J Clin 
Oncol.  2015;33(15):1660-5.
5.
Schiller JH, Adak S, Cella D, et al.  Topotecan versus observation after cisplatin 
plus etoposide in extensive-stage small-cell lung cancer:  E7593--a phase III trial of 
the Eastern Cooperative Oncology Group.  J Clin Oncol.  2001;19:2114-22.
6.
Saunders L, Bankovich A, Anderson W, et al.  A DLL3-targeted antibody-drug 
conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells 
in vivo.  Science Transl Med.  2015;7(302):302ra136.
7.
Chapman G, Sparrow D, Kremmer E, et al.  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.
8.
Dunwoodie S, Henrique D, Harrison S, et al.  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.
9.
Rudin CM, Pietanza MC, Bauer TM, et al.  Rovalpituzumab tesirine, a DLL3-
targeted antibody-drug conjugate, in recurrent small-cell lung cancer:  a first-in-
human, first-in-class, open-label, phase 1 study.  Lancet Oncol.  2017;18(1):42-51.


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10.
Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and 
Inducers (FDA, 2016).
11.
Common Terminology Criteria for Adverse Events, Version 4.0, DCTD, NCI, 
NIH, DHHS.  28 May 2009 [cited 29 Sept 2016].  Available from:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf.
12.
Eisenhauer E, Therasse P, Bogaerts J, et al.  New response evaluation criteria in 
solid tumours:  Revised RECIST guideline (version 1.1).  Eur J Cancer.  
2009;45(2):228-47.
13.
Aaronson N, Ahmedzai S, Bergman B, et al.  The European Organization for 
Research and Treatment of Cancer QLQC30:  a quality-of-life instrument for use in 
international clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-76.
14.
AbbVie Stemcentrx LLC.  Investigator's Brochure for Rovalpituzumab Tesirine 
(SC 16LD6.5) Edition 5.0.  13 September 2016.
15.
Food and Drug Administration.  Guidance for industry clinical trial endpoints for 
the approval of cancer drugs and biologics.  2007.
16.
AbbVie.  Coding Guidelines for MedDRA Term Selection, AbbVie Global 
Pharmaceutical Research and Development (GPRD), Global Pharmacovigilance 
and Clinical Project Team.  Current version on file at AbbVie.
17.
International Conference on Harmonisation.  Guidance for Industry, E6 Good 
Clinical Practice:  Consolidated Guidance.  April 1996.
18.
International Conference on Harmonisation.  Guideline for Industry, Clinical safety 
data management:  definitions and standards for expedited reporting, E2A.  
March 1995.
19.
AbbVie.  Rovalpituzumab Tesirine Dear Rova-T Investigator Letter.  05 December 
2018.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not making any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Pharmacokinetics
Clinical Drug Supply Management
Statistics
Bioanalysis


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Appendix C.
Study Activities
Category
Description
Screening
Treatment (Each Cycle)
Non-Treatment 
Cycle Visita
End of 
Treatmentb
PTFUc
Survival 
FU 
(OS)d
Day –21 to
Day –1
Day
–1
Day 1e
(–3d)
Day 
2
Day 
8
Day 
15
Day 22 
(–3d)
Day 
29
Day 
36
Day 1
(±3d)
Weekly
(Day 8, 15, 22, 
29, 36)
(±3d)
Within 7 Days 
of Decision to 
Discontinue 
Treatment
q6 
Weeks 
(±1wk)
q6
Weeks 
(±1wk)
Location
Clinic Visit
X
X
X
X
X
X
Phone Contact
X
X
X
X
X
X
Safety 
Assessments
Informed Consentf
X
Inclusion/Exclusion 
Criteria
X
Medical and 
Surgical History 
including 
Malignancy 
Historyg
X
Physical 
examinationh
X
X
X
X
X
Vital Signsi
X
X
X
X
X
Hematology and 
Serum Chemistryj
X
Xk
X
X
X
Coagulation Testsj
X
Xk
X
X


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Category
Description
Screening
Treatment (Each Cycle)
Non-Treatment 
Cycle Visita
End of 
Treatmentb
PTFUc
Survival 
FU 
(OS)d
Day –21 to
Day –1
Day
–1
Day 1e
(–3d)
Day 
2
Day 
8
Day 
15
Day 22 
(–3d)
Day 
29
Day 
36
Day 1
(±3d)
Weekly
(Day 8, 15, 22, 
29, 36)
(±3d)
Within 7 Days 
of Decision to 
Discontinue 
Treatment
q6 
Weeks 
(±1wk)
q6
Weeks 
(±1wk)
Safety 
Assessments 
(cont.)
Urinalysisj
X
Xk
X
X
X
Pregnancy Testl
X
X
X
X
X
Electrocardiogram 
(ECG)m
X
X
Echocardiogramn
X
X
X
Performance Status 
(ECOG)
X
X
X
X
Fluid Retention 
Questionnaireo
X
X
X
X
X
X
X
X
X
SAE/Adverse 
Events
SAE/
Procedure
-related 
only
X
X
X
X
X
X
X
X
X
Xp
Xp
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
Xp
Xp


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Category
Description
Screening
Treatment (Each Cycle)
Non-Treatment 
Cycle Visita
End of 
Treatmentb
PTFUc
Survival 
FU 
(OS)d
Day –21 to
Day –1
Day
–1
Day 1e
(–3d)
Day 
2
Day 
8
Day 
15
Day 22 
(–3d)
Day 
29
Day 
36
Day 1
(±3d)
Weekly
(Day 8, 15, 22, 
29, 36)
(±3d)
Within 7 Days 
of Decision to 
Discontinue 
Treatment
q6 
Weeks 
(±1wk)
q6
Weeks 
(±1wk)
Treatment
rovalpituzumab 
tesirine or placebo
X
dexamethasone or 
placebo
X
X
X
Response 
Assessment
Disease/Response 
Assessment 
(Radiographic 
Imaging)q
X
X
X
Xr
X
Central 
Radiographic 
Assessment 
Committee (CRAC) 
Reviews
X
X
X
Xr
X
MRI/CT of the 
Brain
Xt
Health Resource 
Utilization
X
X
X
X
X
Patient Reported 
Outcome (PRO)u
X
X
X
X
X
Survival Status
X


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Category
Description
Screening
Treatment (Each Cycle)
Non-Treatment 
Cycle Visita
End of 
Treatmentb
PTFUc
Survival 
FU 
(OS)d
Day –21 to
Day –1
Day
–1
Day 1e
(–3d)
Day 
2
Day 
8
Day 
15
Day 22 
(–3d)
Day 
29
Day 
36
Day 1
(±3d)
Weekly
(Day 8, 15, 22, 
29, 36)
(±3d)
Within 7 Days 
of Decision to 
Discontinue 
Treatment
q6 
Weeks 
(±1wk)
q6
Weeks 
(±1wk)
Pharmacoki
netic (PK), 
Biomarkers, 
and 
Pharmacoge
netic (PG)
Pharmacokinetics 
(PK), Anti-
therapeutic 
Antibody (ATA), 
and neutralizing 
antibodies (nAb)v
X
X
X
Tumor Material at 
Screeningw
X
Tumor Material at 
Time of Disease 
Progressionf
X
X
Blood (plasma) for 
Inflammatory 
Markers & ctDNAx
X
X
X
Xx
Blood (serum) for 
Tumor & Soluble 
Markersx
X
X
X
Xx
Circulating Tumor 
Cellsy
X
X
Pharmacogeneticsz
X
X
Serosal Fluidaa
Cycle 1 Day 1 through 70 days after last blinded study treatment


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a.
Every third cycle of treatment should be omitted and a clinic visit conducted.  The visit should be performed after the Disease Response/Assessment has been conducted and 
reviewed by the Investigator.  The subject should continue to complete the Fluid Retention Questionnaire, including conducting daily weight assessments, and the site should 
contact the subject weekly during this 42 day non-treatment cycle to review the questionnaire.  The following cycle of treatment may be resumed 42 days ± 3d if the subject 
has not met any reason for study treatment discontinuation as outlined in Section 5.4.
b. 
End of Treatment Visit procedures should be done within 7 days of documentation of the decision to discontinue treatment and prior to subjects beginning any new anti-
cancer therapy if possible.
c.
For subjects who discontinue blinded investigational product for reasons other than disease progression, the first follow-up visit will occur at 6 weeks (± 1 week) after the last 
Disease Response Assessment, then every 6 weeks (± 1 week) until disease progression or initiation of new anti-cancer therapy, whichever occurs first.
d.
Subjects will be followed for subsequent anti-cancer therapies (dates and responses), as well as survival status, every 6 weeks* (± 1 week) until the endpoint of death, the 
subject becomes lost to follow-up or withdraws consent, or termination of the study by AbbVie, whichever occurs first (*or as requested by AbbVie to support data analysis).
e.
Cycle 1 Day 1 procedures, with the exception of weight, do not need to be repeated if performed within 21 days of randomization unless clinically indicated.  Randomization 
may occur within 3 days prior to C1D1.  Starting at C2D1, study assessments may be performed within 3 days prior to the visit.  Disease/Response Assessment and CRAC 
Review may be performed within 7 days prior to the Day 1 visit.
f.
Signed informed consent will be obtained from the subject before any study-specific procedures are undertaken or before any prohibited medications are withheld from the 
subject in order to participate in this study.  Informed consent may be obtained before the 21-day screening window.  Informed consent is also required for the optional tumor 
biopsy at time of disease progression.  The sample can be collected at the EOT or at the time of disease progression.
g.
Medical and Surgical History includes demographics and documentation of clinically significant medical condition, surgical history, and malignancy history.
h.
Height will be collected at the Screening visit only.  For height assessments, the subject should not wear shoes.
i.
Vital signs include weight, sitting blood pressure, heart rate and body temperature.  Weight will be collected in the clinic prior to dosing at each cycle and the recorded weight 
will be utilized for dosing calculations.  If possible, blood pressure and heart rate measurements should not immediately follow scheduled blood collections.  Vital signs 
should be collected prior to the infusion.  
j.
All laboratory samples will be assessed using a certified central laboratory.  A qualified (e.g., certification or accreditation) local laboratory may be used to perform laboratory 
analyses for treatment decisions as per standard of care.  Refer to Table 2, Clinical Laboratory Tests for details.  
k.
The screening clinical laboratory tests do not need to be repeated on C1D1 if performed within 7 days of randomization and meet eligibility criteria, unless clinically 
indicated.  Starting at Cycle 2, lab assessment may be performed 3 days prior to Day 1 visits.


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l.
For female subjects of childbearing potential, a serum pregnancy test will be performed at Screening and the results must be available prior to the administration of the 
first dose of blinded investigational product on C1D1.  Urine pregnancy tests will be performed at Day 1 of each cycle, End of Treatment Visit, and PTFU until 6 months after 
the last dose of blinded investigational product.  Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as defined in Section 5.2.4) 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.
m.
A resting 12-lead ECG will consist of a single 12-lead study performed within a 5-minute window after at least 5 minutes of quiet rest in a supine position.  Additional ECG 
monitoring may occur as clinically indicated during the study.
n.
Echocardiograms are required at Screening, Day 1 of each cycle starting C2D1, and EOT.  Screening echocardiogram will be performed within 7 business days of 
randomization to assess for the presence of any pericardial effusion as well as cardiac function (left ventricular ejection fraction, LVEF).  Subsequent echocardiograms should 
be performed within –3 business days of dosing visit to assess for the presence of any pericardial effusion.  Additional echocardiogram monitoring may occur as clinically 
indicated during the study.
o.
Subjects will be asked about the development of any new or worsening peripheral edema or dyspnea (Appendix I, Fluid Retention Questionnaire).  The assessments on 
Days 8, 15, 29, and 36 may take place by phone, with the site contacting the subject and reviewing the questionnaire.  Starting on Day 1 and through the EOT visit, subjects 
will maintain a diary of daily weights (captured on the Fluid Retention Questionnaire).  
p.
Collection of SAE/AE and Concomitant Medications may be required at this visit in order to meet the collection window requirement of Day 1 of study treatment through 
70 days after last treatment.  Any ongoing SAE/AE that require appropriate standard of care should also be conducted.
q.
Diagnostic quality, spiral CT scan with contrast is recommended for all anatomic areas except brain (MRI is recommended for brain imaging); other CT methods or MRI for 
respective anatomic areas may be used if performed consistently throughout the study for each individual subject and only under circumstances described in Appendix G.  
Scans of the chest and abdomen must be obtained; scans of the neck and pelvis must also be obtained if there is documented or suspected involvement in these regions.  
Screening scans may be performed within 28 days prior to randomization.  Disease response will be determined by the Investigator at each assessment according to 
RECIST v1.1.  Effusion (pleural, pericardial, and etc.) assessments will be performed by a radiologist at each radiographic assessment and any new findings communicated to 
the Investigator prior to the next dose of blinded investigational product.  Effusions should contribute to disease status assessment per RECIST v1.1 only if confirmed 
malignant by cytology or otherwise clearly disease-related.  Whenever possible, scheduled tumor assessments should not be affected by delays in therapy and/or drug 
holidays.  In some cases, mandatory dose delays due to toxicity will lead to a gap between tumor assessment and dosing.  In cases where this gap exceeds 1 week, the TAMD
should be contacted for guidance.  Subjects will continue to be monitored by the same diagnostic method throughout the study every 6 weeks after randomization.
r.
May be omitted if previous assessment was performed within the preceding 6 weeks.
s.
Site will collect the appropriate scans and ship by courier or submit electronically to the central facility at each subject's disease assessment.  
t.
MRI/CT of the brain is required at screening and when clinically indicated (e.g., if CNS progression is suspected) thereafter.
u.
PRO assessments are required at Screening, only C2D1, the first Non-Treatment Cycle, EOT, and PTFU (if applicable). 


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v.
Approximately 6 mL of blood will be collected by venipuncture for pharmacokinetic (PK), Anti-therapeutic antibody (ATA), and neutralizing antibodies (nAb) testing.  The 
pre-infusion sample will be collected prior to dosing on Day 1 (–3 days window is permitted) and the second sample will be collected within 60 minutes post-infusion.  Only 
one collection will be required at the Non-Treatment Cycle visit and EOT visit.  The date and time of each sample collected will be recorded to the nearest minute.
w.
Archived or fresh tumor material must be submitted to the AbbVie designated central IHC laboratory for determination of DLL3 expression prior to randomization.
x.
On Day 1 (–3 days window is permitted) of each cycle, the collection will be pre-infusion.  A sample will also be collected at the EOT or at the time of disease progression.
y.
Whole blood sample will be collected for CTC analysis at pre-dose on Cycle 1 Day 1 (–3 days window is permitted) and EOT only at specific sites based on feasibility.
z.
Pharmacogenetic collection should occur unless precluded by local or national regulations or policies.  Pharmacogentic sample collected pre-infusion on Day 1 of Cycle 1.
aa.
Any pericardial, pleural, and/or ascitic fluid collected as part of routine care (e.g., as part of a therapeutic thoracentesis, pericardiocentesis, or paracentesis) will be procured 
for testing for any AE starting from C1D1 through 70 days after the last blinded study treatment.  Collected fluid must also be tested locally for cytology if disease 
progression due to appearance/worsening of effusion is suspected.


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Appendix D.
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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Appendix E.
Calculated Creatinine Clearance Using Modified Cockcroft-Gault 
Equation
MODIFIED COCKCROFT AND GAULT FORMULA
For the calculation of estimated creatinine clearance rate (eCCR) using Ideal Body 
Mass [IBM] instead of Mass. 
eCCr
=
(140 – Age) ●IBM (kg) ●[0.85 if Female]
72 ●Serum Creatinine (mg/dL)
Or, if serum creatinine is in μmol/L:
eCCr
=
(140 – Age) ●IBM (kg) ●[1.23 if Male, 1.04 if Female]
Serum Creatinine (μmol/L)
Ideal Body Mass should be used:
IBM (kg)
=
[(height cm – 154) ●0.9] + (50 if Male, 45.5 if Female)


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


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Appendix G.
Response Evaluation Criteria for Solid Tumors (RECIST) v 1.1 for 
Tumor Response
Response criteria will be assessed using RECIST (version 1.1).12  Changes in the 
measurable lesions over the course of therapy must be evaluated using the criteria listed 
below.
Measurability
Measurable Lesions
Lesions accurately measured in at least one dimension with a 
minimum size of: 
•
Longest diameter ≥ 10 mm (CT scan slice thickness no 
greater than 5 mm)
•
10 mm caliper measurement by clinical exam
Non-Measurable 
Lesions
All other lesions, including small lesions (longest diameter 
< 10 mm) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include:  leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung and 
also abdominal masses that are not confirmed and followed by 
imaging techniques.
Measurable 
Malignant Lymph 
Nodes
To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the 
short axis will be measured and followed.
Non-Measurable 
Malignant Lymph 
Nodes
Pathological lymph nodes with ≥ 10 to < 15 mm short axis.
Special 
Considerations 
Regarding Lesion 
Measurability
Bone lesions
Lytic bone lesions or mixed lytic-blastic lesions, with 
identifiable soft tissue components, that can be evaluated by 
cross sectional imaging techniques such as MRI/CT can be 
considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.


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Blastic bone lesions are non-measurable.
Cystic lesions
Lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions 
(neither measurable nor non measurable) since they are, by 
definition, simple cysts.
'Cystic lesions' thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above.
However, if non-cystic lesions are present in the same patient, 
these are preferred for selection as target lesions.
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an 
area subjected to other loco-regional therapy, are usually not 
considered measurable unless there has been demonstrated 
progression in the lesion.
All measurements should be taken and recorded in metric notation, using calipers if 
clinically assessed.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and not more than 28 days before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers.  For 
the case of skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is recommended.


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Methods of Measurement
Spiral CT should be performed with cuts of 5 mm or less in slice thickness contiguously.  
This applies to tumors of the chest and abdomen.  A scale should be incorporated into all 
radiographic measurements.  MRI can be performed if required by local law or if CT is 
contraindicated, and should be documented in the subject's source.
If prior to enrollment, it is known a subject is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT 
or MRI should be used to evaluate the subject at baseline and follow-up should be guided 
by the tumor type under investigation and the anatomic location of the disease.  For 
subjects who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI should be made based upon discussion 
with the AbbVie TA MD.
For accurate objective response evaluation, ultrasound (US) should not be used to 
measure tumor lesions.
The utilization of endoscopy and laparoscopy for objective tumor evaluation is not 
advised.  However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.
Cytology and histology can be used to differentiate between partial response (PR) and 
complete response (CR) in rare cases.
Baseline Documentation of "Target" and "Non-Target" Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 


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loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to 
the baseline sum.  The short axis of the node is the diameter normally used by radiologists 
to judge if a node is involved by solid tumor.  Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost always 
the axial plane).  The smaller of these measures is the short axis.  For example, an 
abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis 
≥10 mm but < 15 mm) should be considered non-target lesions.  Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or followed.
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD.  If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response.
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence (stable, increasing or decreasing) or 
absence of each should be noted throughout follow-up.
Evaluation of Target Lesions
Complete Response (CR):
The disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm.


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Partial Response (PR):
At least 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 the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started (baseline or after) or the appearance 
of one or more new lesions.  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started (baseline or after).
Assessment of Target Lesions:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm.  For PR, SD and PD, the actual short axis measurement of the nodes is 
to be included in the sum of target lesions.
All lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (< 5 mm).  
However, sometimes target lesions or lymph nodes become too small to measure.  If it is 
in the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present, but too small to 
measure, a default value of 5 mm should be assigned (as derived from the 5 mm CT slice 


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thickness).  The measurement of these lesions is potentially non-reproducible; therefore 
providing this default value will prevent false responses or progression based upon 
measurement error.
Evaluation of Non-Target Lesions
Complete Response (CR):
The disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.
In this setting, to achieve 'unequivocal progression' on the basis of non-target disease, 
there must be an overall level of substantial worsening in non-target disease such that, 
even in the presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 'increase' in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.
New Lesions
The appearance of new malignant lesions denotes disease.  While there are no specific 
criteria for the identification of new radiographic lesions, the findings of a new lesion 
should be unequivocal; i.e., not attributable to differences in scanning technique, timing of 
scanning, phase of contrast administration, change in imaging modality or finding thought 


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to represent something other than tumor (e.g., some 'new' bone lesions may be simply 
healing or flare of pre-existing lesions).  A lesion identified on a follow-up study in an 
anatomical location that was not scanned at baseline is considered a new lesion and will 
indicate disease progression.  
If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is a 
new lesion, then progression should be declared using the date of the initial scan.


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Appendix H.
CTCAE v 4.0 Grading of Relevant AEs
Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Serosal 
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.
Capillary leak syndrome
–
Symptomatic; medical 
intervention indicated
Severe symptoms; 
intervention indicated
Life-threatening 
consequences; urgent 
intervention indicated


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Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Serosal 
Effusions 
(cont.)
Definition:  A disorder characterized by leakage of intravascular fluids into the extravascular space.  This syndrome is observed in patients who 
demonstrate a state of generalized leaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, 
medications, or poisoning.  It can lead to generalized edema and multiple organ failure.
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.
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.


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Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Edema 
(cont.)
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 × 109/L
< 1500 – 1000/mm3; 
< 1.5 – 1.0 × 109/L
< 1000 – 500/mm3; 
< 1.0 – 0.5 × 109/L
< 500/mm3; < 0.5 × 109/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 × 109/L
< 75,000 – 50,000/mm3; 
< 75.0 – 50.0 × 109/L
< 50,000 – 25,000/mm3;
< 50.0 – 25.0 × 109/L
< 25,000/mm3;
< 25.0 × 109/L
Definition:  A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.


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Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Skin 
Erythema multiforme
Target lesions covering 
< 10% BSA and not 
associated with skin 
tenderness
Target lesions covering 10 –
30% BSA and associated 
with skin tenderness
Target lesions covering 
> 30% BSA and 
associated with oral or 
genital erosions
Target lesions covering 
> 30% BSA; associated 
with fluid or electrolyte 
abnormalities; ICU care 
or burn unit indicated
Definition:  A disorder characterized by target lesions (a pink-red ring around a pale center).
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.


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Group
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Skin 
(cont.)
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.
Cross reference:  NCI CTCAE version 4.011


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Appendix I.
Fluid Retention Questionnaire
Fluid Retention Questionnaire for Study M16-298
Subject ID: ____________________
Over the past 7 days, or since the last time this questionnaire was completed:
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.  Weight should be taken without outer garments 
such as hats, coats or shoes.  Measurements while in light indoor clothing only, 
or undergarments only, are acceptable; however, please try to use the same or 
similar clothing (including any accessories or jewelry) from day to day when 
measuring weight.
●
Please complete one questionnaire for every 7 day/1 week period.
Date (DD/MMM/YYYY)
Weight (Circle One:  lb or kg)
lb or kg
lb or kg
lb or kg
lb or kg
lb or kg
lb or kg
lb or kg
2.
Have you noticed any new or worsening edema – e.g., swelling of the ankles or 
legs during the days above?  
܆Yes or ܆No
3.
Have you noticed any new or worsening shortness of breath during the days above?
܆Yes or ܆No


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4.
Please sign below to confirm that you have completed this questionnaire.
____________________________________ Date: __________________


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Appendix J.
Adverse Events Expected Due to SCLC or Progression of SCLC
Preferred Term (MedDRA Version 19.1)
   Pleural effusion
   Malignant pleural effusion
   Metastases to pleura
   Dyspnoea
   Cough
   Non-cardiac chest pain
   Haemoptysis*
   Oesophageal obstruction
   Pneumonia*
   Vocal cord paralysis
   Dysphonia
   Dysphagia
   Superior vena cava syndrome
   Horner's syndrome
Myasthenic syndrome
   Metastases to bone
   Metastases to lymph nodes
   Metastases to liver
   Metastases to spine
   Metastases to the mediastinum
   Metastases to pleura
   Metastases to adrenals
   Metastases to meninges
   Metastases to central nervous system
   Cancer pain
   Inappropriate Anti-Diuretic Hormone (SIADH) secretion
   Tumour pain
   Fatigue
   Asthenia
Pulmonary embolism*
Shock*
Septic shock*


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Preferred Term (MedDRA Version 19.1)
Deep vein thrombosis*
Lower respiratory tract infection*
Respiratory tract infection*
Upper respiratory tract infection*
Opportunistic infection*
Viral infection*
Fungal infection*
Bacterial infection*
Pulmonary haemorrhage*
Lung abscess*
Empyema*
Sepsis*
Lymphadenopathy
Decreased appetite
Malaise
Weight decreased
Headache
Pain excluding chest pain
Pyrexia
*
Includes life threatening or fatal events.


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Appendix K.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Therapeutic Area Medical Director
AbbVie
200 Sidney Street
Cambridge, MA 02139
Phone:
Fax:
Has been changed to read:
Senior Medical Director
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
USA
Phone:
Cell Phone
Fax:
Email:
Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M16-298
Name of Study Drug:  rovalpituzumab tesirine 
(Rova-T)
Phase of Development:  3
Name of Active Ingredient:  rovalpituzumab 
tesirine
Date of Protocol Synopsis:  09 May 2017
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rovalpituzumab 
Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with 
Extensive Stage Small Cell Lung Cancer (MERU)


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Objectives:
Primary
•
To evaluate if rovalpituzumab tesirine improves progression-free and overall survival in subjects 
with extensive-stage small cell lung cancer (ED SCLC) who have ongoing clinical benefit (SD, 
PR, or CR) following first-line platinum-based chemotherapy (cisplatin or carboplatin plus 
irinotecan or etoposide) compared to placebo.
Secondary
•
To evaluate rovalpituzumab tesirine anti-tumor activity by determining objective response rate 
(ORR), clinical benefit rate (CBR), and duration of responses (DOR)
•
To assess change in patient reported outcomes (PRO) with EORTC QLQ-C30/LC13 
questionnaires.
Exploratory
•
To characterize the pharmacokinetics and incidence of anti-therapeutic antibodies (ATAs) 
against rovalpituzumab tesirine
•
To evaluate pharmacodynamic and predictive biomarkers in blood and tumor for association 
with sensitivity, efficacy and safety
•
To explore DLL3 expression in circulating tumor cells (CTCs) for association with efficacy
•
To assess EQ-5D-5L during treatment with rovalpituzumab tesirine.
Investigators:  Multicenter, International
Study Sites:  Approximately 275
Study Population:  Subjects with extensive-stage Small Cell Lung Cancer (ED SCLC) with ongoing 
clinical benefit (SD, PR, or CR per RECIST v1.1) following completion of 4 cycles of first-line 
platinum-based chemotherapy (cisplatin or carboplatin in combination with etoposide or irinotecan).
Number of Subjects to be Enrolled:  Up to approximately 740 SCLC subjects, to obtain approximately 
480 subjects with DLL3 high expression in tumor (DLL3high).  DLL3high is defined as ≥ 75% tumor cells 
staining positive according to the VENTANA DLL3 (SP347) IHC Assay.


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Methodology:  
This is a Phase 3, randomized, double-blinded, placebo-controlled, multinational, and multicenter study.
ED SCLC subjects who meet all the inclusion criteria and none of the exclusion criteria, and demonstrate 
ongoing clinical benefit (SD, PR, or CR) at the completion of 4 cycles of first-line platinum-based 
chemotherapy (such benefit must be ongoing at the last re-staging assessment prior to randomization), 
will be randomly assigned in a 1:1 ratio to receive 0.3 mg/kg rovalpituzumab tesirine or placebo, and will 
receive their assigned therapy on Day 1 of each 6-week cycle, omitting every third cycle.  Upon 
completion of first-line chemotherapy, eligible subjects must be offered prophylactic cranial irradiation 
(PCI), if offering this procedure is not contradictory to country or institutional guidelines.  Subjects 
receiving PCI must complete it prior to randomization into the study.  Subjects will also receive 8 mg 
orally (PO) of dexamethasone or placebo twice daily on Day –1, Day 1, and Day 2 of each 6-week cycle, 
omitting every third cycle.  Randomization will be stratified by RECIST v1.1 response after completion 
of first-line platinum-based chemotherapy at screening assessment (SD vs. PR/CR), DLL3 expression, 
(Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or above), history of central nervous system 
(CNS) metastases (Yes vs. No), and for subjects with no history of CNS metastases, PCI vs. no PCI.
Survival Follow-up will continue until the endpoint of death, the subject becomes lost to follow-up or 
withdraws consent, or termination of the study by AbbVie, whichever occurs first.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
1.
Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-
specific procedures and should be willing and able to comply with parameters as outlined in the 
protocol.
2.
Subject must be ≥ 18 years of age.
3.
Histologically or cytologically confirmed extensive-stage SCLC with ongoing clinical benefit (SD, 
PR, or CR per RECIST v1.1) following completion of 4 cycles of first-line platinum-based therapy 
(cisplatin or carboplatin in combination with etoposide or irinotecan).
4.
Subjects with a history of CNS metastases prior to the initiation of first-line platinum-based 
chemotherapy must have received definitive local treatment and have documentation of stable or 
improved CNS disease status based on brain imaging within 28 days prior to randomization, off or on 
a stable dose of corticosteroids. 
5.
At least 3 but no more than 9 weeks between the administration of the last cycle of platinum-based 
chemotherapy and randomization.
6.
Availability of archived or representative tumor material for assessment of DLL3 expression. 
7.
Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.  
8.
Recovery to ≤ Grade 1 of any clinically significant toxicity (excluding alopecia) prior to 
randomization.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
9.
Subject must have adequate bone marrow, renal and hepatic function as follows:
a.
Absolute neutrophil count (ANC) ≥ 1,000/μL
b.
Platelet count ≥ 75,000/μL
c.
Hemoglobin ≥ 8.0 g/dL
d.
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with 
Gilbert's disease
e.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN 
(≤5× ULN if evidence of hepatic involvement by malignant disease)
f.
Calculated creatinine clearance ≥ 30 mL/min by the Cockroft-Gault formula
g.
Albumin ≥ 3g/dL
10. If female, subject must be either postmenopausal as 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
•
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
OR a Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method 
of birth control, starting at randomization through at least 6 months after the last dose of blinded 
investigational product.
If the male subject is sexually active, he must agree, from randomization through at least 6 months 
after the last dose of blinded investigational product, to practice the protocol specified contraception.
11. Females of childbearing potential must have a negative serum pregnancy test result at Screening, and 
a negative urine pregnancy test at randomization.
Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as 
defined in the protocol) at Screening do not require pregnancy testing.
Main Exclusion:  
1.
Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint inhibitors, other 
monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, T-cell or other cell-based 
or biologic therapies, or any other anti-cancer therapy than that described in Inclusion Criteria 3 – 5 
for the disease under study.
2.
Any disease-directed radiotherapy (except PCI or pre-planned radiotherapy for CNS metastases 
present prior to start of first-line therapy and non-progressing) after last dose of first-line 
chemotherapy.
3.
Any significant medical condition including any suggested by screening laboratory findings that in 
the opinion of the Investigator or Sponsor may place the subject at undue risk from the study.
4.
Documented history of a cerebral vascular event, unstable angina, myocardial infarction, or cardiac 
symptoms consistent with New York Heart Association (NYHA) Class III – IV heart failure within 
6 months prior to randomization.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):  
5.
Documented history of capillary leak syndrome.
6.
Grade 2 or higher pleural or pericardial effusion within 4 weeks of randomization or earlier history of 
recurrent Grade 2 or higher effusions with ongoing requirement for pericardiocentesis or 
thoracentesis.
7.
Serious infection within 2 weeks prior to randomization, including any Grade 3 or higher (per NCI 
CTCAE version 4.0) viral, bacterial, or fungal infection.
8.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study 
or for approximately 6 months after the last dose of blinded investigational product.
9.
Male subject who is considering fathering a child or donating sperm during the study or for 
approximately 6 months after the last dose of blinded investigational product.
10. Systemic therapy with corticosteroids at > 10 mg/day prednisone or equivalent within 1 week prior to 
randomization.
11. Subject has a history of active malignancies other than SCLC within the past 2 years prior to study 
entry, with the exception of in situ cancer which was curatively treated.
12. Any prior exposure to a pyrrolobenzodiazepine (PBD)- or indolinobenzodiazepine-based drug, prior 
participation in a rovalpituzumab tesirine clinical trial, or known hypersensitivity or other 
contraindications to rovalpituzumab tesirine or excipient contained in the drug formulation.
13. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
Investigational Products:
Rovalpituzumab tesirine or Placebo
Dexamethasone or Placebo
Doses:
Rovalpituzumab tesirine/Placebo:  0.3 mg/kg, Day 1 of each 6-week 
cycle, omitting every third cycle.
Dexamethasone/Placebo 8 mg orally (PO) twice daily on Day –1, Day 1 
(the day of dosing), and Day 2 of each 6 week cycle, omitting every 
third cycle.
Mode of Administration:
Rovalpituzumab tesirine/Placebo:  Intravenous
Dexamethasone/Placebo:  Oral
Duration of Treatment:  Subjects will receive rovalpituzumab tesirine/placebo in combination with 
dexamethasone/placebo on Day 1 of a 6-week cycle, omitting every third cycle until disease progression.
Criteria for Evaluation:
Efficacy: Efficacy assessments will consist of evaluations for tumor progression using Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 and will be based on a Central Radiographic 
Assessment Committee (CRAC) review of medical images, as outlined in the Schedule of Assessments.  
Additionally, efficacy will be assessed by overall survival.  
Pharmacokinetic:  Plasma concentrations of rovalpituzumab tesirine ADC and the presence of anti-
therapeutic antibodies (ATA) will be determined.


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Criteria for Evaluation (Continued):
Biomarkers:  Pharmacodynamic and predictive biomarker assessments will include analyses of tumor 
material and circulating tumor cells for DLL3 expression, blood samples for inflammatory, tumor, and 
soluble markers.  Samples may also be used for other nucleic acid or protein based exploratory 
biomarkers to understand the sensitivity or resistance to rovalpituzumab tesirine and biology of SCLC.
Safety:  Safety assessments include physical exam, vital signs, body weight, ECOG score, clinical 
adverse events, laboratory tests (hematology, serum chemistries, urinalysis, and coagulation), ECGs, 
echocardiogram, fluid retention questionnaire, radiographic images review for fluid retention, and 
monitoring of concomitant medications.
Patient Reported Outcome (PRO): 
Changes in the patient reported outcomes (PROs) EORTC QLQ-C30, EORTC QLQ-LC13, and 
EQ-5D-5L from baseline will be assessed.
Statistical Methods:
Efficacy:  
Progression-free survival (PFS) and overall survival (OS) are the two primary efficacy endpoints.  No 
order of testing of these two endpoints is specified.  To meet global regulatory requirements, a multiple 
testing strategy will be implemented to control the family-wise type I error (alpha) for comparisons of 
rovalpituzumab tesirine arm versus placebo arm with respect to progression-free survival (PFS) per 
CRAC, and overall survival (OS), ORR per CRAC, and physical functioning scale score (EORTC 
QLQ-C30).
The following null hypotheses are considered for subjects with DLL3high:
H1:  Rovalpituzumab tesirine arm is not superior to placebo arm in both PFS and OS. 
H2:  Rovalpituzumab tesirine arm is not superior to placebo arm in ORR per CRAC.
H3:  Rovalpituzumab tesirine arm is not superior to placebo arm in physical functioning scale score 
(EORTC QLQ-C30).
The null hypotheses will be tested in a fixed sequence of {H1, H2, H3} in order.  To maintain the family-
wise type I error for the study, the null hypothesis H1 will be first tested with an alpha-split approach.  
The hypothesis for PFS will be tested at a one-sided 0.25% level of significance and the hypothesis for 
OS at a one-sided 2.25% level of significance.  If either PFS or OS endpoint reaches statistical 
significance, the study is considered positive.  No further tests will be performed if H1 is not rejected.  
Each hypothesis of H2 and H3 will be tested in order specified above if H1 is rejected and the preceding 
hypothesis shows statistically significant results at the 1-sided 2.5% level of significance.  Otherwise 
testing in the hierarchical sequence will stop.
Interim Analysis:
An interim efficacy analysis is planned for overall survival after at least 239 deaths in subjects with 
DLL3high (i.e., 75% of planned deaths are observed) using a one-sided log-rank test.  The O'Brien-
Fleming method will be implemented to protect the type I error rate of 0.0225 for OS.  A one-sided alpha 
spending of 0.0084 for the interim will be allocated for declaring statistical superiority in OS at the time 
of the interim analysis.  The final analysis of OS will be performed at a one-sided nominal alpha level of 
0.01998, adjusting for the interim look at OS data.  


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Statistical Methods (Continued):
Interim Analysis (Continued):
Unblinded interim data will be analyzed and reviewed by the IDMC.  The trial may be considered for 
early stopping for superiority and the Sponsor will be unblinded to the aggregated data by randomized 
treatment arms if the IDMC makes such a recommendation after consideration of the PFS and OS results, 
and all supportive evidence including other efficacy endpoints and safety.
Sample Size:
The sample size of the study is primarily determined by the analysis of OS.  It is assumed, taking into
account the expected patient population for the study, that median overall survival in the placebo arm will 
be around 9 months.  Based on a log-rank test, at a one sided significance level of 0.0225 and a power of 
90%, a total of 319 deaths among subjects with DLL3high are needed to detect an increase of median OS 
to 13 months in rovalpituzumab tesirine arm, corresponding to a hazard ratio of 0.69 (i.e., a reduction in 
the hazard death of 31%).  Assuming a 19-month accrual period and the last enrolled subject followed for 
12 months, at least 480 subjects with DLL3high are expected to be randomized (240 subjects in each arm).  
A total of 740 subjects regardless of DLL3 expression level (including 480 subjects with DLL3high) will 
enroll in the study, assuming an approximate prevalence of 65% for subjects with DLL3high.  It is 
projected that an observed hazard ratio of 0.795 or less, corresponding to a 2.3 months or greater 
improvement in median OS, would result in a statistically significant improvement in the final analysis of 
OS.
It is assumed, taking into account the expected patient population for the study, that median progression-
free survival for the placebo arm will be approximately 3 months.  Treatment with rovalpituzumab 
tesirine is hypothesized to increase median progression-free survival to 4.5 months (i.e., a hazard ratio of 
0.667).  With approximately 407 PFS events assessed by the CRAC for subjects with DLL3high, the study 
provides a 90% power to detect a hazard ratio of 0.667 in PFS at a one-sided significance level of 0.0025.  
It is projected that an observed hazard ratio of 0.757 or less, corresponding to approximately 1 month or 
greater improvement in median PFS, would result in a statistically significant improvement in the PFS.
Pharmacokinetic:  
Individual concentrations of rovalpituzumab tesirine ADC will be tabulated and summarized for subjects 
treated with the active regimen and summary statistics provided.  The incidence of ATA will be 
summarized.
Biomarkers:
Biomarkers will be measured at baseline and post-treatment and analyses performed to identify markers 
associated with rovalpituzumab tesirine response, pharmacodynamics, PK, or safety.
Safety:  
The safety of rovalpituzumab tesirine will be assessed by evaluating the study drug exposure, adverse 
events, all deaths, as well as changes in laboratory determinations and vital sign parameters.
Has been changed to read:
AbbVie Inc.
Protocol Number:  M16-298
Name of Study Drug:  rovalpituzumab tesirine 
(Rova-T)
Phase of Development:  3


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Name of Active Ingredient:  rovalpituzumab 
tesirine
Date of Protocol Synopsis:  05 March 2019
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Rovalpituzumab 
Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with 
Extensive Stage Small Cell Lung Cancer (MERU)
Objectives:
Primary
•
To evaluate if rovalpituzumab tesirine improves progression-free survival, assessed by a Central 
Radiographic Assessment Committee (CRAC) according to RECIST v1.1, and overall survival 
in subjects with extensive-stage small cell lung cancer (ED SCLC) tumors with a high level of 
DLL3 expression (DLL3high) who have ongoing clinical benefit (SD, PR, or CR) following 
first-line platinum-based chemotherapy (cisplatin or carboplatin plus irinotecan or etoposide) 
compared to placebo.
Secondary
•
To evaluate if rovalpituzumab tesirine improves progression-free survival by CRAC and overall 
survival in all randomized subjects compared to placebo. 
•
To assess change in patient reported outcomes (PRO) with physical functioning as measured by 
the EORTC QLQ-C30 questionnaire in all randomized subjects compared to placebo.
Exploratory
•
To evaluate rovalpituzumab tesirine anti-tumor activity by determining objective response rate 
(ORR), clinical benefit rate (CBR), and duration of responses (DOR) by CRAC and Investigator 
assessment in DLL3high and in all randomized subjects.
•
To evaluate if rovalpituzumab tesirine improves progression-free survival by Investigator 
assessment compared to placebo in DLL3high and in all randomized subjects.
•
To assess change from baseline in all patient reported outcomes (PRO) domains (except physical 
functioning) measured by EORTC QLQ-C30/LC13 and EQ-5D-5L.
•
To characterize the pharmacokinetics and incidence of anti-therapeutic antibodies (ATAs) 
against rovalpituzumab tesirine.
•
To evaluate pharmacodynamic and predictive biomarkers in blood and tumor for association 
with sensitivity, efficacy and safety.
•
To explore DLL3 expression in circulating tumor cells (CTCs) for association with efficacy.
Investigators:  Multicenter, International
Study Sites:  Approximately 300
Study Population:  Subjects with extensive-stage Small Cell Lung Cancer (ED SCLC) with ongoing 
clinical benefit (SD, PR, or CR per RECIST v1.1) following completion of 4 cycles of first-line 
platinum-based chemotherapy (cisplatin or carboplatin in combination with etoposide or irinotecan).
Number of Subjects to be Enrolled:  Up to approximately 740 SCLC subjects, to obtain approximately 
480 subjects with DLL3high expression in tumor (DLL3high).  DLL3high is defined as ≥ 75% tumor cells 
staining positive according to the VENTANA DLL3 (SP347) IHC Assay.


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Methodology:  
This is a Phase 3, randomized, double-blinded, placebo-controlled, multinational, and multicenter study.
ED SCLC subjects who meet all the inclusion criteria and none of the exclusion criteria, and demonstrate 
ongoing clinical benefit (SD, PR, or CR) at the completion of 4 cycles of first-line platinum-based 
chemotherapy (such benefit must be ongoing at the last re-staging assessment prior to randomization), 
will be randomly assigned in a 1:1 ratio to receive 0.3 mg/kg rovalpituzumab tesirine or placebo, and will 
receive their assigned therapy on Day 1 of each 6-week cycle, omitting every third cycle.  Upon 
completion of first-line chemotherapy, eligible subjects must be offered prophylactic cranial irradiation 
(PCI), if offering this procedure is not contradictory to country or institutional guidelines.  Subjects 
receiving PCI must complete it prior to randomization into the study.  Subjects will also receive 8 mg 
orally (PO) of dexamethasone or placebo twice daily on Day –1, Day 1, and Day 2 of each 6-week cycle, 
omitting every third cycle.  Randomization will be stratified by RECIST v1.1 response after completion 
of first-line platinum-based chemotherapy at screening assessment (SD vs. PR/CR), DLL3 expression, 
(Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or above), history of central nervous system 
(CNS) metastases (Yes vs. No), and for subjects with no history of CNS metastases, PCI vs. no PCI.
Survival Follow-up will continue until the endpoint of death, the subject becomes lost to follow-up or 
withdraws consent, or termination of the study by AbbVie, whichever occurs first.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
1.
Subject or the subject's legally acceptable representative must voluntarily sign and date an informed 
consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), 
prior to the initiation of any screening or study-specific procedures and should be willing and able to 
comply with parameters as outlined in the protocol.
2.
Subject must be ≥ 18 years of age.
3.
Histologically or cytologically confirmed ED SCLC (extensive stage disease at initial diagnosis), 
with ongoing clinical benefit (SD, PR, or CR per RECIST v1.1) following completion of 4 cycles of 
first-line platinum-based therapy (cisplatin or carboplatin in combination with etoposide or 
irinotecan).
4.
Subjects with a history of CNS metastases prior to the initiation of first-line platinum-based 
chemotherapy must have received definitive local treatment and have documentation of stable or 
improved CNS disease status based on brain imaging within 28 days prior to randomization, off or on 
a stable dose of corticosteroids. 
5.
Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the 
fourth cycle of first-line platinum-based chemotherapy 
6.
Availability of archived or representative tumor material for assessment of DLL3 expression. 
7.
Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.  
8.
Recovery to ≤ Grade 1 of any clinically significant toxicity (excluding alopecia) prior to 
randomization.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
9.
Subject must have adequate bone marrow, renal and hepatic function as follows:
a.
Absolute neutrophil count (ANC) ≥ 1,000/μL
b.
Platelet count ≥ 75,000/μL
c.
Hemoglobin ≥ 8.0 g/dL
d.
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with 
Gilbert's disease
e.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN 
(≤5× ULN if evidence of hepatic involvement by malignant disease)
f.
Calculated creatinine clearance ≥ 30 mL/min by the modified Cockroft-Gault formula (Refer to 
Appendix E).
g.
Albumin ≥ 3g/dL
10. If female, subject must be either postmenopausal as 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
•
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
OR a Women of Childbearing Potential (WOCBP) practicing at least one protocol specified method 
of birth control, starting at randomization through at least 6 months after the last dose of blinded 
investigational product.
If the male subject is sexually active, he must agree, from randomization through at least 6 months 
after the last dose of blinded investigational product, to practice the protocol specified contraception.
11. Females of childbearing potential must have a negative serum pregnancy test result at Screening, and 
a negative urine pregnancy test at randomization.
Females of non-childbearing potential (either postmenopausal or permanently surgically sterile as 
defined in the protocol) at Screening do not require pregnancy testing.
Main Exclusion:  
1.
Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint inhibitors, other 
monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, T-cell or other cell-based 
or biologic therapies, or any other anti-cancer therapy than that described in Inclusion Criteria 3 – 5 
for SCLC.
2.
Any disease-directed radiotherapy (except, PCI, palliative radiotherapy to a radiographically 
documented non-progressing lesion for symptom control, or pre-planned radiotherapy for CNS 
metastases present prior to start of first-line therapy and non-progressing) after last dose of first-line 
chemotherapy.
3.
Any significant medical condition including any suggested by screening laboratory findings that in 
the opinion of the Investigator or Sponsor may place the subject at undue risk from the study.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):  
4.
Documented history of a cerebral vascular event, unstable angina, myocardial infarction, or cardiac 
symptoms consistent with New York Heart Association (NYHA) Class III – IV heart failure (refer to 
Appendix F) within 6 months prior to randomization.
5.
Documented history of capillary leak syndrome.
6.
Grade 2 or higher pleural or pericardial effusion within 4 weeks of randomization or earlier history of 
recurrent Grade 2 or higher effusions with ongoing requirement for pericardiocentesis or 
thoracentesis.
7.
Serious infection within 2 weeks prior to randomization, including any Grade 3 or higher (per NCI 
CTCAE version 4.0) viral, bacterial, or fungal infection.
8.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant during the study 
or for approximately 6 months after the last dose of blinded investigational product.
9.
Male subject who is considering fathering a child or donating sperm during the study or for 
approximately 6 months after the last dose of blinded investigational product.
10. Systemic therapy with corticosteroids at > 10 mg/day prednisone or equivalent within 1 week prior to 
randomization.
11. Subject has a history of active malignancies other than SCLC within the past 2 years prior to study 
entry, with the exception of in situ cancer which was curatively treated.
12. Any prior exposure to a pyrrolobenzodiazepine (PBD-based)-or indolinobenzodiazepine-based drug, 
prior participation in a rovalpituzumab tesirine clinical trial, or known hypersensitivity or other 
contraindications to rovalpituzumab tesirine or excipient contained in the drug formulation.
13. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
Investigational Products:
Rovalpituzumab tesirine or Placebo
Dexamethasone or Placebo
Doses:
Rovalpituzumab tesirine/Placebo:  0.3 mg/kg, Day 1 of each 6-week 
cycle, omitting every third cycle.
Dexamethasone/Placebo 8 mg orally (PO) twice daily on Day –1, Day 1 
(the day of dosing), and Day 2 of each 6 week cycle, omitting every 
third cycle.
Mode of Administration:
Rovalpituzumab tesirine/Placebo:  Intravenous
Dexamethasone/Placebo:  Oral
Duration of Treatment:  Subjects will receive rovalpituzumab tesirine/placebo in combination with 
dexamethasone/placebo on Day 1 of a 6-week cycle, omitting every third cycle until disease progression.
Criteria for Evaluation:
Efficacy: Efficacy assessments will consist of evaluations for tumor progression using Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 and will be based on a Central Radiographic 
Assessment Committee (CRAC) review of medical images, as outlined in the Schedule of Assessments.  
Additionally, efficacy will be assessed by overall survival.  
Pharmacokinetic:  Serum concentrations of rovalpituzumab tesirine ADC and the presence of anti-
therapeutic antibodies (ATA) will be determined.


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Criteria for Evaluation (Continued):
Biomarkers:  Pharmacodynamic and predictive biomarker assessments will include analyses of tumor 
material and circulating tumor cells for DLL3 expression, blood samples for inflammatory, tumor, and 
soluble markers.  Samples may also be used for other nucleic acid or protein based exploratory 
biomarkers to understand the sensitivity or resistance to rovalpituzumab tesirine and biology of SCLC.
Safety:  Safety assessments include physical exam, vital signs, body weight, ECOG score, clinical 
adverse events, laboratory tests (hematology, serum chemistries, urinalysis, and coagulation), ECGs, 
echocardiogram, fluid retention questionnaire, radiographic images review for fluid retention, and 
monitoring of concomitant medications.
Patient Reported Outcome (PRO): 
Changes in the patient reported outcomes (PROs) EORTC QLQ-C30, EORTC QLQ-LC13, and 
EQ-5D-5L from baseline will be assessed.
Statistical Methods:
Efficacy:  
Progression-free survival (PFS) per CRAC and overall survival (OS) in patients with DLL3high ED SCLC 
are the two primary efficacy endpoints.  To meet global regulatory requirements, a multiple testing 
strategy will be implemented to control the family-wise type I error (alpha) for comparisons of 
rovalpituzumab tesirine arm versus placebo arm with respect to progression-free survival (PFS) per 
CRAC in DLL3high patients, overall survival (OS) in DLL3high patients, PFS per CRAC in randomized 
patients, OS in randomized patients, and physical functioning scale score (EORTC QLQ-C30) in the 
randomized set.
The following null hypotheses are considered:
Two hypotheses in H01 are H01a and H01b.
H01a:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in DLL3high set. 
H01b:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in DLL3high set. 
H02:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in randomized set. 
H03:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in randomized set. 
H04:  Rovalpituzumab tesirine arm is not superior to placebo arm in physical functioning scale score 
(EORTC QLQ-C30) in randomized set. 
The null hypotheses will be tested in a fixed sequence of {H01a, H01b, H02, H03, and H04} in order.  To 
maintain the family-wise type I error for the study, the null hypotheses in H01 (H01a and H01b) will be first 
tested with an alpha-split approach.  The one-sided alpha of 0.25% and 2.25% will be assigned for PFS 
and OS hypothesis in H01, respectively.  Out of one-sided alpha of 2.25% allocated to OS hypothesis 
(H01b), the one-sided alpha of 10–6 will be spent for the early look at the OS data for futility analysis.  If 
the hypothesis for PFS in H01 (H01a) is rejected the one-sided alpha of 0.25% will be recycled to the OS 
hypothesis in H01 (H01b).  Hence, the hypothesis for OS in H01 (H01b) will be tested either at a one-sided 
2.4999% or one-sided 2.2499% level of significance depending on the PFS hypothesis in H01 a is rejected 
or not. 
If either PFS or OS endpoint reaches statistical significance, the study is considered positive.  No further 
tests will be performed if the OS endpoint in DLL3high population (H01b) does not reach statistical 
significance.


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Statistical Methods (Continued):
The hypothesis in H02 will be tested if the hypothesis in H01b is rejected.  If the hypothesis in H02 is 
rejected, then, either (i) H03 and H04 will be tested sequentially if the PFS endpoint in DLL3high subjects 
(H01a) is also rejected or (ii) only H04 will be tested if the PFS endpoint in DLL3high subjects (H01a) is not 
rejected.
Futility Analysis:
Unblinded interim data will be analyzed and reviewed by the IDMC.  A futility analysis will be 
conducted when approximately 160 deaths in subjects with DLL3high ED SCLC (approximately 50% of 
the planned deaths) are observed.  The trial may be stopped for futility if the estimated Overall Survival 
Cox HR of Rova-T to Placebo at this analysis exceeds 0.9.  The one-sided alpha of 10–6 will be spent for 
the early look at the efficacy data for futility analysis.
Sample Size:
There are two primary efficacy endpoints for this study:  Progression-free survival (PFS) based on the 
CRAC and overall survival (OS) in subjects with DLL3high ED SCLC.  To maintain the overall 1-sided 
type I error at a 2.5% for this study, the type I error will be split, assigning 0.25% to progression-free 
survival and the remaining 2.25% to overall survival.  However, the OS endpoint will be tested at a 
one-sided 2.2499% significance level as a one-sided alpha of 10–6 will be spent for the early look at the 
OS data for futility analysis. 
The sample size of the study is primarily determined by the analysis of OS.  It is assumed, taking into 
account the expected patient population for the study, that median overall survival in the placebo and 
rovalpituzumab tesirine arm will be around 9 months and 13 months, respectively.  The increase of 
median OS in rovalpituzumab tesirine arm corresponds to a hazard ratio of 0.69, i.e., a reduction in the 
hazard of death by 31%.  With all these assumptions, a total of 319 deaths among subjects with DLL3high
are needed to achieve a 90% power based on a log-rank test at a one-sided significance level of 0.022499.  
Assuming a 19-month accrual period and the last enrolled subject followed for 12 months, at least 
480 subjects with DLL3high are expected to be randomized (240 subjects in each arm).  A total of 
740 subjects regardless of DLL3 expression level (including 480 subjects with DLL3high) will enroll in 
the study, assuming an approximate prevalence of 65% for subjects with DLL3high.  For one-sided 
significance level of 0.022499, it is projected that an observed hazard ratio of 0.799 or less, 
corresponding to a 2.3 months or greater improvement in median OS, would result in a statistically 
significant improvement in the primary analysis of OS.
The primary endpoints of OS and PFS in DLL3high patients will be analyzed at the same time after 
observing at-least 319 OS event.  It is expected at approximately 420 PFS events will be observed at the 
time of the primary analysis.
It is assumed, taking into account the expected patient population for the study, that median progression-
free survival for the placebo and rovalpituzumab tesirine arm will be approximately 3 months and 
4.5 months, respectively.  The increase of median progression-free survival in rovalpituzumab tesirine 
arm corresponds to a hazard ratio of 0.667.  With all these assumptions, a total of 420 PFS events 
assessed by the CRAC for the subjects with DLL3high are needed to achieve a 91% power based on a log-
rank test at a one-sided significance level of 0.0025.  It is projected that an observed hazard ratio of 0.760 
or less, corresponding to approximately 1 month or greater improvement in median PFS, would result in 
a statistically significant improvement in the PFS.


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Statistical Methods (Continued):
Pharmacokinetic:  
Individual concentrations of rovalpituzumab tesirine ADC will be tabulated and summarized for subjects 
treated with the active regimen and summary statistics provided.  The incidence of ATA will be 
summarized.
Biomarkers:
Biomarkers will be measured at baseline and post-treatment and analyses performed to identify markers 
associated with rovalpituzumab tesirine response, pharmacodynamics, PK, or safety.
Safety:  
The safety of rovalpituzumab tesirine will be assessed by evaluating the study drug exposure, adverse 
events, all deaths, as well as changes in laboratory determinations and vital sign parameters.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add: 
LD SCLC
Limited-stage disease small cell lung cancer
Section 3.3  Rovalpituzumab Tesirine
Last paragraph Previuosly read:
In a Phase 1 study (SCRX16-001), rovalpituzumab tesirine dosed at 0.2 – 0.4 mg/kg 
exhibited encouraging efficacy in recurrent SCLC, achieving a 31% (8/26) and 85% 
(22/26) central review-adjudicated confirmed objective response rate (ORR) and clinical 
benefit rate (CBR), respectively, in subjects whose tumors expressed DLL3 in ≥50% of 
cells.  Median overall survival was 7.7 months in DLL3 ≥ 50% subjects at all dose levels, 
with a 1-year survival rate of 30%.9  Therefore, rovalpituzumab tesirine appears to be an 
active anti-cancer therapy.
Has been changed to read:
In the Phase 1 first in human study of rovalpituzumab tesirine (Study SCRX16-001), the 
best overall response (confirmed) for all SCLC subjects (dose escalation, retreatment, and 
maintenance cohorts) was retrospectively assessed by the Independent Review Committee 
(IRC) by RECIST v1.1 criteria.  The ORR (confirmed) was 16% (95% CI:  7.35, 27.42), 


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with 12% achieving PR.  The clinical benefit rate (CBR) was 59% (95% CI:  44.93, 
71.40).  The median duration of response by the IRC was 1.7 months (95% CI:  0.03, 
3.06).  The median progression-free survival by the IRC was 3.0 months (95% CI:  2.56, 
3.84), with a probability of progression-free survival at 12 weeks of 52% (95% CI:  39, 
63).  The median overall survival was 4.3 months (95% CI:  3.22, 5.65).  The probability 
of overall survival at 12 weeks was 69% (95% CI:  52, 81).  In DLL3-positive (≥ 1% 
tumor cells staining positive for DLL3 with murine anti-DLL3 antibody assay) subjects, 
the ORR was 23% (95% CI:  10.42, 40.14), and the CBR was 77% (95% CI:  59.86, 
89.58).  A slightly higher ORR (27%) and CBR (87%) were observed in DLL3-high 
(≥50% tumor cells staining positive for DLL3 with murine anti-DLL3 antibody assay) 
subjects.
In the Phase 2 Study SCRX001-002 (TRINITY) in patients with SCLC recurrent after at 
least two systemic chemotherapy regimens, rovalpituzumab tesirine dosed at 0.3 mg/kg 
every 6 weeks for two cycles (with an option for additional two cycles upon progression 
occurring ≥ 12 weeks after the second dose) resulted in the following: 
●
In DLL3high (Ӌ 75% tumor cells staining positive for DLL3 with VENTANA 
Rabbit IHC (SP347) DLL3 assay) subjects, ORR of 14% per IRC assessment, 
median OS of 5.7 months and median PFS of 3.8 months
●
In DLL3high subjects, the clinical benefit rate was 74% with a median duration 
of clinical benefit of 3.0 months per IRC assessment
Additionally, DLL3 positive (≥ 25% tumor cells staining positive for DLL3 with 
VENTANA Rabbit IHC (SP347) DLL3 assay) and DLL3high groups had comparable 
response rates given highly overlapping populations where approximately 85% of DLL3 
positive subjects were also DLL3high.
In December 2018, enrollment in Study M16-289 TAHOE ("A Randomized, Open-Label, 
Multicenter, Phase 3 Study of Rovalpituzumab Tesirine Compared with Topotecan for 
Subjects with Advanced or Metastatic DLL3high Small Cell Lung Cancer (SCLC) who 
have First Disease Progression During or Following Front-Line Platinum-Based 


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Chemotherapy") was discontinued at the recommendation of the Independent Data 
Monitoring Committee (IDMC) after review of available efficacy data which 
demonstrated shorter overall survival in the rovalpituzumab tesirine arm compared with 
the topotecan control arm.  At the time enrollment was halted, 444 DLL3high (≥ 75% 
tumor cells staining positive for DLL3 with VENTANA Rabbit IHC (SP347) DLL3 
assay) subjects had enrolled on the trial.  The IDMC recommended that investigators and 
subjects make individual decisions as to whether or not to continue treatment based on 
patient level response.  The results of the TAHOE study did not adversely impact the 
safety profile for rovalpituzumab tesirine.19
Section 3.5  Benefits and Risks
Add:  new second paragraph
As of 30 June 2018, 1246 subjects have received study medication in the rovalpituzumab 
tesirine clinical program; an estimated 1039 subjects (with SCLC or other DLL3-
expressing solid tumors) have received at least 1 dose of rovalpituzumab tesirine at doses 
ranging from 0.05 mg/kg to 0.8 mg/kg on a q3w schedule and 0.3 mg/kg to 0.4 mg/kg on 
a q6w schedule.
Section 3.5  Benefits and Risks
Second paragraph, first and second sentence previously read:
The most frequent treatment-emergent adverse event (TEAE) terms considered related to 
rovalpituzumab tesirine have included fatigue (35%), pleural effusion (31%) and 
peripheral edema (27%), while the most frequent, related TEAE groups of Grade 3 or 
higher have included thrombocytopenia (12%), serosal effusions (11%), and skin 
reactions (8%).9  In addition, preclinical toxicology studies conducted in the rat and the 
cynomolgus monkey have identified bone marrow, lung, and kidney as potential sources 
of clinical adverse events (AEs) (AbbVie Stemcentrx data on file).  


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Has been changed to read:
Among subjects with SCLC treated with rovalpituzumab tesirine 0.3 mg/kg q6w, 96.8% 
of subjects reported at least 1 adverse event.  The most frequently reported adverse events 
among subjects with SCLC treated with rovalpituzumab tesirine 0.3 mg/kg q6w were 
decreased appetite (28.0%), photosensitivity reaction (27.7%), oedema peripheral 
(27.2%), dyspnoea (26.6%), and nausea (25.6%).  Important identified risks following 
treatment with rovalpituzumab tesirine include:  pleural effusions (33.9%), pericardial 
effusions (16.7%), generalized edema (2.7%) and photosensitivity reactions (27.7%).  
Important potential risks following treatment with rovalpituzumab tesirine include 
pneumonitis (1%).  The following adverse events of special interest have also been 
identified:  cutaneous reactions (48.7%), thrombocytopenia and hemorrhage events 
(28%), edema (33.8%), hypoalbuminemia (16.2%), hepatotoxicity (19.3%), 
nephrotoxicity (5.9%), anemia (19.7%), neutropenia (9.2%) and infusion related reaction 
(0.2%).  In addition, preclinical toxicology studies conducted in the rat and the 
cynomolgus monkey have identified bone marrow, lung, and kidney as potential sources 
of clinical adverse events (AEs) (AbbVie Investigator Brochure v7).  
Section 4.0  Study Objectives
Previously read:
The primary objective of this study is to evaluate if rovalpituzumab tesirine improves 
progression-free and overall survival in subjects with extensive-stage SCLC who have 
ongoing clinical benefit (SD, PR, or CR) following the completion of 4 cycles of 
first-line, platinum-based chemotherapy (cisplatin or carboplatin plus irinotecan or 
etoposide) compared to placebo.
The secondary objectives are to evaluate rovalpituzumab tesirine anti-tumor activity by 
determining objective response rate (ORR), clinical benefit rate (CBR), and duration of 
responses (DOR), and to assess change in patient reported outcomes (PRO) with 
EORTC QLQ-C30/LC-13 questionnaires.


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The exploratory objectives are to characterize the pharmacokinetics and incidence of 
anti-therapeutic antibodies (ATAs) against rovalpituzumab tesirine, to evaluate 
pharmacodynamic and predictive biomarkers in blood and tumor for association with 
sensitivity, efficacy and safety, to explore the DLL3 expression in circulating tumor cells 
(CTCs) for association with efficacy, and to assess EQ-5D-5L during treatment with 
rovalpituzumab tesirine.
Has been changed to read:
The primary objective of this study is to evaluate if rovalpituzumab tesirine improves
progression-free survival, assessed by CRAC, and overall survival in subjects with 
extensive-stage SCLC tumors with a high level of DLL3 expression (DLL3high) who have 
ongoing clinical benefit (SD, PR, or CR) following the completion of 4 cycles of 
first-line, platinum-based chemotherapy (cisplatin or carboplatin plus irinotecan or 
etoposide) compared to placebo.
The secondary objectives are:
●
To evaluate if rovalpituzumab tesirine improves progression-free survival by 
CRAC and overall survival in all randomized subjects compared to placebo.
●
To assess change in patient reported outcomes (PRO) with physical 
functioning as measured by the EORTC QLQ-C30questionnaire in all 
randomized subjects compared to placebo.
The exploratory objectives are: 
●
To evaluate rovalpituzumab tesirine anti-tumor activity by determining 
objective response rate (ORR), clinical benefit rate (CBR), and duration of 
responses (DOR) by CRAC and investigator assessment in DLL3high and in all 
randomized subjects. 
●
To evaluate if rovalpituzumab tesirine improves progression-free survival by 
investigator assessment compared to placebo in DLL3high and in all 
randomized subjects. 


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●
To assess change from baseline in all patient reported outcomes (PRO) 
domains (except physical functioning) measured by EORTC QLQ-C30/LC13 
and EQ-5D-5L.
●
To characterize the pharmacokinetics and incidence of anti-therapeutic 
antibodies (ATAs) against rovalpituzumab tesirine.
●
To evaluate pharmacodynamic and predictive biomarkers in blood and tumor 
for association with sensitivity, efficacy and safety.
●
To explore the DLL3 expression in circulating tumor cells (CTCs) for 
association with efficacy.
Section 5.1  Overall Study Design and Plan:  Description
Second paragraph, last sentence previously read:
Approximately 275 clinical sites will participate.
Has been changed to read:
Approximately 300 clinical sites will participate.
Figure 1.  Study Schema
Footnote "3." previously read:
At least 3 but no more than 9 weeks between the administration of the last cycle of 
platinum-based chemotherapy and randomization.
Has been changed to read:
Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 of the 
fourth cycle of first-line platinum-based chemotherapy.


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Section 5.2  Selection of Study Population
Add:  new second paragraph
For the purposes of study eligibility, limited stage disease SCLC (LD-SCLC) is defined as
a disease confined to the hemithorax of origin, with or without the involvement of 
regional lymph nodes, including ipsilateral and contralateral hilar, ipsilateral and 
contralateral mediastinal, and ipsilateral supraclavicular nodes.  Extensive stage disease 
SCLC (ED-SCLC) is defined as all other SCLC.
Section 5.2.1  Inclusion Criteria
Criterion 1, 3, and 5 previously read:
1.
Subject must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the 
initiation of any screening or study-specific procedures and should be willing and 
able to comply with parameters as outlined in the protocol.
3.
Histologically or cytologically confirmed extensive-stage SCLC with ongoing 
clinical benefit (SD, PR, or CR per RECIST v.1.1) following completion of 4 cycles 
of first-line platinum-based therapy (cisplatin or carboplatin in combination with 
etoposide or irinotecan).
5.
At least 3 but no more than 9 weeks between the administration of the last cycle of 
platinum-based chemotherapy and randomization.
Has been changed to read:
1.
Subject or the subject's legally acceptable representative must voluntarily sign and 
date an informed consent, approved by an Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or 
study-specific procedures and should be willing and able to comply with parameters 
as outlined in the protocol.


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3.
Histologically or cytologically confirmed ED SCLC (extensive stage disease at 
initial diagnosis), with ongoing clinical benefit (SD, PR, or CR per RECIST v.1.1) 
following completion of 4 cycles of first-line platinum-based therapy (cisplatin or 
carboplatin in combination with etoposide or irinotecan).
5.
Subject is eligible to be randomized at least 3 but no more than 9 weeks from Day 1 
of the fourth cycle of first-line platinum-based chemotherapy.
Section 5.2.1  Inclusion Criteria
Criterion 9f previously read:
Calculated creatinine clearance ≥ 30 mL/min by the Cockroft-Gault formula (Refer to 
Appendix E)
Has been changed to read:
Calculated creatinine clearance ≥ 30 mL/min by the modified Cockroft-Gault formula 
(Refer to Appendix E)
Section 5.2.2  Exclusion Criteria
Criterion 1, 2, 4, and 12 previously read:
1.
Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint 
inhibitors, other monoclonal antibodies, antibody-drug conjugates, 
radioimmunoconjugates, T-cell or other cell-based or biologic therapies, or any 
other anti-cancer therapy than that described in Inclusion Criteria 3 – 5 for the 
disease under study.
2.
Any disease-directed radiotherapy (except PCI or pre-planned radiotherapy for CNS 
metastases present prior to start of first-line therapy and non-progressing) after last 
dose of first-line chemotherapy.
4.
Documented history of a cerebral vascular event, unstable angina, myocardial 
infarction, or cardiac symptoms consistent with New York Heart Association 


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(NYHA) Class III – IV heart failure (refer to Appendix E) within 6 months prior to 
randomization.
12.
Any prior exposure to a pyrrolobenzodiazepine (PBD)- or indolinobenzodiazepine-
based drug, prior participation in a rovalpituzumab tesirine clinical trial, or known 
hypersensitivity or other contraindications to rovalpituzumab tesirine or excipient 
contained in the drug formulation.
Has been changed to read:
1.
Any prior systemic chemotherapy, small molecule inhibitors, immune checkpoint 
inhibitors, other monoclonal antibodies, antibody-drug conjugates, 
radioimmunoconjugates, T-cell or other cell-based or biologic therapies, or any 
other anti-cancer therapy than that described in Inclusion Criteria 3 – 5 for SCLC.
2.
Any disease-directed radiotherapy (except PCI, palliative radiotherapy to a 
radiographically documented non-progressing lesion for symptom control, or pre-
planned radiotherapy for CNS metastases present prior to start of first-line therapy 
and non-progressing) after last dose of first-line chemotherapy.
4.
Documented history of a cerebral vascular event, unstable angina, myocardial 
infarction, or cardiac symptoms consistent with New York Heart Association 
(NYHA) Class III – IV heart failure (refer to Appendix F) within 6 months prior to 
randomization.
12.
Any prior exposure to a pyrrolobenzodiazepine (PBD-based) or 
indolinobenzodiazepine-based drug, prior participation in a rovalpituzumab tesirine
clinical trial, or known hypersensitivity or other contraindications to rovalpituzumab 
tesirine or excipient contained in the drug formulation.


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Section 5.2.3.1  Prior Therapy
First paragraph previously read:
Subjects will have received first-line platinum-based chemotherapy consisting of 4 cycles 
of treatment with combination of either cisplatin or carboplatin with etoposide or 
irinotecan; administration of the last cycle of first-line chemotherapy must be at least 
3 weeks but no more than 9 weeks prior to randomization.
Has been changed to read:
Subjects will have received first-line platinum-based chemotherapy consisting of 4 cycles 
of treatment with combination of either cisplatin or carboplatin with etoposide or 
irinotecan; administration of Day 1 of the last cycle of first-line chemotherapy must be at 
least 3 weeks but no more than 9 weeks prior to randomization.  Subjects previously 
treated for LD-SCLC are not eligible.
Section 5.2.3.2  Concomitant Therapy
Last paragraph, last sentence previously read:
However, due to the potential for rovalpituzumab tesirine-related skin photosensitivity, 
subjects should be advised during treatment and for 30 days after last treatment to avoid 
unprotected sun exposure, use a broad spectrum sunscreen with a sun protection factor 
(SPF) of at least 30 and re-apply sunscreen as activity-appropriate, and wear protective 
clothing, a broad-brimmed hat, and sunglasses when outdoors or when driving or riding in 
a car for more than 1 hour.
Has been changed to read:
However, due to the potential for rovalpituzumab tesirine-related skin photosensitivity, 
Patients should be advised to avoid direct and indirect sun exposure as much as possible 
from Cycle 1 Day 1 until 30 days after the final dose.  When sun exposure is unavoidable, 
patients should wear protective clothing and sunglasses, and use a broad-spectrum 
sunscreen and lip balm (SPF 30 or greater).  Thirty-one to ninety days after last dose of 


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Rova-T/placebo, the patient may resume outdoor activities with appropriate sun protection 
including broad brimmed hat, protective clothing and sunscreen SPF 30 or higher.
Section 5.2.3.2.1  Allowed Concomitant Therapy
First paragraph, third sentence previously read:
Bone modifying agents for bone metastases are also permitted per local institutional 
standards.  
Has been changed to read:
Bone modifying agents (e.g., bisphosphonates, denosumab) for bone metastases are also 
permitted per local institutional standards.  
Section 5.3.1.1  Study Procedures
Subsection Vital Signs
First paragraph, second sentence previously read:
Vital signs include weight, sitting blood pressure, heart rate and body temperature.
Has been changed to read:
Vital signs include actual weight, sitting blood pressure, heart rate and body temperature.
Section 5.3.1.1  Study Procedures
Subsection Vital Signs
Second paragraph previously read:
Weight will be collected in the clinic prior to dosing at each cycle and the recorded weight 
will be utilized for dosing calculations.  For weight assessments, the subject should not 
wear shoes.


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Has been changed to read:
Actual weight will be collected in the clinic prior to dosing at each cycle and the recorded 
weight will be utilized for dosing calculations.  For weight assessments, the subject 
should not wear shoes.  In the event of a 5% or greater increase in weight within 
2 consecutive visits or compared to baseline which ever has the shorter interval, a prompt 
workup for fluid retention (e.g., edema, effusions, etc.) should be conducted.  If weight 
gain is due to proven or suspected fluid retention related to study drug, and dosing is not 
prohibited per Section 5.5.4, dose should be calculated based on actual weight before the 
event of fluid retention.
Section 5.3.1.1  Study Procedures
Subsection Echocardiogram
Previously read:
Echocardiograms will be performed per Appendix C, Study Activities to assess any 
pericardial effusion, if present, as well as cardiac function (left ventricular ejection 
fraction, LVEF).  
Has been changed to read:
Echocardiograms will be performed per Appendix C, Study Activities to rule out 
pericardial effusion (or assess, if present), as well as assess cardiac function (left 
ventricular ejection fraction, LVEF).  
Section 5.3.1.1  Study Procedures
Subsection Disease/Response Assessment (Radiographic Imaging)
Last paragraph previously read:
Scheduled tumor assessments will not be affected by delays in therapy and/or drug 
holidays.  Subjects will continue to be monitored by the same diagnostic method 
throughout the study every 6 weeks after randomization, unless evidence of tumor 
metastases warrants otherwise.  Subjects who discontinue treatment for reasons other than 


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radiographic disease progression will continue to be followed every 6 weeks from C1D1 
to determine the extent of tumor burden, until disease progression occurs.
Has been changed to read:
Scheduled tumor assessments should not be affected by delays in therapy and/or drug 
holidays.  Subjects will continue to be monitored by the same diagnostic method 
throughout the study every 6 weeks after randomization, unless evidence of tumor 
progression warrants otherwise.  In some cases, mandatory dose delays due to toxicity 
will lead to a gap between tumor assessment and dosing.  In cases where this gap exceeds 
1 week, the TAMD should be contacted for guidance.
Subjects who discontinue treatment for reasons other than radiographic disease 
progression will continue to be followed every 6 weeks from randomization to determine 
the extent of tumor burden, until disease progression occurs.
Section 5.3.1.1  Study Procedures
Subsection MRI/CT of the Brain
Last sentence previously read:
MRI/CT of the brain is only required at screening and when clinically indicated (e.g., if 
CNS progression is suspected).
Has been changed to read:
MRI/CT of the brain is required at screening and when clinically indicated (e.g., if CNS 
progression is suspected) thereafter.
Section 5.3.1.1  Study Procedures
Subsection Fluid Retention Questionnaire (Including Subject Daily Weight)
Last paragraph, last sentence previously read:
The site will advise subjects to contact the site in cases where sudden weight gain is 
observed for possible assessment in the clinic.


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Has been changed to read:
The site will advise subjects to contact the site in cases where sudden weight gain (5% or 
greater) is observed for possible assessment in the clinic.
Section 5.3.1.1  Study Procedures
Subsection End of Treatment (EOT) Visit
Add:  new second sentence
The EOT procedures should be done within 7 days of documented decision to discontinue 
treatment and prior to subjects beginning any new anti-cancer therapy if possible.
Section 5.3.1.1  Study Procedures
Subsection End of Treatment (EOT) Visit
Delete:  third sentence
The visit should occur within 7 days of documentation of the decision to discontinue 
treatment and prior to subjects beginning any new anti-cancer therapy if possible.
Section 5.3.3.2  Primary Variables
Previously read:
The primary endpoints are progression-free survival (PFS) determined by a Central 
Radiographic Assessment Committee (CRAC) and overall survival (OS).
Has been changed to read:
The primary endpoints are progression-free survival (PFS) determined by a Central 
Radiographic Assessment Committee (CRAC) per RECIST v. 1.1 and overall survival 
(OS) in DLL3high population.


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Section 5.3.3.3  Secondary Variables
Previously read:
The secondary variables are progression-free survival (PFS) based on investigator 
assessment, objective response rate (ORR) per the CRAC and investigator assessment, 
respectively, and clinical benefit rate (CBR) per the CRAC and investigator assessment, 
respectively, and the duration of response (DOR) per the CRAC and investigator 
assessment, respectively.  Response assessment will be based on RECIST v1.1.  Changes 
in patient reported outcomes (PROs) as measured by European Organization for Research 
and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and Lung 
Cancer Module (QLQ-LC13) are also secondary endpoints in this study.
Has been changed to read:
The secondary variables are progression-free survival (PFS) determined by a Central 
Radiographic Assessment Committee (CRAC) per RECIST v. 1.1 and overall survival 
(OS) in randomized set population.  Change in patient reported outcome (PRO) with 
physical functioning as measured by European Organization for Research and Treatment 
of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) in randomized set 
population is also a secondary endpoint in this study.
Section 5.3.3.4  Exploratory Variables
Add:  new section title and text
5.3.3.4
Exploratory Variables
The exploratory variables are progression-free survival (PFS) based on investigator 
assessment, objective response rate (ORR) per the CRAC and investigator assessment, 
respectively, clinical benefit rate (CBR) per the CRAC and investigator assessment, 
respectively, and the duration of response (DOR) per the CRAC and investigator 
assessment, respectively.  Response assessment will be based on RECIST v1.1.  Changes 
in patient reported outcomes (PROs) as measured by EQ-5D-5L and all other PRO 
domains (except for physical functioning) as measured by European Organization for 


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Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) 
and Lung Cancer Module (QLQ-LC13) are also exploratory endpoints in this study.
Section 5.3.5  Pharmacokinetic Variables
Previously read:
Plasma concentrations of rovalpituzumab tesirine ADC as well as the timing and 
incidence of ATAs will be tabulated and summarized.
Has been changed to read:
Serum concentrations of rovalpituzumab tesirine ADC as well as the timing and incidence 
of ATAs will be tabulated and summarized.
Section 5.5.1  Treatments Administered
First paragraph, last sentence previously read:
If the dose of dexamethasone is vomited within 15 minutes of taking the medication, the 
subject should retake the medication.
Has been changed to read:
If the dose of dexamethasone/placebo is vomited within 15 minutes of taking the 
medication, the subject should retake the medication.
Section 5.5.2.1  Packaging and Labeling
Subsection Rovalpituzumab Tesirine and Placebo
Add:  new last sentence
Rova-T drug product is classified as a Dangerous Goods/Hazardous Material and is 
packaged and shipped by AbbVie according to US Department of Transportation (DOT) 
and International Air Transport Association (IATA) certified regulations.


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Section 5.5.2.2  Storage and Disposition of Blinded Investigational Product(s)
Subsection Rovalpituzumab Tesirine/Placebo
Add:  new last sentence
Specific storage conditions for reconstituted and diluted rovalpituzumab tesirine/placebo 
will be provided in a separate document outside of this protocol.
Section 5.5.2.3  Preparation/Reconstitution of Dosage Form(s)
Fourth sentence previously read:
The rovalpituzumab tesirine drug product is dosed based on body weight.  
Has been changed to read:
The rovalpituzumab tesirine drug product is dosed based on actual body weight.  
Section 5.5.2.3  Preparation/Reconstitution of Dosage Form(s)
Add:  new tenth sentence
Specific dose preparation and documentation details will be provided to the site pharmacy 
in a separate document.
Section 5.5.4.1  Dosing
First paragraph
Add:  new last sentence
In cases of weight gain due to fluid retention, dosing should be based on most recent pre-
fluid retention actual weight.
Table 5.  Dose Reductions and Discontinuation for Unacceptable Toxicities
Toxicity "Grade 4 LFTs or Grade 3 LFTs with concomitant Bilirubin Grade 2 or 
higher" previously read:
Grade 4 LFTs or Grade 3 LFTs with concomitant Bilirubin Grade 2 or higher


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Has been changed to read:
Grade 4 LFTs or Grade 3 LFTs with concomitant Bilirubin Grade 2 or higherb
Table 5.  Dose Reductions and Discontinuation for Unacceptable Toxicities
Add:  new toxicity "Grade 2 pneumonitis" and "Grade ≥ 3 pneumonitis"
Grade 2 pneumonitis
Reduce dose to 0.1 mg/kg
Discontinue Rova-T
Grade ≥ 3 pneumonitis
Discontinue Rova-T
N/A
Table 5.  Dose Reductions and Discontinuation for Unacceptable Toxicities
Add:  new footnote "b."
b. If potential DILI is suspected please follow guidelines of Section 6.1.8.3.
Section 5.5.5.2  Blinding of Data for Independent Data Monitoring Committee 
(IDMC)
Last sentence previously read:
Final PFS data with interim OS data will be analyzed and reviewed by the IDMC for 
recommendation.
Has been changed to read:
For the futility analysis, OS, other efficacy and safety data will be analyzed and reviewed 
by the IDMC for recommendation.
Section 5.5.7  Drug Accountability
Fourth paragraph
Add:  new last sentence
Rova-T is classified as a Dangerous Good/Hazardous Material according to US 
Department of Transportation (DOT) and International Air Transport Association (IATA).  


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Dangerous Goods/Hazardous Materials must be packaged and shipped according to 
applicable regulations.
Section 6.1.1.3  Adverse Events Expected Due to SCLC or Progression of SCLC
Last paragraph previously read:
"Disease progression" should not be captured when reporting AEs or SAEs, even if fatal, 
as disease progression is an efficacy endpoint for the trial.  Rather, symptoms of disease 
progression should be reported as AEs or SAEs as appropriate.
Has been changed to read:
Although exempted from expedited reporting to Health Authorities and Institutional 
Review Boards (IRBs) as individual cases, these SAEs must be reported to the Sponsor 
within 24 hours of the site being made aware of the SAE.  
AEs or SAEs should not be reported as "Disease progression," even if fatal, as PD is an 
efficacy endpoint for the study.  Rather, report the specific disease (clinical) manifestation 
of the progression (eg, 'malignant pleural effusion,' 'spinal bone metastases,' 
'lymphadenopathy,' 'brain metastases') or if not possible, report "malignant neoplasm 
progression" as the AE or SAE as appropriate.
Section 6.1.4  Deaths
Second paragraph previously read:
Deaths that occur during the protocol specified AE reporting period (Section 6.1.6) that 
are more likely related to disease progression will therefore be considered as an expected 
AE and will not be subject to expedited reporting.  These events should be captured as 
disease progression and recorded on the AE eCRF.  After the AE reporting period, deaths 
attributed to progression of disease under study should not be recorded on the AE eCRF.


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Has been changed to read:
Deaths that occur during the protocol specified AE reporting period (Section 6.1.6) that 
are more likely related to disease progression will therefore be considered as an expected 
SAE and will not be subject to expedited reporting.  These events should be recorded on 
the AE eCRF as described in Section 6.1.1.3.  After the AE reporting period, deaths 
attributed to progression of disease under study should not be recorded on the AE eCRF.
Section 6.1.5  Adverse Event Collection Period
First paragraph, first sentence previously read:
All adverse events reported from the time of blinded investigational product 
administration until 70 days following discontinuation of blinded investigational product 
administration will be collected, whether solicited or spontaneously reported by the 
subject.  
Has been changed to read:
All adverse events reported from the time of blinded investigational product 
administration until 70 days following the last dose of blinded investigational product will 
be collected, whether solicited or spontaneously reported by the subject.  
Section 6.1.6  Adverse Event Reporting
"Primary Therapeutic Area Medical Director:" previously read:
Therapeutic Area Medical Director
AbbVie
200 Sidney Street
Cambridge, MA 02139
Telephone Contact Information:
Office:
Mobile:
Email:


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Has been changed to read:
Senior Medical Director
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
USA
Telephone Contact Information:
Office:
Mobile:
Email:
Section 6.1.6  Adverse Event Reporting
Fifth paragraph previously read:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure14 and the most 
current version of the Summary of Product Characteristics (SmPC).
Has been changed to read:
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines and Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI).  The RSI in effect at the start of a DSUR reporting 
period serves as the RSI during the reporting period.  For follow-up reports, the RSI in 
place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be used to 
assess expectedness.


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Section 6.1.8.1  Management of Serosal Effusions/Serositis
First paragraph, first sentence previously read:
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).  
Has been changed to read:
Serosal effusions (pleural or pericardial, or ascites) have been observed with 
rovalpituzumab tesirine and have the potential to be life-threatening (e.g., cardiac 
tamponade).  
Section 6.1.8.1  Management of Serosal Effusions/Serositis
First paragraph
Add:  new fifth and sixth sentence
Effusion events were reported during treatment and may occur up to several months after 
last Rova-T dose.  As a result, subjects should be advised of signs and symptoms of fluid 
retention and contact treating physician if they arise during this time.
Section 6.1.8.2  Management of Skin Reactions
Add:  new second paragraph
Photosensitivity reactions may occur hours to days after sun exposure.  Patients should be 
advised to avoid direct and indirect sun exposure as much as possible from Cycle 1 Day 1 
until 30 days after the final dose.  When sun exposure is unavoidable, patients should 
wear protective clothing and sunglasses, and use a broad-spectrum sunscreen and lip balm 
(SPF 30 or greater).  Thirty-one to ninety days after last dose of Rova-T/placebo, the 
patient may resume outdoor activities with appropriate sun protection including broad 
brimmed hat, protective clothing and sunscreen SPF 30 or higher.  Subjects with a grade 3 
photosensitivity reaction should dose reduce Rova-T/placebo to 0.2 mg/kg after the first 
occurrence and following a second grade 3 photosensitivity reaction, reduce Rova-


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T/placebo to 0.1 mg/kg.  Subjects with a grade 4 photosensitivity reaction must 
permanently discontinue Rova-T/placebo.
Section 6.1.8.2  Management of Skin Reactions
Second paragraph previously read:
If clinically consistent with photosensitivity, the AE should be reported as such (using 
medically accurate and descriptive AE terminology), and managed as described below.
Has been changed to read:
If clinically consistent with photosensitivity, the AE should be reported as such (using 
medically accurate and descriptive AE terminology), and managed as described in 
Table 6.
Section 6.1.8.2  Management of Skin Reactions
Third paragraph, first sentence previously read:
Photo-documentation should be available upon request by the TA MD.  
Has been changed to read:
Photo-documentation of skin toxicity should be available upon request by the TA MD.  
Section 6.1.8.4  Monitoring and Management of Edema
Add:  new section title and text
6.1.8.4
Monitoring and Management of Edema
The majority of the edema events with rovalpituzumab tesirine have been reported as low 
grade 1 or 2 (mild or moderate); however, a small number of fatal events of generalized 
edema have been reported with rovalpituzumab tesirine.  Physical exams and monitoring 
of weight gain and signs or symptoms of fluid retention should be conducted during 
treatment.  Edema events were reported during treatment and may occur up to several 


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months after last Rova-T dose.  As a result subjects should be advised of signs and 
symptoms of fluid retention as well as monitor their weight and contact treating physician 
if they arise during this time.
Consistent with institutional guidelines or standard practice, the use of diuretics with or 
without albumin may be considered in subjects with clinically significant edema and 
hypoalbuminemia.  The selection and use of diuretics in subjects should be based on 
individual clinical characteristics and include monitoring of electrolyte status and signs or 
symptoms of intravascular volume depletion such as hypotension and impaired renal 
function. 
Systemic corticosteroids, when initiated promptly, have been reported to be beneficial in 
some prior cases.


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Reported Term
Grade 1
Grade 2
Grade 3
Grade 4
Generalized 
edema 
(Anasarca)
Noted on exam; 
1+ pitting edema
Interfering with 
instrumental ADLs; oral 
therapy initiated
Interferes with 
self care ADL; 
intravenous 
therapy indicated; 
skin breakdown
Life-
threatening 
consequences
Definition:  A disorder characterized by fluid accumulation in the tissues of the body including the skin.
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.
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
Section 6.1.8.5  Pneumonitis
Add:  new section title and text
6.1.8.5
Pneumonitis
Pneumonitis has been infrequently reported with rovalpituzumab tesirine but has resulted 
in fatal outcomes.  Although the causal role of rovalpituzumab tesirine could not be ruled 
out, the reports of pneumonitis had one or more confounders including underlying 
pulmonary disease/cancer, prior thoracic radiation, prior cytotoxic chemotherapy or 
clinical evidence suggestive of an alternative diagnosis including pneumonia. 


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Heavily pretreated SCLC patients and patients with a history of pneumonitis may be at 
increased risk, and careful monitoring for signs and symptoms of pneumonitis is 
important.  The risk of pneumonitis is increased with prior radiation to lung.
In general, signs and symptoms coinciding with or preceding pneumonitis may include 
new or worsening cough, chest pain and/or shortness of breath, fever, and radiographic
changes (reticular markings, ground glass opacities).  Protocol defined disease 
assessments provide the opportunity for on study pulmonary monitoring with "gold 
standard" diagnostic method for detection of pneumonitis.  The protocol allows for 
additional imaging per physician discretion for signs and symptoms of pulmonary 
toxicity.
The diagnosis of drug induced pneumonitis is one of exclusion.  Other etiologies 
including infection, which is a common cause of pulmonary infiltrates with clinical and 
radiographic appearance similar to drug-induced pneumonitis, need to be carefully 
considered and excluded before the diagnosis of drug induced pneumonitis can be 
established. 
If pneumonitis is suspected, close monitoring including additional laboratory and imaging 
investigation per institutional guidelines may be necessary.  Systemic corticosteroids may 
be beneficial for rapidly progressive or more severe pneumonitis.  For events of Grade 1 
pneumonitis close monitoring is recommended; while dose modifications for Grade 2 and 
discontinuation of Rova-T for Grades 3 and 4 are required.  Please see Table 5.


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Section 7.0  Protocol Deviations
Contact Information previously read:
Primary Contact: 
Study Management Associate III
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Office:
Fax:
Email:
Alternate Contact:
Study Project Manager I
AbbVie
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Fax:
Email:
Has been changed to read:
Primary Contact: 
Study Project Manager II
AbbVie Corporation
8401 Trans-Canada Highway
Saint-Laurent, Québec
H4S 1Z1
Canada
Phone:
Fax:
Email:
Alternate Contact:
Study Project Manager I
AbbVie s.r.o.
METRONOM BUSINESS CENTER
Bucharova 2817/13, Stodulky,
158 00 Praha 5
Czech Republic
Phone:
Fax:
Email:
Section 8.1  Statistical and Analytical Plans
Second paragraph previously read:
Two analyses are planned for this study.  The first will be performed when at least 
407 progression-free survival (PFS) events, assessed by a Central Radiographic 


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Assessment Committee (CRAC) according to RECIST v1.1, and at least 239 deaths have 
occurred in subjects with DLL3high.  The second analysis will be performed when at least 
319 deaths have occurred in subjects with DLL3high.
Has been changed to read:
The primary endpoints of OS and progress free survival (PFS) assessed by a Central 
Radiographic Assessment Committee (CRAC) according to RECIST v1.1 in DLL3high
patients will be analyzed at the same time after observing at least 319 OS events.  It is 
expected at approximately 420 PFS events will be observed at the time of the primary 
analysis.
Section 8.1  Statistical and Analytical Plans
First and second bullet previously read:
●
DLL3high Set:  It includes all randomized subjects with DLL3high.  Subjects 
will be classified according to the treatment arm to which they are randomized 
regardless the actual treatment received, following intent-to-treat principle.  
The DLL3high set will be the primary analysis set for the analysis of efficacy 
endpoints.
●
Randomized Set:  It includes all randomized subjects, with subjects grouped 
according to the treatment arm to which they are randomized regardless the 
actual treatment received, following intent-to-treat principle.  The randomized 
set will be used for supportive analysis of efficacy endpoints.


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Has been changed to read:
●
DLL3high Set:  It includes all randomized subjects with DLL3high ED SCLC.  
Subjects will be classified according to the treatment arm to which they are 
randomized regardless the actual treatment received, following intent-to-treat 
principle.  The DLL3high set will be the analysis set for the analysis of the 
primary efficacy endpoints of OS and PFS.  All the exploratory efficacy 
endpoints will be analyzed based on the DLL3high set unless the OS and PFS 
based on the randomized set are statistically significant.
●
Randomized Set:  It includes all randomized subjects, with subjects grouped 
according to the treatment arm to which they are randomized regardless the 
actual treatment received, following intent-to-treat principle.  The randomized 
set will be the analysis set for key secondary efficacy endpoints of OS and 
PFS, and key secondary endpoint of EORTC QLQ-C30 physical functioning 
domain.  All the exploratory efficacy endpoints will be analyzed based on the
randomization set if the OS and PFS based on the randomization set are 
statistically significant.
Section 8.1.3  Efficacy Endpoints and Analyses
Delete:  first sentence
Unless specified otherwise, efficacy analyses will be performed in the DLL3high set.  
Section 8.1.4  Primary Efficacy Endpoints
First paragraph previously read:
Progression-free survival (PFS) and overall survival (OS) are the two primary efficacy 
endpoints.  No order of testing of these two endpoints is specified.
Has been changed to read:
Progression-free survival (PFS) and overall survival (OS) in subjects with DLL3high ED 
SCLC are the two primary efficacy endpoints.


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Section 8.1.4  Primary Efficacy Endpoints
Third paragraph, second sentence previously read:
The hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's 
proportional hazards model stratified by randomization stratification factors.  
Has been changed to read:
The hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's 
proportional hazards regression model adjusting for the main-effects of the stratification 
factors.  
Section 8.1.4  Primary Efficacy Endpoints
Third paragraph, last sentence previously read:
Estimates of the treatment effect will be expressed as hazard ratio including 95% 
confidence intervals estimated through a Cox proportional-hazards analysis stratified by 
randomization stratification factors.
Has been changed to read:
Estimates of the treatment effect will be expressed as hazard ratio including 95% 
confidence intervals estimated through a Cox proportional-hazards regression model 
adjusting for the main-effects of the stratification factors.
Section 8.1.4  Primary Efficacy Endpoints
Last paragraph, third sentence previously read:
The hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's 
proportional hazards model stratified by randomization stratification factors.  


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Has been changed to read:
The hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's 
proportional hazards regression model adjusting for the main-effects of the stratification 
factors.  
Section 8.1.4  Primary Efficacy Endpoints
Last paragraph, last sentence previously read:
Estimates of the treatment effect on will be expressed as hazard ratio including 95% 
confidence intervals estimated through a Cox proportional-hazards analysis stratified by 
randomization stratification factors.
Has been changed to read:
Estimates of the treatment effect on will be expressed as hazard ratio including 95% 
confidence intervals estimated through Cox proportional-hazards regression models 
adjusting for the main-effects of the stratification factors.
Section 8.1.5  Secondary Efficacy Endpoints
Previously read:
8.1.5
Secondary Efficacy Endpoints
The secondary efficacy endpoints in the DLL3high set are: 
●
Objective response rate (ORR) per the CRAC based on RECIST v1.1
●
Change in patient reported outcomes (PROs) – physical functioning domain
●
PFS per investigator assessment based on RECIST v1.1
●
ORR per investigator assessment based on RECIST v1.1
●
Clinical benefit rate (CBR) per the CRAC and investigator assessment, 
respectively, based on RECIST v1.1 
●
Duration of response (DOR) per CRAC and investigator assessment, 
respectively


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The following endpoints in the randomized set are also included in the secondary efficacy 
endpoints:
●
OS
●
PFS per the CRAC based on RECIST v1.1
●
ORR per the CRAC based on RECIST v1.1
Secondary time-to-event endpoints (PFS and OS) will be analyzed using the similar 
statistical methods described for the primary endpoints.  
The duration of overall response for a given subject will be defined as the number of 
months from the day the criteria are met for complete response (CR) or partial response 
(PR) by CRAC (whichever is recorded first) to the date of progressive disease or death, 
whichever comes first.  If a subject is still responding (i.e., has not progressed nor died 
after CR or PR), then the subject's data will be censored at date of the last radiographic 
assessment by CRAC.  For subjects who never experienced CR or PR, these subjects' data 
will not be included in the duration of response analysis.  Distribution of the duration of 
response will be estimated for each treatment arm using Kaplan-Meier methodology.  
Median duration of overall response with corresponding 95% CI for each treatment arm 
will be provided.
ORR and CBR in the treatment arm will be compared using Cochran-Mantel-Haenszel 
test stratified by randomization stratification factors.  Rates and 95% confidence intervals 
will be reported for each treatment arm. 
Has been changed to read:
8.1.5
Secondary Efficacy Endpoints
The secondary efficacy endpoints in the randomized set are: 
●
OS  


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●
PFS per the CRAC based on RECIST v1.1 
●
EORTC QLQ-C30 physical functioning domain 
Secondary time-to-event endpoints (PFS and OS) will be analyzed using the similar 
statistical methods described for the primary endpoints.  
8.1.6
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints in both DLL3high and randomization set are: 
●
Objective response rate (ORR) per the CRAC based on RECIST v1.1
●
PFS per investigator assessment based on RECIST v1.1
●
ORR per investigator assessment based on RECIST v1.1
●
Clinical benefit rate (CBR) per the CRAC and investigator assessment, 
respectively, based on RECIST v1.1 
●
Duration of response (DOR) per CRAC and investigator assessment, 
respectively 
●
Change from baseline in all PRO domains (except physical functioning) 
measured by EORTC QLQ-C30/LC13 and EQ-5D-5L
ORR is defined as the proportion of patients with a best overall response (BOR) of 
confirmed complete response (CR) or partial response (PR) by CRAC review according to 
RECIST v1.1.
CBR is defined as the proportion of patients with a BOR of CR or PR, or SD by CRAC 
review according to RECIST v1.1. 
ORR and CBR in treatment arms will be compared using Cochran-Mantel-Haenszel test 
stratified by randomization stratification factors.  Rates and 95% confidence intervals will 
be reported for each treatment arm. 
The duration of overall response for a given subject will be defined as the number of 
months from the day the criteria are met for confirmed complete response (CR) or partial 


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response (PR) by CRAC (whichever is recorded first) to the date of progressive disease or 
death, whichever comes first.  If a subject is still responding (i.e., has not progressed nor 
died after CR or PR), then the subject's data will be censored at date of the last 
radiographic assessment by CRAC.  For subjects who never experienced CR or PR, these 
subjects' data will not be included in the duration of response analysis.  Distribution of the 
duration of response will be estimated for each treatment arm using Kaplan-Meier 
methodology.  Median duration of overall response with corresponding 95% CI for each 
treatment arm will be provided.
Section 8.1.6  Patient Reported Outcomes (PRO)
First sentence previously read:
Physical functioning scale score in EORTC QLQ-C30 is the primary PRO endpoint.  
Has been changed to read:
Physical functioning scale score in EORTC QLQ-C30 is the key secondary endpoint.  
Section 8.1.7  Planned Sensitivity and Subgroup Analyses
Delete:  first paragraph
Efficacy analyses for PFS per investigator assessment and ORR per investigator 
assessment will be performed in the randomized set.
Section 8.1.7  Planned Sensitivity and Subgroup Analyses
Delete:  third paragraph
The physical functioning scale score (EORTC QLQ-C30) will be evaluated using an 
ANOVA model in the randomized set.


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Section 8.1.7  Planned Sensitivity and Subgroup Analyses
Delete:  last paragraph
In the DLL3high and randomized sets, CRAC assessed ORR will be compared between the 
2 arms, using a chi-square test for each subgroup.  Odds ratios will be presented.
Section 8.1.8  Pharmacokinetic and Exposure-Response Analyses
First paragraph previously read:
Plasma concentrations of rovalpituzumab tesirine ADC as well as the incidence and 
timing of ATA formation will be tabulated and summary statistics will be computed.  
Plasma concentration and ATA data from this study may be combined with data from 
other studies and analyzed using population pharmacokinetic methodologies.
Has been changed to read:
Serum concentrations of rovalpituzumab tesirine ADC as well as the incidence and timing 
of ATA formation will be tabulated and summary statistics will be computed.  Serum 
concentration and ATA data from this study may be combined with data from other 
studies and analyzed using population pharmacokinetic methodologies.
Section 8.3  Type I Error Adjustment Procedure for Multiple Testing
Previously read:
To meet global regulatory requirements, a multiple testing strategy will be implemented to 
control the family-wise type I error (alpha) for comparisons of rovalpituzumab tesirine 
arm versus placebo arm with respect to progression-free survival (PFS) per CRAC, 
overall survival (OS), ORR per CRAC, and physical functioning scale score (EORTC 
QLQ-C30).
The following null hypotheses are considered for subjects with DLL3high:
H1:  Rovalpituzumab tesirine arm is not superior to placebo arm in both PFS and OS. 


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H2:  Rovalpituzumab tesirine arm is not superior to placebo arm in ORR per CRAC.
H3:  Rovalpituzumab tesirine arm is not superior to placebo arm in physical functioning 
scale score (EORTC QLQ-C30).
The null hypotheses will be tested in a fixed sequence of {H1, H2, H3} in order.  To 
maintain the family-wise type I error for the study, the null hypothesis H1 will be first 
tested with an alpha-split approach.  The hypothesis for PFS will be tested at a one-sided 
0.25% level of significance and the hypothesis for OS at a one-sided 2.25% level of 
significance.  If either PFS or OS endpoint reaches statistical significance, the study is 
considered positive.  No further tests will be performed if H1 is not rejected.  Each 
hypothesis of H2 and H3 will be tested in order specified above if H1 is rejected and the 
preceding hypothesis shows statistically significant results at the 1-sided 2.5% level of 
significance.  Otherwise testing in the hierarchical sequence will stop.
The secondary efficacy endpoints, e.g., PFS per investigator assessment, ORR per 
investigator assessment, CBR per CRAC, CBR per investigator assessment, DOR per 
CRAC, DOR per investigator assessment, and PRO evaluations in the DLL3high set will be 
tested at a one-sided 2.5% level of significance.  Similarly, OS, PFS per CRAC, and ORR 
per CRAC in the randomized set will be tested at a one-sided 2.5% level.
Has been changed to read:
To meet global regulatory requirements, a multiple testing strategy will be implemented to 
control the family-wise type I error (alpha) to one-sided 0.025 level for comparisons of 
rovalpituzumab tesirine arm versus placebo arm with respect to progression-free survival 
(PFS) per CRAC in DLL3high set, overall survival (OS) in DLL3high set, PFS per CRAC in 
randomized set, OS in randomized set, and physical functioning scale score (EORTC 
QLQ-C30) in randomized set.
The following null hypotheses are considered:
Two hypotheses in H01 are H01a and H01b.


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H01a:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in 
DLL3high set. 
H01b:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in DLL3high set. 
H02:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in randomized set. 
H03:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in 
randomized set. 
H04:  Rovalpituzumab tesirine arm is not superior to placebo arm in physical functioning 
scale score (EORTC QLQ-C30) in randomized set.
The null hypotheses will be tested in a fixed sequence of {H01a, H01b, H02, H03, and H04} in 
order.  To maintain the family-wise type I error for the study, the null hypotheses in H01
(H01a and H01b) will be first tested with an alpha-split approach.  The one-sided alpha of 
0.25% and 2.25% will be assigned for PFS and OS hypothesis in H01, respectively.  Out of 
one-sided alpha of 2.25% allocated to OS hypothesis (H01b), the one-sided alpha of 10–6
will be spent for the early look at the OS data for futility analysis.  If the hypothesis for 
PFS in H01 (H01a) is rejected the one-sided alpha of 0.25% will be recycled to the OS 
hypothesis in H01 (H01b).  Hence, the hypothesis for OS in H01 (H01b) will be tested either 
at a one-sided 2.4999% or one-sided 2.2499% level of significance depending on the PFS 
hypothesis in H01a is rejected or not. 
If either PFS or OS endpoint reaches statistical significance, the study is considered 
positive.  No further tests will be performed if the OS endpoint in DLL3high population 
(H01b) does not reach statistical significance. 
The hypothesis in H02 will be tested if the hypothesis in H01b is rejected.  If the hypothesis 
in H02 is rejected, then, either (i) H03 and H04 will be tested sequentially if the PFS 
endpoint in DLL3high subjects (H01a) is also rejected or (ii) only H04 will be tested if the 
PFS endpoint in DLL3high subjects (H01a) is not rejected. 


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Diagram of Hierarchical Testing of Primary and Secondary Endpoints is described in 
Figure 3.
Figure 3.
Diagram of Hierarchical Testing of Primary and Secondary 
Endpoints


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Section 8.4  Determination of Sample Size
Previously read:
There are two primary efficacy endpoints for this study:  Progression-free survival (PFS) 
based on the CRAC and overall survival (OS).  To maintain the overall 1-sided type I 
error at a 2.5% for this study, the type I error will be split, assigning 0.25% to 
progression-free survival and the remaining 2.25% to overall survival.  
The sample size of the study is primarily determined by the analysis of OS.  It is assumed, 
taking into account the expected patient population for the study, that median overall 
survival in the placebo arm will be around 9 months.4,5  Based on a log-rank test, at a 
one-sided significance level of 0.0225 and a power of 90%, a total of 319 deaths among 
subjects with DLL3high are needed to detect an increase of median OS to 13 months in 
rovalpituzumab tesirine arm, corresponding to a hazard ratio of 0.69 (i.e., a reduction in 
the hazard death of 31%).  Assuming a 19-month accrual period and the last enrolled 
subject followed for 12 months, at least 480 subjects with DLL3high are expected to be 
randomized (240 subjects in each arm).  A total of 740 subjects regardless of DLL3 
expression level (including 480 subjects with DLL3high) will enroll in the study, assuming 
an approximate prevalence of 65% for subjects with DLL3high.  It is projected that an 
observed hazard ratio of 0.795 or less, corresponding to a 2.3 months or greater 
improvement in median OS, would result in a statistically significant improvement in the 
final analysis of OS.
It is assumed, taking into account the expected patient population for the study, that 
median progression-free survival for the placebo arm will be approximately 3 months.4,5  
Treatment with rovalpituzumab tesirine is hypothesized to increase median progression-
free survival to 4.5 months (i.e., a hazard ratio of 0.667).  With approximately 407 PFS 
events assessed by the CRAC for subjects with DLL3high, the study provides a 90% power 
to detect a hazard ratio of 0.667 in PFS at a one-sided significance level of 0.0025.  It is 
projected that an observed hazard ratio of 0.757 or less, corresponding to approximately 


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1 month or greater improvement in median PFS, would result in a statistically significant 
improvement in the PFS.
The primary analysis of PFS will take place when at least 407 CRAC assessed PFS events 
and at least 239 deaths (an interim efficacy analysis of OS with approximately 75% of 
targeted 319 deaths) have occurred in subjects with DLL3high.  When both conditions 
specified for the numbers of PFS and OS events are satisfied, the primary analysis of PFS 
and the interim efficacy analysis of OS will be performed at the same time.  The final 
analysis of OS is projected to be approximately 31 months from first subject enrolled 
when approximately 319 deaths have occurred in subjects with DLL3high.
Has been changed to read:
There are two primary efficacy endpoints for this study:  Progression-free survival (PFS) 
based on the CRAC and overall survival (OS) in DLL3high ED SCLC patients.  To 
maintain the overall 1-sided type I error at a 2.5% for this study, the type I error will be 
split, assigning 0.25% to progression-free survival and the remaining 2.25% to overall 
survival.  However, the OS endpoint will be tested at a one-sided 2.2499% significance 
level as a one-sided alpha of 10–6 will be spent for the early look at the OS data for futility 
analysis.
The sample size of the study is primarily determined by the analysis of OS.  It is assumed, 
taking into account the expected patient population for the study, that median overall 
survival in the placebo and rovalpituzumab tesirine arm will be around 9 months and 13 
months, respectively.  The increase of median OS in rovalpituzumab tesirine arm 
corresponds to a hazard ratio of 0.69, i.e., a reduction in the hazard of death by 31%.  
With all these assumptions, a total of 319 deaths among subjects with DLL3high are needed 
to achieve a 90% power based on a log-rank test at a one-sided significance level of 
0.022499.  Assuming a 19-month accrual period and the last enrolled subject followed for 
12 months, at least 480 subjects with DLL3high are expected to be randomized 
(240 subjects in each arm).  A total of 740 subjects regardless of DLL3 expression level 
(including 480 subjects with DLL3high) will enroll in the study, assuming an approximate 


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prevalence of 65% for subjects with DLL3high.  For one-sided significance level of 
0.022499, it is projected that an observed hazard ratio of 0.799 or less, corresponding to a 
2.3 months or greater improvement in median OS, would result in a statistically 
significant improvement in the primary analysis of OS.
The primary endpoints of OS and PFS in DLL3high patients will be analyzed at the same 
time after observing at-least 319 OS event.  It is expected at approximately 420 PFS 
events will be observed at the time of the primary analysis.
It is assumed, taking into account the expected patient population for the study, that 
median progression-free survival for the placebo and rovalpituzumab tesirine arm will be 
approximately 3 months and 4.5 months, respectively.  The increase of median 
progression-free survival in rovalpituzumab tesirine arm corresponds to a hazard ratio of 
0.667.  With all these assumptions, a total of approximately 420 PFS events assessed by 
the CRAC for the subjects with DLL3high are needed to achieve a 91% power based on a 
log-rank test at a one-sided significance level of 0.0025.  It is projected that an observed 
hazard ratio of 0.760 or less, corresponding to approximately 1 month or greater 
improvement in median PFS, would result in a statistically significant improvement in the 
PFS.
Section 8.5  Interim Analysis
Section title and text previously read:
8.5
Interim Analysis
An interim efficacy analysis is planned for overall survival after at least 239 deaths in 
subjects with DLL3high (i.e., 75% of planned deaths are observed) using a one-sided log-
rank test.  
The O'Brien-Fleming method will be implemented to protect the type I error rate of 
0.0225 for OS.  A one-sided alpha spending of 0.0084 for the interim will be allocated for 
declaring statistical superiority in OS at the time of the interim analysis.  The final 
analysis of OS will be performed at a one-sided nominal alpha level of 0.01998, adjusting 


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for the interim look at OS data.  If the interim analysis of OS meets the O'Brien-Fleming 
boundary for statistical significance, the final OS analysis will be considered descriptive.
Unblinded interim data will be analyzed and reviewed by the IDMC.  The trial may be
considered for early stopping for superiority and the Sponsor will be unblinded to the 
aggregated data by randomized treatment arms if the IDMC makes such a 
recommendation after consideration of the PFS and OS results, and all supportive 
evidence including other efficacy endpoints and safety.
In the event that the IDMC recommends continuing the study due to lack of evidence for 
superiority, the unblinded interim results will be kept confidential to the investigators, 
subjects, sponsors, and personnel involved in the conduct of the study until the end of the 
study, since the final analyses of OS and all other endpoints will be performed in an 
inferentially seamless manner.  Subjects already enrolled in the study will continue 
rovalpituzumab tesirine or placebo treatment in a blinded fashion to obtain more mature 
OS data for a robust characterization of treatment effect.  
Details for the interim efficacy analysis will be provided in the IDMC charter.
Has been changed to read:
8.5
Futility Analysis
A futility analysis will be conducted when approximately 160 deaths in subjects with 
DLL3high ED SCLC (approximately 50% of the planned deaths) are observed.  The trial 
may be stopped for futility if the estimated Overall Survival Cox HR of Rova-T to 
Placebo in the DLL3high set at futility analysis exceeds 0.9.  The one-sided alpha of 10–6
will be spent for the early look at the efficacy data for futility analysis.
Unblinded interim data will be analyzed and reviewed by the IDMC.  The trial may be 
considered for early stopping for futility and the Sponsor will be unblinded to the 
aggregated data by randomized treatment arms if the IDMC makes such a 


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recommendation after consideration of the OS results and other supportive evidence 
including other relevant efficacy and safety data.
Details for the futility analysis will be provided in the IDMC charter.
Section 8.6  Accrual/Study Duration Considerations
Last sentence previously read:
It is projected that 480 subjects with DLL3high will have enrolled for the interim analysis 
by the time at least 407 PFS events per CRAC and at least 239 OS events should be 
observed in subjects with DLL3high, and subjects have completed approximately 5 months 
of follow-up.  
Has been changed to read:
It is projected that 480 subjects with DLL3high ED SCLC will have enrolled for the 
primary analysis by the time approximately 420 PFS events per CRAC and at least 319 
OS events should be observed in DLL3high subjects after approximately 8 - 10 months of 
follow-up.
Section 10.1  Source Documents
First paragraph, fourth and fifth sentence previously read:
The Investigator Awareness Date (SAE CRF) may serve as the source for this data point.  
This adverse event data point required for eCRF completion can be entered directly in the 
eCRF.
Has been changed to read:
The Investigator Awareness Date of SAE should be noted in the source.


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Section 15.0  References
Add:  new Reference 19
AbbVie.  Rovalpituzumab Tesirine Dear Rova-T Investigator Letter.  05 December 2018.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Pharmacokinetics
Clinical Drug Supply Management
Statistics
Bioanalysis
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Pharmacokinetics
Clinical Drug Supply Management
Statistics
Bioanalysis


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Appendix C.  Study Activities
Category "Echocardiogramn" previously read:
Category
Description
Screening
Treatment (Each Cycle)
Non-Treatment 
Cycle Visita
End of 
Treatmentb
PTFUc
Survival 
FU 
(OS)d
Day –21 to
Day –1
Day
–1
Day 1e
(–3d)
Day 
2
Day 
8
Day 
15
Day 22 
(–3d)
Day 
29
Day 
36
Day 1
(±3d)
Weekly
(Day 8, 15, 22, 
29, 36)
(±3d)
Within 7 Days 
of Decision to 
Discontinue 
Treatment
q6 
Weeks 
(±1wk)
q6
Weeks 
(±1wk)
Safety 
Assessments
Echocardiogramn
X
X
Has been changed to read:
Category
Description
Screening
Treatment (Each Cycle)
Non-Treatment 
Cycle Visita
End of 
Treatmentb
PTFUc
Survival 
FU 
(OS)d
Day –21 to
Day –1
Day
–1
Day 1e
(–3d)
Day 
2
Day 
8
Day 
15
Day 22 
(–3d)
Day 
29
Day 
36
Day 1
(±3d)
Weekly
(Day 8, 15, 22, 
29, 36)
(±3d)
Within 7 Days 
of Decision to 
Discontinue 
Treatment
q6 
Weeks 
(±1wk)
q6
Weeks 
(±1wk)
Safety 
Assessments
Echocardiogramn
X
X
X


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Appendix C.  Study Activities
Table note "b." previously read:
End of Treatment Visit occurs within 7 days of documentation of the decision to 
discontinue treatment and prior to subjects beginning any new anti-cancer therapy if 
possible.
Has been changed to read:
End of Treatment Visit procedures should be done within 7 days of documentation of the 
decision to discontinue treatment and prior to subjects beginning any new anti-cancer 
therapy if possible.
Appendix C.  Study Activities
Table note "e.," first sentence previously read:
Cycle 1 Day 1 procedures do not need to be repeated if performed within 21 days of 
randomization unless clinically indicated.  
Has been changed to read:
Cycle 1 Day 1 procedures, with the exception of weight, do not need to be repeated if 
performed within 21 days of randomization unless clinically indicated.  
Appendix C.  Study Activities
Table note "n." previously read:
Echocardiogram will be performed to assess any pericardial effusion, if present, as well as 
cardiac function (left ventricular ejection fraction, LVEF).
Has been changed to read:
Echocardiograms are required at Screening, Day 1 of each cycle starting C2D1, and EOT.  
Screening echocardiogram will be performed within 7 business days of randomization to 


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assess for the presence of any pericardial effusion as well as cardiac function (left 
ventricular ejection fraction, LVEF). Subsequent echocardiograms should be performed 
within –3 business days of dosing visit to assess for the presence of any pericardial 
effusion.  Additional echocardiogram monitoring may occur as clinically indicated during 
the study.
Appendix C.  Study Activities
Table note "q.," seventh sentence previously read:
Scheduled tumor assessments will not be affected by delays in therapy and/or drug 
holidays.  
Has been changed to read:
Whenever possible, scheduled tumor assessments should not be affected by delays in 
therapy and/or drug holidays.  In some cases, mandatory dose delays due to toxicity will 
lead to a gap between tumor assessment and dosing.  In cases where this gap exceeds 
1 week, the TAMD should be contacted for guidance.
Appendix C.  Study Activities
Table note "t." previously read:
MRI/CT of the brain is only required at screening and when clinically indicated (e.g., if 
CNS progression is suspected).
Has been changed to read:
MRI/CT of the brain is required at screening and when clinically indicated (e.g., if CNS 
progression is suspected) thereafter.

SAP_001.pdf: 
Rovalpituzumab Tesirine
M16-298 (MERU) – Statistical Analysis Plan
Version 1.0 – 29 May 2019
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1.0
Title Page
Statistical Analysis Plan
Study M16-298
A Randomized, Double-Blind, Placebo-Controlled 
Phase 3 Study of Rovalpituzumab Tesirine as 
Maintenance Therapy Following First-Line Platinum 
Based Chemotherapy in Subjects with Extensive 
Stage Small Cell Lung Cancer (MERU)
Date:  29 May 2019
Version 1.0
NCT03033511


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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................4
4.0
Study Objectives and Design..................................................4
4.1
Objectives ..................................................................................................4
4.2
Design Diagram .........................................................................................5
4.3
Randomization and Stratification...............................................................6
4.4
Sample Size................................................................................................7
4.5
Independent Data Monitoring Committee (IDMC) ...................................8
4.6
Planned Analyses .......................................................................................8
4.6.1
Futility Analysis.........................................................................................8
4.6.2
Final Analysis ............................................................................................9
4.7
Type I Error Adjustment Procedures for Multiple Testing........................9
5.0
Analysis Sets...........................................................................12
6.0
Analysis Conventions ............................................................14
6.1
Dealing with Multiple Values on the Same Day......................................14
6.2
Definition of Baseline..............................................................................14
6.3
Definition of Final Observation...............................................................14
6.4
Missing Data ............................................................................................15
6.5
Definition of Study Days and Rx Days....................................................15
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications, and 
Prior Oncology Therapies.....................................................17
7.1
Demographic and Baseline Characteristics .............................................17
7.2
Medical History .......................................................................................18
7.3
Prior and Concomitant Medications ........................................................19
7.4
Prior Anti-Cancer Therapy and Surgery..................................................20
8.0
Subject Disposition................................................................20
9.0
Study Drug Exposure............................................................20
10.0
Efficacy Analysis....................................................................22
10.1
General Considerations............................................................................22


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10.1.1
Statistical Analysis Methods....................................................................22
10.2
Efficacy Endpoints and Analyses ............................................................25
10.2.1
Primary Efficacy Endpoints.....................................................................25
10.2.2
Secondary Efficacy Endpoints.................................................................27
10.2.3
Exploratory Efficacy Endpoints...............................................................27
10.3
Sensitivity Analyses.................................................................................33
10.4
Subgroup Analyses ..................................................................................34
11.0
Safety Analysis.......................................................................35
11.1
General Considerations............................................................................35
11.2
Analysis of Adverse Events.....................................................................36
11.3
Adverse Events of Special Interest (AESIs) ............................................37
11.4
Listing of Adverse Events........................................................................41
11.5
Analysis of Laboratory, Vital Signs, and ECG Data ...............................41
11.6
Analysis of ECOG Performance Status ...................................................43
11.7
Analysis of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values...................................................................43
12.0
References...............................................................................44
List of Tables
Table 1.
Visit Window for Laboratory#, Vital Sign Assessments and 
Physical Examination...............................................................................16
Table 2.
Visit Window for Coagulations Tests and Patient Reported 
Outcomes (PRO)......................................................................................17
Table 3.
Adverse Events of Special Interest ..........................................................38
Table 4.
Clinical Laboratory Tests.........................................................................43
List of Figures
Figure 1.
Study Schema.............................................................................................6
Figure 2.
Diagram of Hierarchical Testing of Primary and Secondary 
Endpoints1................................................................................................12


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3.0
Introduction
This statistical analysis plan (SAP) describes the detailed statistical methods for the 
analysis of efficacy and safety data collected in Study M16-298 (MERU) as outlined in 
the protocol for Study M16-298 Amendment 4 dated March 05, 2019 and will describe 
analysis conventions to guide the statistical programming work.
Efficacy and safety analyses will be performed using SAS Version 9.3 or higher (SAS 
Institute, Inc., Cary, NC  27513) under the UNIX operating system.  The SAP will be 
finalized before the study database is unblinded.
4.0
Study Objectives and Design
4.1
Objectives
Primary Objective
●
To evaluate if rovalpituzumab tesirine improves progression-free survival 
assessed by CRAC, and overall survival in subjects with extensive-stage 
SCLC with a high level of DLL3 expression (DLL3high) who have ongoing 
clinical benefit (SD, PR, or CR) following the completion of 4 cycles of 
first line, platinum-based chemotherapy (cisplatin or carboplatin plus 
irinotecan or etoposide) compared to placebo.
Secondary objectives 
●
To evaluate if rovalpituzumab tesirine improves progression-free survival by 
CRAC and overall survival in all randomized subjects compared to placebo.
●
To assess change in patient reported outcomes (PRO) with physical 
functioning as measured by the EORTC QLQ-C30 questionnaire in all 
randomized subjects compared to placebo.


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Exploratory objectives: 
●
To evaluate rovalpituzumab tesirine anti-tumor activity by determining 
objective response rate (ORR), clinical benefit rate (CBR), and duration of 
responses (DOR) by CRAC and investigator assessment in DLL3high and in all 
randomized subjects.
●
To evaluate if rovalpituzumab tesirine improves progression-free survival by 
investigator assessment in DLL3high and in all randomized subjects.
●
To assess change from baseline in all patient reported outcomes (PRO) 
domains measured by EORTC QLQ-C-30 (except physical functioning), 
EORTC-QLQ-LC-13, and EQ-5D-5L in DLL3high and in all randomized 
subjects. 
4.2
Design Diagram
This is a Phase 3, randomized, double-blinded, placebo-controlled, multinational, and 
multicenter study comparing the efficacy and safety of rovalpituzumab tesirine to placebo 
in subjects with extensive-stage SCLC with a high level of DLL3 expression (DLL3high) 
as well as in any subjects with extensive-stage SCLC.  
Eligible subjects will be randomly assigned in a 1:1 ratio to receive 0.3 mg/kg 
rovalpituzumab tesirine or matching placebo, and will receive their assigned therapy on 
Day 1 of each 6-week cycle, omitting every third cycle.  Subjects will also receive 8 mg 
orally (PO) of dexamethasone or matching placebo twice daily on Day –1, Day 1 (the day 
of dosing), and Day 2 of each 6-week cycle in which rovalpituzumab tesirine/placebo is 
administered.  Subjects will be stratified by RECIST v1.1 response after completion of 
first-line platinum-based chemotherapy at screening assessment (SD vs. PR/CR), DLL3 
expression (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or above), history of 
central nervous system (CNS) metastases (Yes vs. No), and for subjects with no history of 
CNS metastases, PCI vs. no PCI.  Survival Follow-up will continue until the endpoint of 
death, the subject becomes lost to follow-up or withdraws consent or termination of the 
study by AbbVie, whichever occurs first.


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A schematic of the study is provided in Figure 1, Study Schema.
Figure 1.
Study Schema
Arrowheads = blinded investigational product administration; CR = complete response; OS = overall survival; 
PR = partial response; PTFU = post-treatment follow-up; SD = stable disease
1.
Upon completion of first-line platinum-based chemotherapy, eligible subjects must be offered prophylactic cranial 
irradiation (PCI), if offering this procedure is not contradictory to country or institutional guidelines.  Subjects 
receiving PCI must complete it prior to randomization into the study.
2.
Collection of tumor material for DLL3 testing will be provided any time after the signing of the informed consent 
and prior to randomization.
3.
At least 3 but no more than 9 weeks between the administration of the last cycle of platinum-based chemotherapy 
and randomization.
4.3
Randomization and Stratification
All subjects in the study will be randomized using an IRT system.  The site will contact 
the IRT to obtain a Screening (subject) number once the subject has signed the informed 
consent.  Once the screening number is assigned, if the subject is not eligible to be 
randomized into the study, the reason for screen failure will be documented in the source 
document and in the eCRF.  For others, the site will access the system and a unique 
randomization number will be provided.
The IRT will randomize subjects in a 1:1 ratio to the rovalpituzumab tesirine treatment 
arm or to the placebo arm.  The stratification factors used for the randomization should be 
the last values on or prior to the date of randomization.


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The stratification factors are:
●
RECIST v1.1 response after completion of first-line platinum-based therapy at 
screening assessment (SD vs. PR/CR),
●
DLL3 expression (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or 
above), 
●
History of CNS metastases (Yes vs. No), 
●
For subjects with no history of CNS metastases, PCI vs. no PCI. 
4.4
Sample Size
There are two primary efficacy endpoints for this study:  Progression-free survival (PFS) 
based on the CRAC and overall survival (OS) in DLL3high ED SCLC subjects.  To 
maintain the overall 1-sided type I error rate at a 2.5% for this study, the type I error will 
be split, assigning 0.25% to progression-free survival and the remaining 2.25% to overall 
survival.  However, the OS endpoint will be tested as a one-sided 2.2499% significance 
level as a one-sided alpha of 10–6 will be spent for the early look at the OS data for futility 
analysis.
Sample size of the study is primarily determined by the analysis of OS.  It is assumed, 
taking into account the expected patient population for the study, that median overall 
survival in the placebo and rovalpituzumab tesirine arm will be around 9 months and 
13 months, respectively.  The increase of median OS in rovalpituzumab tesirine arm 
corresponds to a hazard ratio of 0.69, i.e., a reduction in the hazard of death by 31%.  
With all these assumptions, a total of 319 deaths among subjects with DLL3high are 
needed to achieve 90% power based on a log-rank test at a one-sided significance level of 
0.022499.  Assuming a 19-month accrual period and the last enrolled subject followed for 
12 months, at least 480 subjects with DLL3high are expected to be randomized 
(240 subjects in each arm).  A total of 740 subjects regardless of DLL3 expression level 
(including 480 subjects with DLL3high) will enroll in the study, assuming an approximate 
prevalence of 65% for subjects with DLL3high. 


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The primary endpoints of OS and PFS will be analyzed at the same time after observing at 
least 319 OS events in subjects with DLL3high.  It is expected that approximately 420 PFS 
events assessed by the CRAC will be observed at the time of the primary analysis.
It is assumed, taking into account the expected patient population for the study, that 
median progression-free survival for the placebo and rovalpituzumab tesirine arm will be 
approximately 3 months and 4.5 months, respectively.  The increase of median 
progression-free survival in rovalpituzumab tesirine arm corresponds to a hazard ratio of 
0.667.  With all these assumptions, a total of approximately 420 PFS events assessed by 
the CRAC for the subjects with DLL3high are needed to achieve 91% power based on a 
log-rank test at a one-sided significance level of 0.0025. 
4.5
Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will be formed and constituted 
according to appropriate regulatory guidelines.  The IDMC will review unblinded data 
from the study with respect to subject accrual, pretreatment characteristics of accrued 
subjects, the frequency and severity of toxicities and morbidity, and provide 
recommendations according to the charter.  Detailed information regarding the 
composition of the committee and procedures including frequency of meetings and scope 
of reviews will be documented in a separate charter.  
4.6
Planned Analyses 
4.6.1
Futility Analysis
A futility analysis will be conducted when approximately 160 deaths in subjects with 
DLL3high ED SCLC (i.e., 50% of planned deaths) are observed.  
The trial may be stopped for futility if the estimated Overall Survival (OS) hazard ratio of 
rovalpituzumab tesirine to placebo using Cox proportional-hazard regression model 
adjusting for randomization stratification factors exceeds 0.9.  A one-sided alpha of 10–6
will be spent for the futility analysis for the early look at OS data.  


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Unblinded interim data will be analyzed and reviewed by the IDMC.  The trial may be 
considered for early stopping for futility and the Sponsor will be unblinded to the 
aggregated data by randomized treatment arms if the IDMC makes such a 
recommendation after consideration of the OS results, and other supportive evidence 
including other relevant efficacy and safety data. 
In the event that the IDMC recommends continuing the study due to lack of evidence for 
futility, the unblinded interim results will be kept confidential to the investigators, 
subjects, sponsors, and personnel involved in the conduct of the study until the end of the 
study, since the final analyses of OS and all other endpoints will be performed in an 
inferentially seamless manner.  Subjects already enrolled in the study will continue 
rovalpituzumab tesirine or placebo treatment in a blinded fashion to obtain more mature 
OS data for a robust characterization of treatment effect.  
Details for the futility analysis will be provided in the IDMC charter.
4.6.2
Final Analysis
The final analysis will be performed when at least 319 deaths have observed in DLL3high
subjects.  It is projected that 420 PFS events assessed by CRAC would be observed in 
DLL3high subjects at the time of the final analysis.
4.7
Type I Error Adjustment Procedures for Multiple Testing
To meet global regulatory requirements, a multiple testing strategy will be implemented to 
control the family-wise type I error (alpha) for comparisons of rovalpituzumab tesirine 
arm versus placebo arm with respect to progression-free survival (PFS) per CRAC in 
DLL3high Set, overall survival (OS) in DLL3high Set, PFS per CRAC in Randomized Set, 
OS in Randomized Set, and physical functioning scale score (EORTC QLQ-C30) in 
Randomized Set. 


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The following null hypotheses are considered:
H01a:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in 
DLL3high Set. 
H01b:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in DLL3high
Set. 
H02:  Rovalpituzumab tesirine arm is not superior to placebo arm in OS in 
Randomized Set.
H03:  Rovalpituzumab tesirine arm is not superior to placebo arm in PFS per CRAC in 
Randomized Set.
H04:  Rovalpituzumab tesirine arm is not superior to placebo arm in physical 
functioning scale score (EORTC QLQ-C30) in Randomized Set.
The null hypotheses will be tested in a fixed sequence of {H01a, H01b, H02, H03, and H04} in 
order.  To maintain the family-wise type I error rate for the primary endpoints at 2.5%, the 
null hypotheses in H01 (H01a and H01b) will be first tested with an alpha-split approach.  
The one-sided alpha of 0.25% and 2.25% will be assigned to PFS and OS hypotheses in 
H01, respectively.  Out of the one-sided alpha of 2.25% allocated to OS hypothesis (H01b), 
the one-sided alpha of 10–6 will be spent for the early look at the OS data for futility 
analysis.  If the hypothesis for PFS in H01 (H01a) is rejected, the one-sided alpha of 0.25% 
will be recycled to the OS hypothesis in H01 (H01b).  Hence, the OS hypothesis in H01
(H01b) will be tested either at a one-sided 2.4999% or one-sided 2.2499% alpha level of 
significance depending on the PFS in H01 (H01a) is rejected or not.
If either PFS or OS endpoint reaches statistical significance, the study is considered 
positive.  No further tests will be performed if OS hypothesis in H01 (H01b) does not reach 
statistical significance.  


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The hypothesis in H02 will be tested if the hypothesis in H01b is rejected.  If the hypothesis 
in H02 is rejected, then, either (i) H03 and H04 will be sequentially tested if the PFS 
endpoint in DLL3high Set (H01a) shows statistical significance; or (ii) only H04 will be 
tested if the PFS endpoint in DLL3high Set (H01a) is not rejected.
Diagram of Hierarchical Testing of Primary and Secondary Endpoints is in Figure 2.


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Figure 2.
Diagram of Hierarchical Testing of Primary and Secondary 
Endpoints1
5.0
Analysis Sets
The following analysis sets will be used for analysis of safety and efficacy endpoints of 
the study.


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DLL3high Set will comprise all randomized subjects with DLL3high.  Subjects with 
unknown DLL3 status based on the sample collected at the time or before randomization 
be excluded.  Subjects will be classified according to the treatment arm to which they are 
randomized regardless the actual treatment received, following intent-to-treat principle.  
The DLL3high Set will be the primary analysis set for the analysis of efficacy endpoints of 
OS and PFS.  All the exploratory efficacy endpoints will be analyzed based on the 
DLL3high Set unless the OS and PFS based on the Randomized Set are statistically 
significant.
Randomized Set will comprise all randomized subjects, with subjects grouped according 
to the treatment arm to which they are randomized regardless the actual treatment 
received, following intent-to-treat principle.  The randomized set will be the analysis set 
for secondary efficacy endpoints of OS and PFS, and secondary endpoint of EORTC 
QLQ-C30 physical functioning domain.  All the exploratory efficacy endpoints will be 
analyzed based on the Randomized Set if the OS and PFS based on the Randomized Set 
are statistically significant.
Per Protocol Set (PPS) will comprise all subjects in the randomized set without any 
major protocol violations which may affect the evaluation of the primary efficacy 
endpoint.  
Subjects meeting any of the following criteria will be excluded or censored from PPS: 
●
Those entered into the study even though did not satisfy the entry criteria
●
Those who developed withdrawal criteria during the study but were not 
withdrawn will be censored when they develop the withdrawal criteria 
●
Those who received the wrong treatment
●
Those who received an excluded concomitant treatment
●
Those who were randomized but did not receive any dose of study medication.
Subjects will be classified according to treatment assigned at the time of randomization.  
The Per Protocol Set will be used for supportive analysis of efficacy endpoints.


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Safety Set will comprise all subjects who receive at least one dose of study drug and 
subjects will be classified according to treatment received.  Thus a subject who is 
randomized to the rovalpituzumab tesirine arm but does not receive rovalpituzumab 
tesirine will be considered in the placebo arm for safety analysis.  Dexamethasone 
treatment will not be taken into consideration for subjects' classification in the Safety set.
6.0
Analysis Conventions
This section provides general considerations for data handling, summary, and analysis.  
Continuous variables will be summarized by sample size (N), mean, standard deviation 
(St. Dev.), median, minimum, and maximum.  Frequency and percentage will be provided 
for categorical variables and 95% confidence intervals (CIs) will be generated for 
parameter estimates of interest, unless specified otherwise.
6.1
Dealing with Multiple Values on the Same Day
In cases where multiple values are collected on the same day at baseline or post-baseline 
visit, either the arithmetic average (e.g., for continuous summary) or worst value (e.g., for 
shift tables) will be used for further analyses. 
6.2
Definition of Baseline
Unless otherwise specified, the baseline observation is defined as the last non-missing 
measurement collected prior to or on the first dose date of blinded investigational product 
(rovalpituzumab tesirine or matching placebo; dexamethasone or matching placebo).
6.3
Definition of Final Observation
For lab and vital sign parameters, the final observation is defined as the last non-missing 
post-baseline measurement collected not more than 70 days after the last dose of study 
drug. 


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6.4
Missing Data
No missing data imputation will be implemented, unless specified otherwise.
6.5
Definition of Study Days and Rx Days
Study Day of any observation is defined for post-randomization observations as: 
Study Day = Date of observation – Date of randomization + 1,
and for observations pre-dating randomization as:
Study Day = Date of observation – Date of randomization.
Thus, the day of randomization is defined as Study Day 1, while the day prior to the 
randomization is defined as Study Day –1 (there is no Study Day 0).
Study Rx Day of any post-baseline observation is defined as the number of days from the 
day of the first dose of any study drug (rovalpituzumab tesirine, Dexamethasone, 
matching placebo) to the date of observation.  It is calculated for each post-treatment 
observation as follows:
Study Rx Day = Date of observation – Date of first dose of any study drug + 1
Definition of Analysis Windows
During the treatment period, all time points and corresponding time windows are based on 
Study Rx Days, unless specified otherwise.  For longitudinal analyses, especially for the 
laboratory data (hematology, chemistry, and urinalysis), the time windows specified 
below describe how data collected at protocol specified visits will be assigned to.  If more 
than one observation is included in a time window, the observation closest to the nominal 
day should be used.  If there are two observations equally distant to the nominal day, the 
later one will be used in analyses.


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Table 1.
Visit Window for Laboratory#, Vital Sign Assessments and Physical 
Examination
Study Visit (Week)*
Nominal Study Rx Day
Time Window (Study Rx Days Range)
Baseline
1
≤ 1
3
22
2 to ≤ 32
6
43
33 to ≤ 53
9
64
54 to ≤ 74
12
85
75 to ≤ 106
18
127
107 to ≤ 137
21
148
138 to ≤ 158
24
169
159 to ≤ 179
27
190
180 to ≤ 200
30
211
201 to ≤ 232
…
…
…
…
…
…
18•X
7•18•X + 1
7•18•X - 19 to ≤ 7•18•X + 11
18•X + 3
7• (18•X + 3) + 1
7•18•X + 12 to ≤ 7•(18•X + 3) + 11
18•X + 6
7• (18•X + 6) + 1
7•(18•X + 3) + 12 to ≤ 7•(18•X + 6) + 11
18•X + 9
7• (18•X + 9) + 1
7•(18•X +6) + 12 to ≤ 7•(18•X + 9) + 11
18•X + 12
7• (18•X + 12) + 1
7•(18•X +9) + 12 to ≤ 7•(18•X + 12) + 22
…
…
…
#
laboratory tests include hematology, serum chemistry and urinalysis.
*
Every third cycle (6-week cycle) treatment will be omitted.


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Table 2.
Visit Window for Coagulations Tests and Patient Reported 
Outcomes (PRO)
Study Visit (Week)*
Nominal Study Rx Day
Time Window (Study Rx Days Range)
Baseline
1
≤ 1
6
43
2 to ≤ 64
12
85
65 to ≤ 106
18
127
107 to ≤ 148
24
169
149 to ≤ 190
30
211
191 to ≤ 232
…
…
…
…
…
…
6•X
7•6•X + 1
7•6•X + 1 - 20 to ≤ 7•6•X + 1 + 21
…
…
…
*
Every third cycle (6-week cycle) treatment will be omitted. 
Coagulation tests are performed at screening visit, first day of each cycle, and end of treatment visit.
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications, and 
Prior Oncology Therapies
Data for demographic, baseline characteristics, medical/surgical history, 
previous/concomitant medications and prior oncological procedures will be summarized 
for each treatment arm and overall on both the DLL3high Set and Randomized Set.
7.1
Demographic and Baseline Characteristics
The following demographic, current disease history and baseline disease characteristics 
(including stratification variables) will be summarized by treatment groups.


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Demographic variable
Baseline disease characteristics
•
Age
•
Weight
•
Sex 
•
Race (White, Black or African American, 
Asian, American Indian or Alaskan Native, 
Native Hawaiian or Pacific Islander)
•
Ethnicity (Hispanic or Latino, Not Hispanic 
or Latino, Other)
•
Age 
o
< 40, 40 - < 65, ≥ 65 yr
•
History of tobacco product use and alcohol 
use (current, former, never, unknown)
•
Region of the world (North America, Asia, 
Europe, Rest of the world)
•
TNM staging at the start of the FL treatment
•
RECIST v1.1 response after completion of 
first line platinum-based therapy at screening 
assessment (SD, CR/PR) 
•
History of CNS metastases (Yes, No)
•
PCI status (PCI, No PCI, NA)
•
DLL3 expression level (unknown, < 25%, 
25% - < 75%, ≥ 75%)
•
ECOG performance score 
•
LDH:  ≤ ULN vs. > ULN
Baseline disease status
•
Time from initial diagnosis to start of 
randomization
•
Time from most recent prior cancer therapy 
(as defined by C4D1 in the frontline platinum 
therapy) to randomization
•
Number of metastatic sites, 0 – 1 vs. > 1
Continuous data (e.g., age, height, and weight) will be summarized with N, mean, 
standard deviation (St. Dev.), median, minimum, and maximum.  Frequencies and 
percentages will be computed for the categorical variables. 
There will be no statistical comparison for demographic and baseline measurements.
7.2
Medical History
Medical history data will be summarized and presented using conditions/diagnoses as 
captured on the eCRF.  The conditions/diagnoses will be presented in alphabetical order.  
The number and percentage of subjects with a particular condition/diagnosis will be 
summarized for each treatment arm.  Subjects reporting more than 
one condition/diagnosis will be counted only once for that condition/diagnosis.  There 
will be no statistical comparison for the medical history between treatment arms.


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7.3
Prior and Concomitant Medications 
A prior medication is defined as any medication with start date prior to the date of 
randomization and collected on the electronic case report forms (eCRFs).  A concomitant 
medication is defined as any drug that taken on the day of or after randomization, but not 
70 days after the last study drug administration (rovalpituzumab tesirine or matching 
placebo; dexamethasone or matching placebo) regardless of the start and stop date.  
Medications taken on the day of the first dose of study drug are counted as concomitant 
medications.  
For reporting purpose, the following conservative approach will be followed for 
determination of prior and concomitant medication:
Start date
End date
Prior to Study Day 1 
Prior to Study Day 1
Prior medication
Missing
Prior to Study Day 1
Prior medication
Prior to Study Day 1
Study Day 1 to Last dose + 70 day
Both prior medication and 
concomitant medication
Study Day 1 to Last dose + 70 day
Study Day 1 to Last dose + 70 day
Concomitant medication
Missing 
Study Day 1 to Last dose + 70 day
Concomitant medication
Study Day 1 to Last dose + 70 day
Missing
Concomitant medication
Missing
Missing
Concomitant medication
The frequency and percentage of subjects who took at least one dose of medication other 
than study drug (rovalpituzumab tesirine and dexamethasone) will be summarized by the 
anatomical therapeutic chemical (ATC) codes in the World Health Organization (WHO)
Drug dictionary.  Prior and concomitant medications will be summarized separately.  
A similar summary will be prepared for prior medications.  
There will be no statistical comparison for the prior and concomitant medications between 
treatment arms.


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7.4
Prior Anti-Cancer Therapy and Surgery
For each prior anti-cancer therapy/surgery, the frequency and percentage of subjects who 
had the prior anti-cancer therapy/surgery will be provided.  In addition, the number of 
cycles and treatment duration will be summarized for prior anti-cancer therapy.
There will be no statistical comparison for prior anti-cancer treatment/surgery between 
treatment arms.
8.0
Subject Disposition
Subject disposition (number and percentage of subjects) will be presented on all subjects 
who are screened by investigator site and overall.  The following information will be 
presented:
●
Subjects who were screened
●
Subjects who screen failed
●
Subjects who were randomized
●
Randomized subjects who were DLL3high
●
Subjects who were included in the Per Protocol Set
●
Subjects who took at least 1 dose of blinded study drug
●
Subjects who discontinued the study drug (by primary reason and by any 
reason)
●
Subjects who discontinued the study (by primary reason and by any reason)
Primary and all reasons for study drug discontinuation will be summarized by each of 
rovalpituzumab tesirine and dexamethasone.
No statistical tests will be performed.
9.0
Study Drug Exposure 
Analyses for rovalpituzumab tesirine exposure will be performed on the Safety Set. 


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Duration of rovalpituzumab tesirine treatment, defined as the total number of weeks a 
subject received rovalpituzumab tesirine, accounting for (1) study drug was administered 
on Day 1 of each 6-week cycle, and (2) every 3rd cycle was omitted:
Treatment cycle #*
Duration of Rova-T 
treatment (weeks)
Theoretical duration of 
Rova-T treatment (weeks)
Planned dose 
(mg/kg)
1 + 3 × X†
(Date of last dose – date of 
first dose + 42)/7
6 × (1 + 3 × X)
0.3 + 0.6 × X
2 + 3 × X
(Date of last dose – date of 
first dose + 84)/7
6 × 3 × (1 + X)
0.6 × (1 + X)
*
The last treatment cycle that subject received non-zero dose of Rova-T.
†
X = 0, 1, 2, … corresponding to Cycle 1, 2, 4, 5….
Summary statistics for duration of rovalpituzumab tesirine treatment will be presented by 
treatment arm for the following categories:  < = 6 weeks, 6 to < = 18 weeks, 18 to 
≤24 weeks, 24 to ≤ 36 weeks, etc.
Cumulative dose, defined as the sum of the doses (mg/kg) administered to a subject 
during the treatment period, and will be summarized by N, mean, standard deviation (St. 
Dev.), median, minimum, and maximum.  Summary statistics for average dose 
administered by treatment arm will be presented at each cycle.  
Dose intensity (mg/kg/week), defined as the ratio of the total dose received to the total 
duration of exposure.
ܦܫ௢௕௦௘௥௩௘ௗൌ
ܥݑ݉ݑ݈ܽݐ݅ݒ݁ ݀݋ݏ݁ ሺ݉݃/݇݃ሻ
ܦݑݎܽݐ݅݋݊ ݋݂ ݐݎ݁ܽݐ݉݁݊ݐ ሺݓ݁݁݇ݏሻ
Relative dose intensity 1 (RDI1) is calculated as the ratio of observed dose intensity to the 
theoretical dose intensity indicated in the protocol, expressed in percent (%).  
ܦܫ௣௥௢௧௢௖௢௟ൌ 
݈ܲܽ݊݊݁݀ ݀݋ݏ݁ ൬݉݃
݇݃൰
݄ܶ݁݋ݎ݁ݐ݈݅ܿܽ ݀ݑݎܽݐ݅݋݊ ݋݂ ݐݎ݁ܽݐ݉݁݊ݐ ሺݓ݁݁݇ݏሻ
ܴܦܫଵሺ%ሻൌ ܦܫ௢௕௦௘௥௩௘ௗ
ܦܫ௣௥௢௧௢௖௢௟
 ൈ100


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Relative dose intensity 2 (RDI2) is calculated as the ratio of cumulative dose to the 
planned dose indicated in the protocol, expressed in percent (%).  
ܴܦܫଶሺ%ሻൌ ܥݑ݉ݑ݈ܽݐ݅ݒ݁ ݀݋ݏ݁ ሺ݉݃/݇݃ሻ
݈ܲܽ݊݊݁݀ ݀݋ݏ݁ ሺ݉݃/݇݃ሻ
 ൈ100
Summary statistics for RDI1 and RDI2 will be presented.  The number of subjects in the 
following categories (e.g., RDI < 70%, 70% to < 90%, 90% to < 110%, 110% to < 120%, 
120% or higher) will also be presented.
10.0
Efficacy Analysis
10.1
General Considerations
Efficacy endpoints of response and progression used in analyses per Central Radiographic 
Assessment Committee (CRAC) and investigator assessment will be based RECIST v1.1.  
For subjects whose tumor meets the criteria of complete or partial response (CR or PR), 
tumor response must be confirmed by repeated assessments.  Disease progression will be 
defined as radiographic progression of disease. 
The statistical comparisons for the primary and secondary endpoints will be done 
according to the multiplicity adjustment plan described in Section 4.7 to preserve the 
familywise one-sided type 1 error rate to 2.5%.  The statistical comparisons for all the 
exploratory efficacy endpoints will be performed at a nominal one-sided 
2.5% significance level.  Confidence intervals for parameters (e.g., median survival times, 
HR) will be constructed with 2-sided 95% confidence level, whenever applicable.  No 
type I error adjustment for multiple comparisons will be carried out for these exploratory 
endpoints.
10.1.1
Statistical Analysis Methods 
Time-to-Event Endpoints
All time to event (TTE) endpoints are defined using a time variable and an event 
indicator.  All TTE efficacy endpoints in this study are concerned with only the 


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first occurrence of the event of interest, all recurrence of the same event is not considered 
for endpoint derivation or analysis.  An event however may be defined in a composite 
manner, i.e., as the occurrence of one among several different outcomes.  The composite 
event is observed when at least one of the component events occurs, and the time to the 
earliest among the occurring component events is considered to be the TTE for the 
composite event.
The time variable will be computed in days and converted into months (1 month = 
30.4375 days).  Thus, for subjects who experience the event of interest, time to event will 
be defined as the time from randomization to the first occurrence of the event.  When 
multiple assessments are needed to ascertain the occurrence of an event, the earliest date 
among all of these assessments is taken to be date of the event or censoring.  For a subject 
who does not experience an event on the study, time will be right censored at the time of 
his last available adequate post-baseline assessment that rules out the occurrence of the 
event.  If a subject had no post-baseline assessment and did not experience the event of 
interest, then TTE will be censored at the date of randomization and we will set TTE = 1 
day, by convention.
Follow-up time for TTE endpoints will be derived as follows: 
TTE = Date of first occurrence of an event or censoring – date of randomization + 1.
TTE endpoints will be summarized by number of events observed, number of subjects 
censored, and times corresponding to 25% (1st quartile), 50% (median) and 75% 
(3rd quartile) event probabilities.  Kaplan-Meier (KM) estimates will be calculated and 
plotted.  Comparison between treatment arms will be based on stratified log-rank tests as 
specified. 
A Cox proportional-hazards regression model with the treatment group and stratification 
factors as covariates will be used to estimate the hazard ratio (HR) of rovalpituzumab 
tesirine to placebo and its two-sided 95% confidence interval (CI).2,3  Only the main 
effects of the stratification variables will be fitted.


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In the presence of sparse strata that could potentially lead to biased treatment effect 
estimation and/or model convergence issue, the following modified stratification factors 
would be used:
●
RECIST v1.1 response after completion of first-line platinum-based therapy at 
screening assessment (SD vs. PR/CR),
●
DLL3 expression (Unknown or 0% to < 75% vs. 75% or above), 
●
History of CNS metastases (Yes vs. No), 
●
For subjects with no history of CNS metastases, PCI vs. no PCI. 
In cases the treatment effect estimation and/or model convergence issues persist with 
above modified stratification factors, and RECIST v1.1 response after completion of 
first-line platinum-based therapy has been confirmed not prognostic of disease outcome, 
this factor could be removed from both stratified log-rank test and Cox proportional 
hazards model.
Measure of treatment effects will be provided in terms of HR (rovalpituzumab tesirine to 
Topotecan) from the above model with HR value less than 1 representing treatment 
benefit.  
Continuous Variables and Changes from Baseline
Summary of continuous endpoints at baseline, post-baseline and change from baseline (as 
available) will be provided by treatment arms.  Change from baseline values will be 
analyzed using an analysis of covariance (ANCOVA) model including stratification 
factors and baseline as covariates and 95% CI for treatment group difference will be 
provided.  For change from baseline analysis of PROs, patients with missing baseline 
value will be excluded.  These summaries will also be further broken down by individual 
levels of each stratification factors.


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Categorical Variables and Response Rates in the Study
Summary of categorical endpoints (e.g., frequency, percentage) will be provided by 
treatment arms.  The response rates in treatment arms will be compared using Cochran-
Mantel-Haenszel test stratified by randomization stratification factors.  Rates and 95% 
confidence intervals will be reported for each treatment arm.
Stratification Factors Used in Statistical Tests and Models
Since approximately 75% of subjects enrolled are expected to have DLL3 expression 
≥75%, very sparse data is expected in the three remaining strata for DLL3 expression 
(namely, Unknown, 0% to < 25% and 25% to < 75%) that can lead to loss of power for 
the stratified log rank test, Cochran-Mantel-Haenszel test, ANCOVA, and result in 
instability and biases in estimation of parameters of the Cox regression model. 
Hence, all categories of DLL3 expression < 75% or unknown will be combined into one 
category for analysis.  If a statistical estimation procedure does not converge even after 
simplification of the DLL3 expression-based stratification, additional variable selection 
methods will be employed based on univariate assessment of the prognostic importance of 
individual factors on the associated endpoint (using an ad hoc p-value threshold of 0.2) 
and consideration of pairwise correlations between factors.  If statistical models, tests and 
estimation remain unstable after the previous step or no other factors can be dropped from 
analysis, an unstratified analysis will be performed.
10.2
Efficacy Endpoints and Analyses
10.2.1
Primary Efficacy Endpoints
The primary efficacy endpoints are:
●
Progression-free survival (PFS) determined by the CRAC 
●
Overall survival (OS)


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Progression Free Survival (PFS)
PFS will be defined as the number of months from randomization to disease progression, 
as assessed by the CRAC per RECIST v1.1, or death of any cause, whichever occurs first.  
Any death that occurs > 12 weeks (two consecutive missing scans) after the previous 
radiographic disease assessment, or any PD or death happened after the initiation of new 
anti-cancer therapy will be excluded disregarded from the analysis.  Subject without an 
event will be censored at the last date of post-baseline radiographic assessment.  Subject 
with no post-baseline assessment and did not experience death event within 12 weeks of 
randomization will be censored at the date of randomization. 
Differences between the treatment arm and the placebo arm in PFS will be assessed by a 
log-rank test stratified by the randomization stratification factors, testing the null 
hypothesis (rovalpituzumab tesirine arm is not superior to placebo arm in PFS).  The 
hazard ratio of the treatment arm over the placebo arm will be calculated by a Cox's 
proportional hazards regression model adjusting for the main-effects of the stratification 
factors.  Median PFS and 95% confidence intervals will be estimated using Kaplan-Meier 
survival methodology, with the Kaplan-Meier survival curves presented to provide a 
visual description.  PFS rates at 3, 6, 9, and 12 months after randomization with 95% 
confidence intervals will be reported.  Estimates of the treatment effect will be expressed 
as hazard ratio including 95% confidence intervals estimated through a Cox proportional-
hazards regression model adjusting for the main-effects of the stratification factors.  The
same methodology will be applied to PFS based on investigator assessment.
Overall Survival (OS)
OS is defined as time from the randomization to death due to any cause.  For subjects who 
are alive at the end of this study, OS will be right-censored on the last date the subject is 
known to be alive.
Differences between the treatment arm and the placebo arm in OS will be assessed by a 
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hypothesis (rovalpituzumab tesirine arm is not superior to placebo arm in OS).  The 
hazard ratios of the treatment arm over the placebo arm will be calculated by a Cox's 
proportional hazards regression model adjusting for the main-effects of the stratification 
factors.  Median OS and 95% confidence intervals will be estimated using Kaplan-Meier 
survival methodology, with the Kaplan-Meier survival curves presented to provide a 
visual description.  OS rate at 6, 12, 18, and 24 months and corresponding 95% 
confidence intervals will be reported.  Estimates of the treatment effect on will be 
expressed as hazard ratio including 95% confidence intervals estimated through Cox 
proportional-hazards regression models adjusting for the main-effects of the stratification 
factors.
10.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints in Randomized Set are: 
●
OS
●
PFS determined by the CRAC 
●
EORTC QLQ-C30 physical functioning domain
OS in the Randomized Set and PFS by CRAC in Randomized Set will be analyzed using 
similar statistical methods described for the primary endpoints.
Change from baseline of the items and domains of the EORTC QLQ-C30 physical 
functioning domain will be summarized by treatment arm.  The treatment group 
differences will be evaluated by analyzing the change from baseline using the analysis of 
covariance (ANCOVA) model.  Detailed scoring methods are provided in Section 10.2.3.
10.2.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints in both DLL3high Set and Randomized Set are:
●
Objective Response Rate (ORR) per CRAC  
●
PFS per investigator assessment 
●
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●
Clinical Benefit Rate (CBR) per CRAC and investigator assessment, 
respectively 
●
Duration of Response (DOR) per CRAC and investigator assessment, 
respectively 
●
Change from baseline in all PRO domains (except physical functioning) 
measured by EORTC QLQ-C30/LC13 and EQ-5D-5L.
Objective Response Rate (ORR)
ORR is defined as the proportion of patients with a best overall response (BOR) of 
confirmed complete response (CR) or confirmed partial response (PR) by CRAC review 
according to RECIST v1.1. 
All subjects with measurable disease who were randomized regardless of whether they 
had any post-baseline assessment will be included in the analysis.  Any subject who did 
not meet confirmed CR or PR criteria, including those who did not have post-baseline 
radiological assessments will be considered as non-responder.
ORR in treatment arms will be compared using Cochran-Mantel-Haenszel test stratified 
by randomization stratification factors.  Rates and 95% confidence intervals will be 
reported for each treatment arm.
Similarly, analysis of ORR assessed by investigator will be performed.
Clinical Benefit Rate (CBR)
CBR is defined as the proportion of patients with a BOR of CR or PR, or stable disease 
(SD) by CRAC review according to RECIST v1.1.
All subjects with measurable disease who were randomized regardless of whether they 
had any post-baseline assessment will be included in the analysis.  Any subject who did 
not meet CR, PR, or SD criteria, including those who did not have post-baseline 
radiological assessments will be considered as having no clinical benefit.


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The same methodology as for the analysis of ORR will be applied.  Similarly, analysis of 
CBR assessed by investigator will be performed as well.
Similarly, analysis of CBR assessed by investigator will be performed.
Duration of Response (DOR)
The duration of response (DOR) for a given subject will be defined as the number of 
months from the day the criteria are met for confirmed complete response (CR) or partial 
response (PR) by CRAC (whichever is recorded first) to the date of progressive disease or 
death, whichever occurs first.  If a subject is still responding (i.e., has not progressed nor 
died after CR or PR), then the subject's data will be censored at date of the last 
radiographic assessment by CRAC.  For subjects who never experienced CR or PR, these 
subjects' data will not be included in the DOR analysis.  Distribution of the DOR will be 
estimated for each treatment arm using Kaplan-Meier methodology.  Median DOR with 
corresponding 95% CI for each treatment arm will be provided.
The same methodology will be applied to analysis of the duration of response per 
investigator assessment.
Patients Reported Outcomes (PRO)
PRO assessments are performed at screening, Cycle 2 Day 1 only, the first Non-Treatment 
cycle, end of treatment (EOT), and post-treatment follow-up visits (if applicable).  The 
EORTC QLQ-C30/LC13 scoring manual will be used to transform the raw scores into the 
domain scores (global heath, functional scales, symptom scales/items).  Change from 
baseline of the items and domains of the EORTC QLQ-C30/LC13 will be summarized by 
treatment arm.  The EQ-5D-5L manual and the published weights will be used to convert 
the individual items to the utility scores.  Change from baseline of the EQ-5D-5L utility 
score and VAS will be summarized by treatment arm.  The treatment group differences 
will be evaluated by analyzing the change from baseline using the analysis of covariance 
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The EORTC QLQ-C30 is composed of global health status/QoL scale; five functional 
scales (physical, role, emotional, cognitive, and social); three symptom scales (fatigue, 
nausea and vomiting, and pain); and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties).4
EORTC QLQ-C30
Item (Question) Numbers
Item Range*
Global health status/QoL
Global health status/QoL
29, 30
6
Functional scales
Physical functioning
1, 2, 3, 4, 5
3
Role functioning
6, 7
3
Emotional functioning
21, 22, 23, 24
3
Cognitive functioning
20, 25
3
Social functioning
26, 27
3
Symptom scales/Items
Fatigue
10, 12, 18
3
Nausea and vomiting
14, 15
3
Pain
9, 19
3
Dyspnea
8
3
Insomnia
11
3
Appetite loss
13
3
Constipation
16
3
Diarrhea
17
3
Financial difficulties
28
*
Item range is the difference between the possible maximum and the minimum responses to individual items; most 
items take values from 1 to 4, giving range = 3.
The lung cancer module (QLQ-LC13) is meant for use among lung cancer subjects in 
parallel with the core QLQ-C30.  It is composed of one multi-item scale to assess 
dyspnea, and a serious of single items assessing coughing, sore mouth, dysphagia, 
peripheral neuropathy, alopecia, hemoptysis, and pain.


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QLQ-LC13
Item (Question) Numbers
Item Range*
Symptom scales/items
Dyspnea
3, 4, 5
3
Coughing
1
3
Hemoptysis
2
3
Sore mouth
6
3
Dysphagia
7
3
Peripheral neuropathy
8
3
Alopecia
9
3
Pain in chest
10
3
Pain in arm or shoulder
11
3
Pain in other parts
12
3
Pain medication
13
3
*
Item range is the difference between the possible maximum and the minimum responses to individual items.
All scales and single items are reported on categorical responses and will be linearly 
converted to 0 through 100 numeric values.  Given a scale, the raw score (RS) is 
computed as the mean of component items over the number of items answered for that 
scale.  Then the scale score (SS) will be computed as following.
For Global health status/QoL, and Symptom scales/Items,
SS = {(RS - 1)/range}•100.
For Functional scales,
SS = {1 - (RS - 1)/range}•100.
If 50% or more of the items are answered for a given scale, the scale score will be 
computed as described above.  If not, the scale score will not be computed.  For example, 
physical functioning contains 5 items (questions 1 through 5), and the scale score is 
calculated if at least 3 of the items are answered.  For single-item measures (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties), none of the 


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single-item measures can be computed if not answered.  If a scale score cannot be 
computed, the outcome for that score is left blank.  
The scoring approach for the QLQ-LC13 is identical in principle to that for the symptom 
scales/single items of the EORTC QLQ-C30.   
For each scale, the treatment group differences will be evaluated by analyzing the change 
from baseline each of the post-baseline assessments and to the final measurement (last 
PRO assessment per subject) using the analysis of covariance (ANCOVA) model.  Simple 
summary statistics for QoL assessments at each timepoint will also be presented. 
Changes in QoL scores at the scale level or at the domain level per time point will be 
evaluated by classifying them according to the 10-point change threshold into 
3 categories:5
●
Improved is defined as a 10 point or more improvement (i.e., increase for 
functional scales and decrease for symptom scales) from baseline.
●
Stable is defined as a less than 10 point change from baseline.
●
Deteriorated is defined as a 10 point or more deterioration (i.e., decrease for 
functional scales and increase for symptom scales) from baseline.  Subjects 
without a valid QoL outcome will be considered as having deteriorated.  
The EuroQol 5 Dimensions 5 Level (EQ-5D-5L) is a preference based measure of health 
status that consists of EQ-5D descriptive system and EQ visual analogue scale (VAS).  
The EQ-5D descriptive system comprises the following 5 dimensions:  mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression.  Each of the dimensions is 
divided into 5 levels of perceived problems:  Level 1 (indicating no problem), Level 2 
(indicating slight problems), Level 3 (indicating moderate problems), Level 4 (indicating 
severe problems), and Level 5 (indicating extreme problems).  EQ-5D-5L health status, 
defined by the EQ-5D-5L descriptive system, will be converted into a single preference –
weighted health status or "utility" index score by applying country-specific weights (if 


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available) or U.S. weights (if not available).  If country is not available in the look-up 
table, then weights based on the United States will be applied.
The EQ VAS records the respondent's self-rated health on a visual analogue scale (0 to
100).  The VAS score will be measured separately.
The analyses will be performed in the DLL3high and randomized sets.  Mean change from 
baseline in EQ-5D-5L "utility" index score to each applicable post-baseline time point, 
and to the final measurement will be presented by treatment arm.  The treatment group 
difference will be evaluated by analyzing the change from baseline using the analysis of 
covariance (ANCOVA) model.  The same methodology will apply to the mean change 
from baseline in VAS score.
10.3
Sensitivity Analyses
Efficacy analyses for the primary endpoints (PFS per CRAC and OS) will be performed in 
the Per Protocol Set.
Two sensitivity analyses will be carried out for PFS endpoint by implementing different 
censoring rules in the definition of PFS (i.e., modified PFS endpoint).  These sensitivity 
analyses will be conducted in either DLL3high Set or Randomized Set. 
Sensitivity analysis 1:  PFS will be defined as the number of months from randomization 
to disease progression, as assessed by the CRAC per RECIST v1.1, or death of any cause, 
whichever occurs first.  Subjects without an event will be right-censored at the date of last 
follow up for disease progression.  Patients with no post baseline follow up for 
progression and who doesn't experience a death event will be censored at the day of 
randomization.
Sensitivity analysis 2:  PFS will be defined as the number of months from randomization 
to disease progression, as assessed by the CRAC per RECIST v1.1, or death of any cause, 
whichever occurs first. Subjects with 2 or more consecutive missed assessments 
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event (i.e., progression or death) will be considered progressed at the planned date of the 
earliest missed scan date (i.e., last scan date prior to event + 6 weeks).  Subjects without 
an event or receives new anti-cancer therapy will be right-censored at the date of last 
follow up for disease progression.
10.4
Subgroup Analyses
In the DLL3high or randomized sets, treatment effects for the primary endpoints (PFS per 
CRAC and OS) will be assessed in the following subgroups:
●
RECIST v1.1 response after completion of first-line platinum-based therapy at
screening assessment (SD vs. PR/CR)
●
DLL3 expression (Unknown vs. 0% to < 25% vs. 25% to < 75% vs. 75% or
above) for the randomized set only
●
History of CNS metastases (Yes vs. No)
●
For subjects with no history of CNS metastases, PCI vs. No PCI
●
Lactate dehydrogenase (LDH), ≤ ULN vs. > ULN
●
Number of metastatic sites, 0 – 1 vs. > 1
●
Age group (age < 40 vs. 40 to < 65 vs. 65 or older)
●
Gender
●
Race
●
ECOG (0 vs. 1)
The relationship between DLL3 expression level and outcome measures of OS and PFS 
by CRAC will be explored using additional subgroup analysis, as well as by multivariable 
Cox's model. 
Differences between rovalpituzumab tesirine arm and the placebo arm for time-to-event 
endpoints will be assessed by an unstratified log-rank test for each subgroup.  Hazard 
ratios of treatment arm over the placebo arm will be calculated by a Cox's model.


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11.0
Safety Analysis
11.1
General Considerations
Unless otherwise specified, safety analyses will be performed on the Safety Set.  No 
statistical comparisons will be performed between arms.  No p-values and CIs will be 
provided.
Unless specified, all summaries/analyses involving AEs will only include treatment-
emergent adverse events (TEAEs).  TEAEs are defined as any adverse event with onset or 
increase severity after the first dose of study drug (rovalpituzumab tesirine or matching 
placebo; dexamethasone or matching placebo) and no more than 70 days after the last 
dose of study drug administration.  AEs where the onset date is the same as the study drug 
start date are assumed to be treatment-emergent, unless the study drug start time and the 
AE start time are collected and the AE start time is prior to the study drug start time.  If an 
incomplete onset date was collected for an AE, the AE will be assumed to be treatment-
emergent unless there is evidence that confirms that the AE was not treatment-emergent 
(e.g., the AE end date was prior to the date of the first dose of study drug).
Adverse events will be coded and summarized by system organ class and preferred term 
(and severity) according to the Medical Dictionary for Regulatory Activities (MedDRA) 
version 21.0 or higher.  The table of clinical toxicity grades modified from the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.0 will be used in the grading of adverse events and laboratory abnormalities that 
are reported as adverse events.
Summary of continuous safety endpoints (e.g., change from baseline values in laboratory 
values, vital signs parameters) will include the mean, standard deviation, median and 
range.  In the context of change from baseline analyses, summary of baseline and post-
baseline data will also be provided.  Categorical safety endpoints (e.g., incidence of AEs 
or clinically significant ECG values) will be summarized using frequencies and 
percentages.  All the analyses will be carried out by treatment group.


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Unscheduled assessment will not be included in the summary of change from baseline, 
but will be included in producing shift tables and summary of lab abnormalities.
11.2
Analysis of Adverse Events
The number and percentage of subjects having treatment-emergent adverse events will be 
tabulated by MedDRA system organ class (SOC) and preferred term (PT) for each 
treatment group.  Subjects reporting more than one adverse event for a given MedDRA 
PT will be counted only once for that term.  Subjects reporting more than one type of 
adverse event within a MedDRA SOC will be counted only once for that SOC.  Subjects 
reporting more than one type of adverse event will be counted only once in the overall 
total.
The tabulations will also be provided with further breakdowns by maximum severity per 
NCI CTCAE v4.0 grade.  If a subject has an AE with unknown severity, then the subject 
will be counted in the severity category of "unknown," unless the subject does not have 
another occurrence of the same AE with a severity present.  If a subject has multiple 
occurrences of an AE with the same organ class and preferred term, the most severe event 
will be presented.
Adverse events possibly related to study drug (rovalpituzumab tesirine or dexamethasone) 
as assessed by the investigator in each treatment arm.  If a subject has an AE with 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," unless the subject does not have another occurrence of the same AE with a 
relationship present.
Serious adverse events, adverse events leading to dose reduction, discontinuation of 
treatment, and adverse events leading to death will be summarized. 
An overview of AEs will be presented, by treatment arm and overall, consisting of the 
number and percentage of subjects experiencing the following adverse event categories:
●
Any treatment-emergent adverse event


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●
Any treatment-emergent adverse event NCI toxicity grade 3 or 4 
●
Any treatment-emergent adverse event that is rated as a reasonable possibility 
of being related to study drug
●
Any treatment-emergent adverse event NCI toxicity grade 3 or 4 that is rated 
as a reasonable possibility of being related to study drug
●
Any treatment-emergent serious adverse event 
●
Any treatment-emergent serious adverse event NCI toxicity grade 3 or 4 
●
Any treatment-emergent serious adverse event that is rated as a reasonable 
possibility of being related to study drug
●
Any treatment-emergent adverse event leading to discontinuation of
rovalpituzumab tesirine 
●
Any treatment-emergent adverse event leading to delay/interruption of 
rovalpituzumab tesirine
●
Any treatment-emergent adverse event leading to reduction of rovalpituzumab 
tesirine
●
Any treatment-emergent adverse event leading to death
●
Any treatment-emergent adverse event leading to death that is rated as a 
reasonable possibility of being related to study drug
●
Any treatment-emergent serious adverse event leading to discontinuation of 
rovalpituzumab tesirine 
●
Any treatment-emergent serious adverse event leading to delay/interruption of 
rovalpituzumab tesirine
●
Any treatment-emergent serious adverse event leading to reduction of 
rovalpituzumab tesirine
●
Any treatment-emergent serious adverse event leading to death
11.3
Adverse Events of Special Interest (AESIs)
Treatment-emergent AESIs, including important identified risks and potential risks, will 
be identified by the search criteria provided in Table 3.


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Table 3.
Adverse Events of Special Interest
Adverse Events of 
Special Interest
MedDRA Search Criteria/Codes
important identified risks
Pleural Effusion
PTs:
10035598 Pleural Effusion 
10003522 Aspiration Pleural Cavity 10063045 Effusion
Pericardial Effusion
PTs:
10034474 Pericardial Effusion 
10007610 Cardiac Tamponade 
10034471 Pericardial Drainage 
10063045 Effusion
Generalized Edema
PT 10018092 Generalised Oedema
Photosensitivity 
Reaction
PT 10034972 Photosensitivity Reaction
Important Potential Risks
Pneumonitis
PTs:
10035742 Pneumonitis 
10035745 Pneumonitis Chemical 
10037765 Radiation Pneumonitis
10066728 Acute Interstitial Pneumonitis
10022611 Interstitial Lung Disease


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Table 3.
Adverse Events of Special Interest (Continued)
Adverse Events of 
Special Interest
MedDRA Search Criteria/Codes
important identified risks
Pleural Effusion
PTs:
10035598 Pleural Effusion 
10003522 Aspiration Pleural Cavity 10063045 Effusion
Pericardial Effusion
PTs:
10034474 Pericardial Effusion 
10007610 Cardiac Tamponade 
10034471 Pericardial Drainage 
10063045 Effusion
Generalized Edema
PT 10018092 Generalised Oedema
Photosensitivity 
Reaction
PT 10034972 Photosensitivity Reaction
Important Potential Risks
Pneumonitis
PTs:
10035742 Pneumonitis 
10035745 Pneumonitis Chemical 
10037765 Radiation Pneumonitis
10066728 Acute Interstitial Pneumonitis
10022611 Interstitial Lung Disease
Other AESIs
Anemia
SMQ 20000029: Haematopoietic Erythropenia (broad)
Neutropenia
SMQ 20000030: Haematopoietic Leukopenia (broad)
Infusion-Related 
Reaction
10051792 Infusion related reaction
Thrombocytopenia
SMQ 20000031 Haematopoietic Thrombocytopenia (broad)
Haemorrhages
SMQ 20000039 Haemorrhage Terms (Excluding Laboratory
Terms; narrow)
Hypoalbuminemia
PTs:
10020942 Hypoalbuminaemia 
10005287 Blood Albumin Decreased 
10005286 Blood Albumin Abnormal


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Table 3.
Adverse Events of Special Interest (Continued)
Adverse Events of 
Special Interest
MedDRA Search Criteria/Codes
Other AESIs
Cutaneous Reaction
SOC 10040785 Skin and Subcutaneous Tissue Disorders
The observed TEAEs under this SOC will be medically adjudicated to maintain a list of 
PTs that are not medically relevant and that will be excluded from the analysis.
Current list of PTs to exclude: 
10001760 Alopecia
10002424 Angioedema
10011985 Decubitus Ulcer 
10014080 Ecchymosis 
10020642 Hyperhidrosis 
10051235 Madarosis 
10070533 Nail Bed Disorder 
10028694 Nail Disorder 
10062283 Nail Ridging 
10028692 Nail Discolouration 
10029410 Night Sweats 
10034754 Petechiae 
10037087 Pruritus
10052576 Pruritus generalised
10037549 Purpura 
10042682 Swelling Face
Edema
PTs:
10030095 Oedema
10030124 Oedema Peripheral 
10048961 Localised Oedema 
10018092 Generalised Oedema 
10042674 Swelling
10016807 Fluid Retention
10016803 Fluid Overload 
10024770 Local Swelling 
10048959 Peripheral Swelling
10007196 Capillary Leak Syndrome
10015993 Eyelid Oedema 
10016029 Face Oedema 
10052139 Eye Oedema 
10034545 Periorbital Oedema
Hepatotoxicity
SMQs:
20000007 Drug-Related Hepatic Disorders (severe events only; broad)
20000009 Cholestastis and Jaundice of Hepatic Origin (broad)
20000008 Liver Related Investigations, Signs and Symptoms (broad)
Exclude PT 10020942 Hypoalbuminaemia from this search since hypoalbuminemia is 
associated with chronic liver disease and therefore not included in AESI


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Time to onset
Time to onset is the Rx Day of the start date of the first occurrence of AESI.  If a subject 
has not experienced an AESI, the subject will be censored on the day of the subject's last 
assessment (i.e., the day of the subject's last known laboratory assessment, last known 
vital sign assessment, last known physical exam, last known tumor assessment, or last 
known follow-up visit, whichever is the latest) or 70 days from the last study drug 
administered, whichever is earliest; if the subject has not experienced an AESI and had no 
post-baseline assessment (i.e., none of laboratory assessment, vital sign assessment, 
physical exam, or tumor assessment), the subject will be censored on the day of the 
subject's first study drug.
Median onset time will be estimated using a Kaplan-Meier method with corresponding 
95% CI for the median for each treatment arm. 
11.4
Listing of Adverse Events
The following additional summaries of adverse events will be provided:
●
Listing of treatment-emergent serious adverse events
●
Listing of treatment-emergent adverse events that lead to discontinuation of 
study drug
●
Listing of treatment-emergent fatal adverse events
●
Listing of Grade 3 or higher adverse events
●
Listings of SAEs leading to death
●
Listings of SAEs leading to treatment discontinuation.
11.5
Analysis of Laboratory, Vital Signs, and ECG Data
Clinical laboratory variables are listed in Table 4.
For laboratory (hematology, chemistry, urinalysis, and coagulation), vital signs, and ECG 
parameters, changes from baseline are analyzed for each post-baseline visit (as specified 


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in Section 6.0 Analysis of Conventions) and the final visit.  If more than one measurement 
exists for a subject on a particular day, an arithmetic average will be calculated and 
considered to be the subject's measurement of that day.  
Descriptive statistics will be presented for baseline, each post-baseline, and the final visit 
(the last valid record) by each treatment arm.  Mean change from baseline to each post 
baseline visit, and to the final visit within each treatment arm will also be presented.  The 
highest and lowest values of each parameter will be identified for each subject, and 
descriptive statistics for mean change from baseline within each treatment arm will be 
presented.
Laboratory grade determinations will be categorized according to NCI CTCAE version 
4.0 grades, and shifts from baseline grades to maximum and final post-baseline grades 
will be assessed.  The baseline and final grades will be defined respectively as the grade 
of the last measurement collected prior to or on the first dose of study drug, and as the 
grade of the last post-baseline measurement collected no more than 70 days after the last 
dose of study drug.  Frequency and percentage of subjects will be presented by treatment 
arm:  1) baseline grade vs. maximum post-baseline grades, and 2) baseline grade vs. final 
post-baseline grade.  Frequency and percentage of subjects experiencing a shift from 
baseline grades of 0 to 2 to maximum post-baseline grades of 3 to 4, and from baseline 
grades of 0 to 2 to final post-baseline grades of 3 to 4 will be presented by treatment arm.
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 biochemistry 
and hematology values will be provided.  All measurements collected, regardless of the 
number of days after the last dose of study drug, will be included in these listings.  A 
listing will be provided for out-of-normal range as well as clinically significant abnormal 
lab values.
Descriptive summary statistics for categorical ECG status data will be presented for 
baseline and post-baseline visits.  Shift tables will also be provided.


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Table 4.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis (Dipstick)
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils 
Bands (if indicated)
Lymphocytes
Monocytes
Basophils (if indicated)
Eosinophils (if indicated) 
Platelet count (estimate not
acceptable)
Mean corpuscular volume
Mean corpuscular hemoglobin 
concentration
RBC distribution width
Blood urea nitrogen (BUN)
Serum creatinine
Total bilirubin
Serum glutamic-pyruvic
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Total protein
Glucose
Albumin
Magnesium
Chloride
Amylase
Lipase
Lactate dehydrogenase (LDH)
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocyte esterase
Coagulation
Serum Pregnancy Test
Activated Partial
Thromboplastin Time
(aPTT)
Prothrombin time (PT)
International Normalized Ratio
(INR)
Beta-Human Chorionic 
Gonadotropin (β-hCG) (if 
applicable)
Follicle-stimulating hormone 
(FSH) (if applicable)
11.6
Analysis of ECOG Performance Status
ECOG performance status will be summarized for each visit by treatment arm.  Shifts 
from baseline to the best and worst post-baseline score will be tabulated.
11.7
Analysis of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Vital signs values will be assessed for potential clinical significance through the 
application of criteria developed by the sponsor as detailed in the table below.


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Systolic Blood Pressure
> 150 mmHg and > 20 mmHg higher than baseline 
< 70 mmHg and a decrease of ≥ 30 mmHg from baseline
Diastolic Blood Pressure
> 100 mmHg and higher than baseline 
< 50 mmHg and a decrease of ≥ 20 mmHg from baseline
Pulse Rate
> 120 bpm and an increase of ≥ 30 bpm from baseline 
< 50 bpm and a decrease of ≥ 30 bpm from baseline
Temperature
≥ 38.9°C 
≤ 35.6°C
The number and percentage of subjects with post baseline values meeting Criteria for 
Potentially Clinically Significant Vital Signs values will be summarized.  Except for the 
temperature, subjects who have a baseline measurement and at least one post-baseline 
measurement will be included in the summary.  A separate listing of all the subjects and 
values that meeting the criteria will be provided.  No comparisons of the rates of subjects 
met the above criteria between the treatment arms will be performed.
12.0
References 
1.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
2.
Brookmeyer R, Crowley JA.  Confidence Interval for the Median Survival Time.  
Biometrics.  1982;38:29-41.
3.
Cox DR.  Regression Models and Life Tables.  Journal of the Royal Statistical 
Society.  Series B.  1972;20:187-220.  With discussion.
4.
Aaronson N, Ahmedzai S, Bergman B, et al.  The European Organization for 
Research and Treatment of Cancer QLQC30:  a quality-of-life instrument for use in 
international clinical trials in oncology.  J Natl Cancer Inst.  1993;85(5):365-76.
5.
Jacobson NS, Truax P.  Clinical significance:  a statistical approach to defining 
meaningful change in psychotherapy research.  J Consult Clin Psychol.  
1991;59(1):12-9.